a(SCHEM:Calcium) -> complex(p(HGNC:C1R),p(HGNC:C1S))

Copyright (c) 2011-2012, Selventa. All rights reserved.

The Ca2+-dependent interaction between complement serine proteases C1r and C1s is mediated by their alpha regions, encompassing the major part of their N-terminal CUB-EGF-CUB (where EGF is epidermal growth factor) module array.

a(CHEBI:"reactive oxygen species") -> r(HGNC:TGFB1I1)

The Hic-5 protein is encoded by a transforming growth factor-beta1- and hydrogen peroxide-inducible gene, hic-5, and has striking similarity to paxillin, especially in their C-terminal LIM domains.

cat(p(HGNC:CD40)) -| bp(GO:"cell growth")

Following exposure to either CD40-specific mAbs or the soluble trimeric ligand (sCD40L), high responder (HR) lines showed rapid aggregation, activation of NF-kappa B, up-regulation of cell surface markers ICAM-1/CD54 and Fas/CD95, and growth inhibition

cat(p(HGNC:CD40)) -> tscript(complex(NCH:"Nfkb Complex"))

kin(p(MGI:Cdk2)) => p(MGI:Mybl2,pmod(P,T,524))

p(HGNC:ARRB1) -| cat(p(PFH:"ADRB Family"))

betaarrestins mediate the desensitization of the beta2-adrenergic receptor (beta2AR) and many other G protein-coupled receptors (GPCRs)

complex(p(HGNC:PPARG),p(HGNC:RXRA)) -> tscript(p(HGNC:PPARG))

(LPL) gene. A conserved DNA recognition element (-171 to -149 bp) within the promoter functions as a transcriptional enhancer when bound by the peroxisome proliferator-activated receptor-gamma2 (PPARgamma2)/retinoid X receptor alpha (RXRalpha) heterodimer

a(SCHEM:Thiazolidinedione) -> r(MGI:Lpl)

Nuclear hormone receptor ligands such as thiazolidinediones [peroxisome proliferator-activated receptors (PPARs)] or hydrocortisone (glucocorticoid receptor) induce LPL transcription, whereas proinflammatory cytokines, such as tumor necrosis factor-, are inhibitory

Fasted rats received intravenous infusion of PTH and CT with or without gastrin. PTH raised the blood Ca2+ concentration, whereas CT infusion lowered it.

cat(p(HGNC:ADORA2B)) -> kin(p(HGNC:MAPK8))

cat(p(HGNC:ADORA2A)) -> kin(p(HGNC:MAPK8))

FLI-1 also prevented the rapid downregulation of cyclin D2 and D3 expression normally observed during Epo-induced differentiation and delayed the downregulation of several other genes involved in cell cycle or cell proliferation control.

kin(p(MGI:Kdr)) => p(MGI:Kdr,pmod(P,Y,996))

We have previously reported the identification of four autophosphorylation sites on the KDR VEGF receptor. Two of these sites (tyrosines 951 and 996) are located in the receptor's kinase insert domain, and two (tyrosines 1054 and 1059) are located in the catalytic domain

# Ariadne: In contrast, caspase-1 is strongly activated by NGF and other injury stimuli, further supporting the association of specific caspases with inflammatory conditions. [Regulation]

Caspase-2 in its pro-form was processed to its intermediate forms and to final active product p14 when treated with NGF. Caspase-2 was preferentially activated 3.5-fold during NGF-induced oligodendrocyte apoptosis.

NGF treatment resulted in a 6-fold increase in the active form (p18) of the protease, Caspase-3. Thus Caspase-3 was also activated during NGF-induced through p75 neurotrophin receptor mediated oligodendrocyte cell death.

IGFBP4 expression in myeloma cells may be modulated by cytokines released by stromal cells and T cells in the microenvironment.

a(SCHEM:"serum insulin") -> path(SDIS:"muscle glucose import")
p(HGNC:ADRB2) -> (a(SCHEM:"serum insulin") -> path(SDIS:"muscle glucose import"))

Desensitization of b-adrenergic receptors by isoproterenol increases insulin-stimulated glucose uptake in white adipocytes

kin(p(HGNC:EGFR)) => p(HGNC:GAB1,pmod(P,Y))

Gab-1 is heavily phosphorylated by the epidermal growth factor receptor, but poorly by the insulin receptor

kin(p(HGNC:INSR)) => p(HGNC:GAB1,pmod(P,Y))

a(SCHEM:"serum insulin") -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

However, in brown adipocytes (Klein, J., and Kahn, C.R., unpublished data) and white adipocytes (123), stimulation of the b-adrenergic receptor decreases insulin-stimulated PI3-kinase activity.

bp(MESHPP:Obesity) negativeCorrelation p(HGNC:IRS1,pmod(P,Y))

IRS-1-associated tyrosine phosphorylation and PI3-kinase activity is decreased in skeletal muscle and adipocytes both in obesity and type 2 diabetes (109-112)

In smooth muscle cells, blocking ligand occupancy of aVb3 integrin reduces IGF-1-induced IRS-1 phosphorylation

complex(p(HGNC:IRS1),p(HGNC:ITGAV)) -> (p(HGNC:IGF1) -> p(HGNC:IRS1,pmod(P,Y)))

a(SCHEM:"serum insulin") -| path(SDIS:"adipocyte lipolysis")
kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> (a(SCHEM:"serum insulin") -| path(SDIS:"adipocyte lipolysis"))

Inhibition of PI3-kinase activity using a dominant negative mutant (30), or pharmacological agents such as wortmannin or LY294002 (31), abolishes insulin stimulated glucose uptake and inhibits GLUT4 vesicle translocation to the plasma membrane. Many other cellular effects of insulin, such as antilipolysis, activation of fatty acid synthesis, acetyl CoA-carboxylase, glycogen synthase, Akt phosphorylation, glycogen synthase kinase 3b inactivation, and stimulation of protein synthesis and DNA synthesis, are also inhibited by PI3- kinase suppression PIP3, rather than PIP2, is the major mediator of PI3- kinase dependent biological actions of insulin

a(SCHEM:"serum insulin") -> p(HGNC:IRS1,pmod(P,Y))

Insulin and IGF-1 stimulation also promote association between IRS-1 and aVb3 integrin (vitronectin receptor)

Insulin receptor substrates are a growing family of proteins that are phosphorylated by the activated insulin receptor. To date, nine members of this family have been identified, including IRS-1 (17, 18), IRS-2 (19), IRS-3 (20), and IRS-4 (21), which are generally viewed as the most specific for insulin signaling; Gab-1 (22); Shc, which has three isoforms (23); and p62dok Following insulin binding, the receptor undergoes autophosphorylation on multiple tyrosine residues. This results in activation of the receptor kinase and tyrosine phosphorylation of a family of insulin receptor substrate (IRS) proteins.

kin(p(MGI:Insr)) => p(MGI:Irs3,pmod(P,Y))

bp(MESHPP:Obesity) negativeCorrelation r(HGNC:INSR)

Obese human subjects have decreased insulin receptor expression level and tyrosine kinase activity in skeletal muscle (103) and adipocytes (104).

bp(MESHPP:Obesity) negativeCorrelation kin(p(HGNC:INSR))

p(HGNC:INSR,pmod(P,Y,960)) => kin(p(HGNC:INSR))

Phosphotyrosine at site 960 of the b subunit just inside the membrane creates an NPXpY-recognition motif for the PTB domain of the IRS proteins. Modification of this tyrosine completely inhibits subsequent phosphorylation of IRS-1 and other insulin receptor substrates and leads to loss of most insulin-dependent biological actions

kin(p(HGNC:INSR)) => p(HGNC:IRS1,pmod(P,Y))

kin(p(HGNC:INSR)) => p(HGNC:IRS4,pmod(P,Y))

Recently, b1 integrins have also been reported to enhance IRS-1 phosphorylation and interaction, but not glucose transport, with downstream molecules such as PI3-kinase and Akt (74). These results suggest that integrins and insulin/IGF-1 receptor signaling pathways converge at an early point in the signaling cascade around the IRS proteins.

a(CHEBI:glucosamine) -| (a(SCHEM:"serum insulin") -> kin(complex(NCH:"p85/p110 PI3Kinase Complex")))

The ability of a variety of nutrients to activate the hexosamine pathway has led to the theory that this pathway serves as a general nutrient sensing pathway, through which hyperglycemia or hyperlipidemia could decrease insulin sensitivity of cells when nutrient excess prevails (148). In cell culture, omission of glutamine (a cofactor of GFA) from the media, or addition of glutamine analogues, blunts the desensitizing effect of glucose on insulin sensitivity (150). Glucosamine infusion for two to six hours will decrease insulin-stimulated IRS-1 tyrosine phosphorylation, PI3-kinase activation, and activation of glycogen synthase in a manner that parallels the decrease in insulin-stimulated glucose uptake in skeletal muscle. This effect can be seen both in acute and chronic stimulation with insulin (151) (Patti, M.E., personal communication).

a(SCHEM:"serum insulin") -> cat(p(HGNC:GYS2))

a(SCHEM:"serum insulin") -> complex(p(HGNC:FYN),p(HGNC:CBL))

c-Cbl is tyrosine-phosphorylated, binds to Fyn upon insulin stimulation, and is translocated to small invaginations of the plasma membrane, called caveolae, after insulin stimulation

kin(p(HGNC:MAPK1)) => p(HGNC:STAT5A,pmod(P,S,780))

complex(p(MGI:Elk1),p(MGI:Elk4)) => tscript(p(MGI:Elk1))

. This region contains three juxtaposed SRE (serum response element)/Ets site pairs known to be important for egr-1 activity in response to exogenous stimuli. Site-specific mutations of individual SRE and Ets sites within this region each reduced GH inducibility of the promoter. Use of these site-specific mutations in EMSA showed that disruption of either Ets or SRE sites abrogated ternary complex formation at the composite sites. DNA binding of ternary complexes, but not binary complexes, in EMSA was rapidly and transiently increased by GH. EMSA supershifts indicated these ternary complexes contained serum response factor (SRF) and the Ets factors Elk-1 and Sap-1a. Coexpression of Sap-1a and Elk-1 resulted in a marked increase in GH induction of egr-1 promoter activity, although transfection with expression vectors for either Ets factor alone did not significantly enhance the GH response.

p(HGNC:IGF1) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

Insulin-like growth factor 1 activates only phosphatidylinositol-3 kinase.

Ngf induced the tyrosine phosphorylation of Erk1 in tyrosine receptor kinase-expressing cells. Erk1 remained phosphorylated for 1 to 4 hours after Ngf treatment. Ngf treatment induced a 6- to 8-fold increase in MAP kinase activity within 5 minutes of treatment and the activity remained elevated up to 4 hours. This indicated that Erk1 phosphorylation was brought about by tyrosine receptor kinase A after treatment with Ngf.

p(HGNC:PDGFB) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

The activation of phosphatidylinositol-3 kinase, however, was 10-fold greater in response to PDGF-BB compared with NGF.

The neurotrophin, nerve growth factor (NGF), and insulin-like growth factor 1 induce the migration but not the proliferation of smooth muscle cells, whereas PDGF-BB stimulates both responses.

cat(p(HGNC:ADRA2C)) -> kin(p(HGNC:MAPK3))

alpha2-AR-mediated activation of either endogenous or cotransfected p42/p44 mitogen-activated protein (MAP) kinase

kin(p(MGI:Mapk1)) -| tscript(p(MGI:Smad2))

Furthermore, studies of patients with insulin-secreting tumors suggest that inhibition of hepatic glucose production is the major mechanism whereby insulin lowers plasma glucose in the fasting state. Insulin first acts directly upon adipose tissue to suppress lipolysis and decrease levels of circulating free fatty acids. This, in turn, may cause the inhibition of hepatic glucose production

a(SCHEM:"serum insulin") -> bp(GO:"glucose transport")

Insulin promotes the deposition of glycogen in liver and triglyceride in adipose tissue, and also activates glucose transport and glycogen synthesis in muscle.

p(MGI:Insr) -> bp(MESHPP:"Insulin Resistance")

Skeletal Muscle. Insulin receptor function has been inhibited in two ways: muscle-specific knockout of the insulin receptor (MIRKO; Bruning et al., 1998) and muscle-specific expression of a dominant-negative mutant insulin receptor (IR-A1134T) in transgenic mice (Moller et al., 1996). In both models, skeletal muscle was insulin resistant when studied in vitro.

The insulin receptor, a ligand-stimulated tyrosine kinase, mediates the first steps in insulin action (White and Yenush, 1998). The activated receptor phosphorylates multiple proteins-e.g., insulin receptor substrates (IRS)-1, -2, -3, and -4. Phosphorylation of tyrosine residues in these substrates leads to activation of multiple downstream signaling pathways.

Eotaxin in association with IL-2 and IL-4 up-regulated ICAM-1 expression on T lymphocytes within 8 hours. The ICAM-1 expression was up-regulated to more than 80% by 16 hours and to 97% by 24 hours.

a(SCHEM:"Ro 31-7549") -| kin(p(PFM:"Prkc Family"))

RO31-7549 (protein kinase C (PKC) inhibitor) inhibited activation of PDE4 by PMA.

a(SCHEM:"AG-490") -| (p(MGI:Il4) -> cat(p(MGI:Pde3b)))

TNF-alpha, AG-490 (Janus kinase inhibitor), and wortmannin (PI3-K inhibitor) inhibited activation of PDE3 and PDE4 by IL-4. TNF-alpha also blocked IL-4-induced tyrosine phosphorylation of IRS-2, but not of STAT6. AG-490 and wortmannin, not TNF-alpha, inhibited activation of PDE4 by IL-3

p(MGI:Tnf) -| (p(MGI:Il4) -> p(MGI:Irs2,pmod(P,Y)))

a(SCHEM:"PD 98,059") -| (a(SCHEM:"Tetradecanoylphorbol acetate") -> kin(p(PFM:"MAPK Erk1/3 Family")))
a(SCHEM:"Tetradecanoylphorbol acetate") -> kin(p(PFM:"MAPK Erk1/3 Family"))

The MAP kinase kinase (MEK-1) inhibitor PD98059 inhibited IL-4-, IL-3-, and PMA-induced activation of MAP kinase and PDE4

Haloperidol (0.1-8 mg/kg) and (-)-sulpiride (10-100 mg/kg), induced NGF mRNA in a dose-dependent fashion haloperidol and (-)-sulpiride induce the expression of c-fos and c-jun mRNAs and increase their AP-1 DNA binding activities. Thus, the data suggest that neuroleptics induce NGF gene expression by increasing AP-1 DNA binding activity.

a(CHEBI:haloperidol) -> tscript(complex(NCH:"AP-1 Complex"))

kin(p(HGNC:SRC)) => p(HGNC:RAF1,pmod(P,Y,341))

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(MGI:Fgf1)

In fact, the levels of this particular mRNA are dramatically increased upon phorbol 12-myristate 13-acetate, serum, and transforming growth factor-beta stimulation. These observations point to a more complex mechanism of Fgf1 regulation,

p(MGI:Myc) -> bp(GO:"cell proliferation")

The c-Myc oncoprotein induces cell proliferation

kin(p(PFH:"PDGFR Family")) -> tscript(p(HGNC:STAT3))

We conclude that the mechanisms of activation of Stat1 and Stat3 by PDGFR are distinct. Stat1 activation appears to result from a direct interaction with the receptor, whereas Stat3 activation additionally requires JAK proteins.

p(HGNC:STAT5B,pmod(P)) => tscript(p(HGNC:STAT5B))

We show here that BCR/ABL induces phosphorylation and activation of STAT5

kin(p(HGNC:SRC)) => p(HGNC:GSN,pmod(P,Y,465))

tscript(p(HGNC:PRRX1)) => tscript(p(HGNC:SRF))

In addition, Phox1 and Elk-1 potentiate the ability of SRF to transcriptionally activate the c- fos promoter in response to growth-mediated events ( 18 ).

kin(p(HGNC:MAPK1)) -> p(HGNC:EIF4E,pmod(P))

PGF2alpha also induced eIF4E and 4E-BP1 phosphorylation, global protein synthesis and basic fibroblast growth factor-2 (bFGF-2) expression in VSMC

Androgen treatment upregulates the calreticulin expression in LNCaP cells. Androgen treatment time for inducing calreticulin mRNA in LNCaP cells was 36 hour in the presence of CHX and anisomycin. Similar to mRNA protein levels of calreticulin was also regulated by androgen.

p(HGNC:BTC) => kin(complex(p(HGNC:EGFR),p(HGNC:ERBB2)))

Table 2: Classification of ligands according to their relative affinities toward ErbB-IgGs. I only too the High affinity (1-100 nM) and Very high affinity (<1 nM).

p(HGNC:EGF) => complex(p(HGNC:ERBB4),p(HGNC:ERBB2))

p(HGNC:HBEGF) => complex(p(HGNC:EGFR),p(HGNC:EGFR))

p(HGNC:HBEGF) => complex(p(HGNC:EGFR),p(HGNC:ERBB2))

p(HGNC:NRG1) => kin(complex(p(HGNC:ERBB4),p(HGNC:ERBB4)))

complex(p(HGNC:EGFR),p(HGNC:ERBB2)) => kin(complex(p(HGNC:EGFR),p(HGNC:ERBB2)))

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -| tscript(p(HGNC:FOXO4))

To investigate whether PI(3)K and protein kinase B (PKB) were involved in insulin-induced phosphorylation of AFX, we co-expressed HA±AFX with active forms of PI(3)K or PKB. Constitutively active, but not inactive, forms of PI(3)K or PKB induced a strong increase in HA±AFX phosphorylation (Fig. 1c).

Such conditional mutant mice (knockout of wild type IL6ST under the Cre-Lox system) have normal cardiac structure and function, but during aortic pressure overload, these mice display rapid onset of dilated cardiomyopathy and massive induction of myocyte apoptosis versus the control mice that exhibit compensatory hypertrophy.

Nerve growth factor (NGF) upregulated expression of the MAG binding molecule in a dose dependent manner.

cat(p(RGD:Agtr1b)) -> tscript(p(RGD:Stat1))

stimulation of AT2 receptor in AT2 receptor cDNA-transfected rat adult vascular smooth muscle cells (VSMCs) inhibited angiotensin II type 1 (AT1) receptor-mediated tyrosine phosphorylation of STAT (signal transducers and activators of transcription) 1alpha/beta, STAT2, and STAT3 without influence on Janus kinase

cat(p(RGD:Agtr1b)) -> tscript(p(RGD:Stat2))

path(SDIS:"bacterial infection") -> r(MGI:Msr1)

The administration of LPS, zymosan, BCG, or L. monocytogenes to mice resulted in ... the upregulation of MSR-A expression in the liver and spleen

kin(p(PFH:"AKT Family")) => p(HGNC:TERT,pmod(P,S,227))

phos(p(HGNC:DUSP3)) -| kin(p(HGNC:MAPK3))

Subsequent kinetic analyses and transfection studies demonstrated that VHR specifically dephosphorylates and inactivates ERK1 and ERK2 in vitro and in vivo.

path(SDIS:"tissue damage") -> r(HGNC:NACA)

we identified a gene that was strongly induced as early as 12 h after wounding. Sequence analysis revealed the identity of the corresponding protein with skeletal muscle nascent polypeptide-associated complex (skNAC)

H4 cells were treated with 500ng/ml of bovine growth hormone for 10 minutes. It was observed that a fraction of the immunoprecipitated JAK2 had been phosphorylated on tyrosine residues. Insulin (100 Nm) pretreatment for 16 hours, significantly inhibited the ability of bGH to induce tyrosine phosphorylation of immunoprecipitated JAK2.

tport(p(MGI:Fabp3)) -| path(SDIS:"cardiomyocyte hypertrophy")

H-FABP deficiency is only incompletely compensated, however, causing acute exercise intolerance and, at old age, a localized cardiac hypertrophy

p(HGNC:FGF1) -> bp(GO:"cell proliferation")

Acidic fibroblast growth factor (FGF-1), a prototype member of the heparin-binding growth factor family, influences proliferation, differentiation, and protein synthesis in different cell types

Receptor stimulation results in the activation of distinct combinations of Janus family protein tyrosine kinases (Jak PTKs); Jak1/Tyk2 and Jak1/Jak2 for IFN-alpha/beta and IFN-gamma, respectively.

cat(p(HGNC:CD40)) -> kin(complex(NCH:"IkappaB Kinase Complex"))

This study demonstrates that the engagement of CD40 results in the activation of the recently described IkappaB kinase (IKK) in a human B cell line

cellular treatment with H2O2 negatively modulates GR function and decreases glucocorticoid-inducible gene expression. Impaired cellular response to glucocorticoids is rescued by overexpression of TRX, most probably through the functional replenishment of the GR. Moreover, not only the ligand binding domain but the DNA binding domain of the GR is also suggested to be a direct target of TRX.

Transforming growth factor-beta1 increased dermatopontin mRNA and protein levels, while interleukin-4 reduced dermatopontin expression.

phos(p(HGNC:PTPRF)) -> bp(MESHPP:Apoptosis)

The over-expression of LAR in mammalian tissue culture cells does not affect cell adhesion but induces caspase-dependent apoptosis.

p(HGNC:BCAR1,pmod(P,Y)) -> p(HGNC:BCAR1)

The over-expression of LAR in tissue culture cells specifically decreased the steady state protein level of p130Cas, a multifunctional signal assembly protein in signal transduction, by reducing the tyrosine phosphorylation and protein stability of p130Cas.

a(CHEBI:"nitric oxide") => cat(complex(NCH:"GUCY1 Complex"))

sGC is a hemoprotein; it is through the specific interaction of NO with the sGC heme that sGC is activated.

bp(GO:"cell differentiation") -> r(HGNC:TGM1)

Expression of the transglutaminase type1 gene (TGM1), which encodes an epithelial cell-specific protein cross-linking enzyme, is limited to particular stages of epidermal development and keratinocyte differentiation.

path(SDIS:"G0 phase of mitotic cell cycle") => tscript(p(PFM:"Mef2 Family"))

Because our results indicated that the combination of MEF2C-VP16 and E2F1-pRb(SP) could support the activity of MCK-reporter constructs as efficiently as could pRb, we further evaluated the ability of these two proteins to synergistically activate the expression of endogenous muscle genes. In pRb-deficient fibroblasts, MyoD transfection by itself induced low amounts of MHC expression and little or no detectable MCK (Figure 5a-c). In contrast, cells transfected with both MyoD and pRb produced high levels of MHC and MCK (Figure 5d-f). Cotransfection of MyoD with either MEF2C-VP16 or E2F1-pRb(SP) alone led to a relatively small increase in the intensity of MHC staining and low amounts of endogenous MCK expression (Figure 5g-l). However, the combination of MyoD, MEF2C-VP16, and E2F1-pRb(SP) produced cells that expressed very high levels of both MHC and MCK (Figure 5m-o), again mimicking the phenotype of cells transfected with MyoD and pRb. In summary, these results indicate that the ability of pRb to promote muscle differentiation can be fully substituted by the combination of E2F1-pRb(SP) and MEF2C-VP16, suggesting that the requirement for pRb to promote expression of late muscle-differentiation markers reflects the ability of this molecule both to arrest cells in G0 and to potentiate MyoD-mediated activation of the MEF2 TAD.

p(MGI:Mef2c,pmod(P,S,387)) => tscript(p(MGI:Mef2c))

Because these residues are required for enhanced MEF2C activity in monocytic cells, we tested whether MyoD activation of Gal4-MEF2C required the same amino acids. The combined mutation of both Thr293 and Thr300 to alanine (T293;300A) did not affect the basal activity of Gal4-MEF2C (Figure 3b, compare columns 3 and 5), but did enhance the activity of Gal4-MEF2C when MyoD+E12 were co-expressed (Figure 3b, compare columns 4 and 6). In contrast, mutation of Ser387 to alanine (S387A) decreased the basal activity of Gal4-MEF2C and completely eliminated its activation by co-transfected MyoD+E12 (Figure 3b, columns 7,8). Importantly, activation of the p38 kinase pathway did stimulate the function of the S387A Gal4-MEF2C mutant (data not shown; see also [25,27]), indicating that this mutation does not simply inactivate the protein. Therefore, MyoD activation of the MEF2C TAD requires Ser387, but neither Thr293 nor Thr300, of MEF2C.

complex(p(MGI:Myod1),p(MGI:Tcf3)) -> tscript(p(PFM:"Mef2 Family"))

Gal4-MEF2C alone weakly activated a co-transfected Gal4-reporter construct, but the inclusion of MyoD and E12 increased this activity at least 10-fold (Figure 3b, compare columns 3 and 4). In 10T1/2 cells, activation of MEF2 reporter constructs was maximally enhanced by the co-expression of MyoD with E12 (data not shown); we therefore included exogenous E12 in this and in subsequent experiments.

The retinoblastoma tumor-suppressor protein (pRb) plays a critical role in establishing the G0 arrest observed in differentiated myocytes; muscle cells lacking pRb fail to exit the cell cycle and are susceptible to apoptotic cell death [10-13].

a(CHEBI:"linoleic acid") -> tscript(complex(NCH:"Nfkb Complex"))

tscript(p(PFH:"E2F Family")) => r(HGNC:MCM5)

Our results demonstrated that the growth-regulated expression of mammalian MCM5 and MCM6 genes, and presumably other MCM members, is primarily regulated by E2F through binding to multiple E2F sites in the promoters.

tscript(p(PFH:"E2F Family")) => r(HGNC:MCM6)

The rPLD1b mRNA increased within 6 h following dbcAMP treatment and maintained a high level up to 24 h.

Endogenously produced NO, by IFN-gamma pretreatment or exogenous nitrodonors, resulted in the upregulation of Fas receptor mRNA

Here we demonstrate that the expression of the human MMP-2 gene is enhanced by a synergistic action of retinoic acid (RA) and dibutyryl cyclic AMP

p(HGNC:FGF7) -| (path(MESHD:Hyperoxia) -> r(HGNC:BAX))

The induction of p53, Bax, and Bcl-x mRNAs during hyperoxia was to a large extent prevented by KGF.

p(HGNC:FGF7) -| (path(MESHD:Hyperoxia) -> r(HGNC:TP53))

kin(p(HGNC:PTK2B)) -> kin(p(HGNC:MAPK3))

the Grb2/Sos complex connects Pyk2 to the activation of ERK, whereas adaptor proteins p130Cas and Crk link Pyk2 with the JNK pathway.

Using an electrophoretic mobility shift assay, we further show that RFX1, RFX2, and RFX3 homodimers and heterodimers specifically bind to the cis element of the IL-5Ralpha promoter.

kin(p(HGNC:MAPK1)) => p(HGNC:ERF,pmod(P,S,161))

cat(p(HGNC:CHRM1)) -> tscript(p(HGNC:MEF2C))

# Ariadne: The transactivation domains of MEF2A and MEF2C are activated by m1 G protein-coupled receptors. [Regulation]

p(HGNC:TRIM28) -> bp(GO:"chromatin silencing")

Mapping of the region in KAP-1 required for HP1 interaction showed that amino acid substitutions which abolish HP1 binding in vitro reduce KAP-1 mediated repression in vivo.

kin(p(PFH:"PRKC Family")) -| r(HGNC:TNFSF13B)

TALL-1 expression is dramatically down-regulated by phorbol myristate acetate/ionomycin.

a(CHEBI:lipopolysaccharide) -> a(CHEBI:"hydrogen peroxide")

LPS treatment increased vascular O2- (from 35+/-2 cpm/ring at baseline to 166+/-21 cpm/ring at 12 hours and 225+/-16 cpm/ring at 30 hours) and H2O2 formation

a(CHEBI:"lithocholic acid") -> tscript(p(MGI:Nr1h4))

physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid and deoxycholic acid activated Fxr, an orphan nuclear receptor as ligands, these bile acids and their conjugates modulated interaction of Fxr with a peptide derived from steroid receptor coactivator 1 these results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis

kin(p(PFH:"PRKA Family")) -> r(HGNC:CKB)

transcription of brain creatine kinase (CKB) mRNA in U87-MG glioblastoma cells is stimulated by a forskolin-mediated increase in cyclic AMP (cAMP) via a pathway involving protein kinase A (PKA)

p(HGNC:MAPK14,pmod(P,T,180)) => kin(p(HGNC:MAPK14))

MAP kinases help to mediate diverse processes ranging from transcription of protooncogenes to programmed cell death. More than a dozen mammalian MAP kinase family members have been discovered and include, among others, the well studied ERKs and several stress-sensitive enzymes. MAP kinases lie within protein kinase cascades. Each cascade consists of no fewer than three enzymes that are activated in series. Cascades convey information to effectors, coordinates incoming information from other signaling pathways, amplify signals, and allow for a variety of response patterns. Subcellular localization of enzymes in the cascades is an important aspect of their mechanisms of action and contributes to cell-type and ligand-specific responses. Recent findings on these properties of MAP kinase cascades are the major focus of this review.

We now show that in osteoblast-like cells, rhBMP-2 inhibits NCAM expression, while HOXC6 increases its expression, both acting via the same region of the promoter.

The Src tyrosine kinases c-Src, c-Yes, c-Fyn, and c-Hck were tyrosine phosphorylated in the M1/WT cells in response to CSF-1 and bound to the WT CSF-1R through their SH2 domains.

tscript(p(HGNC:FOXO1)) => r(HGNC:IGFBP1)

Reporter gene studies in HepG2 hepatoma cells show that FKHR stimulates insulin-like growth factor-binding protein-1 promoter activity through an IRS, and introduction of IRSs confers this effect on a heterologous promoter.

kin(p(MGI:Map2k1)) -> p(MGI:Fosl2,pmod(P,T))

Ariadne: Thus, the major components of the AP-1 in MEK-DD-transformed CEFs were shown to be Fra-2 and c-Jun, and Fra-2 was highly phosphorylated, as reported in CEFs transformed by v- src , Ha- ras , and activated raf (17 , 22) . [Regulation] Here, we report that the transcriptional activity of Fra-2/c-Jun heterodimer was greatly enhanced by cotransfecting a constitutively active mutant of MEK1 gene (MEK-DD) into F9 cells, indicating that Fra-2 was converted into an active transactivator after phosphorylation by MAPK.

tscript(complex(NCM:"AP-1 Complex")) => r(MGI:Fosl2)

High-level expression of MEK-DD alone was sufficient to induce clear cellular transformation of chicken embryo fibroblasts, which caused constitutive activation of endogenous MAPK, hyperphosphorylation of Fra-2, and elevation of fra-2 and c-jun gene expression. These results indicate that phosphorylation of Fra-2 by MAPK plays an important role in stimulating endogenous AP-1 activity in a positive autoregulation mechanism, in which phosphorylated Fra-2 induces fra-2 expression through AP-1 binding sites present in its promoter.

p(HGNC:TNF) -> complex(p(HGNC:TNFRSF1A),p(HGNC:GRB2))

The TNFR-I/Grb2 interaction is essential for the TNF-alpha-dependent activation of c-Raf-1 kinase

Notch1 activates Hes1 promoter, a downstream target of the notch signaling pathway. Activation of Hes1 promoter was reduced by 70% in PS1-KO cells relative to PS1-wt cells, suggesting that PS1 potentiates Notch1 signaling activity.

A STAT-1/STAT-3 binding element, located at nucleotides -72 to -64, was essential for LIF stimulation of SOCS-3 promoter activity. Electrophoretic mobility-shift assay analysis confirmed specific binding of STAT-1 and STAT-3 to this region.

Pituitary corticotroph SOCS-3 is inhibiting LIF-activated Janus kinase-signal transducers and activators of transcription (STAT) signaling in a negative autoregulatory loop. We now demonstrate in corticotroph AtT-20 cells that LIF-stimulated endogenous SOCS-3 mRNA expression is blocked in stable transfectants of SOCS-3 wild type or in dominant negative STAT-3 mutants, respectively.

bp(GO:"response to stress") -> r(RGD:Glul)

Acute stress or direct glucocorticoid administration raises muscle GS mRNA levels dramatically without a parallel increase in GS protein levels.

a(CHEBI:lipopolysaccharide) -> r(HGNC:TNF)

Moreover, both isoproterenol and dibutyryl cAMP inhibited LPS-induced TNF-alpha mRNA expression.

EGF stimulation of Akt kinase activity blocked Fas-induced apoptosis

kin(p(PFH:"PRKC Family")) -> gtp(p(HGNC:RAC2))

stimulation of human neutrophils with the Gi-coupled receptor agonists N-formyl-methionyl-leucyl-phenylalanine (fMLP) and leukotriene B4 (LTB4) leads to a rapid and transient increase in the GTP-bound state of Rac2, whereas phorbol myristate acetate (PMA) causes a slow but more sustained activation of Rac2

Levels of AFP mRNA but not albumin mRNA were elevated by simvastatin in a dose-dependent manner (1-10 micromol/l).

IL-13 inhibited collagenase 3 production, IL-4 had little effect, and IL-10 had none.

a(SCHEM:"cyclic AMP") -> tloc(p(HGNC:BTG1),GOCCACC:"GO:0005737",GOCCACC:"GO:0005634")

T3 or 8-Br-cAMP increases BTG1 nuclear accumulation in confluent myoblast cultures. In this study, we report that BTG1 is essentially expressed at cell confluence and in differentiated myotubes

p(HGNC:BTG1) -> bp(GO:"myoblast differentiation")

the stimulation of BTG1 nuclear accumulation by T3 or 8-Br-cAMP probably results from an increased nuclear import or retention in the nucleus. Lastly, BTG1 overexpression in quail myoblasts mimicked the T3 or 8-Br-cAMP myogenic influence: (i) inhibition of myoblast proliferation due to an increased rate of myoblast withdrawal from the cell cycle; and (ii) stimulation of terminal differentiation

kin(p(PFH:"PRKC Family")) => p(HGNC:GRIA4,pmod(P,T,850))

cat(p(HGNC:IRS1)) -> kin(p(PFH:"MAPK Erk1/3 Family"))

Cells transfected with IRS-1 had increased levels of DNA synthesis, PCNA, GAPDH, and activated MAPK

a(SCHEM:"serum insulin") -> cat(p(HGNC:PDE3B))

Phosphodiesterase 3 (PDE3) activity was stimulated by ASP and insulin, whereas PDE4 activity was slightly increased by ASP only.

a(SCHEM:"serum insulin") -| path(SDIS:"fatty acid import")
cat(p(HGNC:PDE3B)) -> (a(SCHEM:"serum insulin") -| path(SDIS:"fatty acid import"))

Selective PDE3 inhibition reversed the effects of both ASP and insulin on fractional FFA re-esterification and lipolysis

a(SCHEM:"serum insulin") -> path(SDIS:"fatty acid esterification")
cat(p(HGNC:PDE3A)) -> (a(SCHEM:"serum insulin") -> path(SDIS:"fatty acid esterification"))

bp(GO:"cell adhesion") -> p(HGNC:PTK2,pmod(P,Y,576))

Following cell adhesion to components of the extracellular matrix, FAK becomes phosphorylated at multiple sites, including tyrosines 397, 576, and 577. Tyr-397 is an autophosphorylation site that promotes interaction with c-Src or Fyn.

cat(p(HGNC:SH2B2)) -| tscript(p(PFH:"STAT5 Family"))

Co-expression of APS and c-Cbl, but not expression of either alone inhibited EPO-dependent STAT5 activation in 293 cells. This required the C-terminal phosphorylation site, as well as PH and SH2 domains of APS. Therefore, one of the major functions of APS is in recruitment of c-Cbl into the receptor/JAK complex, thereby inhibiting JAK signaling activity.

kin(p(HGNC:JAK2)) -> p(HGNC:SH2B2,pmod(P,Y))

Here, we report that APS was tyrosine phosphorylated by Janus kinase-2 (JAK2) at its C-terminal tyrosine residue and interacted with c-Cbl.

Exogenously added heregulin induced Erk activation, which was blocked by herceptin, which is an antibody against HER-2/neu.

These EC adhesion molecules include vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, and P-selectin.6,7

a(CHEBI:fenofibrate) -| (tscript(complex(NCH:"Nfkb Complex")) => r(HGNC:VCAM1))
tscript(complex(NCH:"Nfkb Complex")) => r(HGNC:VCAM1)

Transient transfection of deletional VCAM-1 promoter constructs and electrophoretic mobility shift assays indicate that fenofibrate inhibits VCAM-1 transcription in part by inhibiting NF-kappaB.

Treatment of female mice with testosterone increases the amounts of AO mRNA and of the relative translation product to levels similar to those in male animals.

complex(p(HGNC:KIT),p(HGNC:KIT)) => kin(p(HGNC:KIT))

% In this paper we demonstrate the presence of two novel in vivo autophosphorylation sites in the c-Kit/stem cell factor receptor (c-Kit/SCFR): Tyr-703 in the kinase insert and Tyr-936 in the C-terminal tail.

kin(p(HGNC:KIT)) => p(HGNC:KIT,pmod(P,Y,703))

In this paper we demonstrate the presence of two novel in vivo autophosphorylation sites in the c-Kit/stem cell factor receptor (c-Kit/SCFR): Tyr-703 in the kinase insert and Tyr-936 in the C-terminal tail. We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936,

kin(p(HGNC:KIT)) => p(HGNC:KIT,pmod(P,Y,936))

a(CHEBI:caffeine) -| cat(p(PFM:"Pde Family"))

caffeine, a non-specific phosphodiesterase (PDE) inhibitor

tscript(complex(NCH:"AP-1 Complex")) -> r(HGNC:MSR1)

We could demonstrate that alpha-tocopherol down-regulates scavenger receptor activity in macrophages in a dose-dependent manner. Scavenger receptor activity was reduced by 13, 16, 18 and 24% in the presence of 1, 5, 10 and 50 microM alpha-tocopherol, respectively. This effect was associated with a reduced SR-A mRNA expression and activity of AP-1 binding transcription factors in the presence of alpha-tocopherol

HER2-overexpressing cell lines and cells with coexpression of HER2 and HER3 receptors exhibited elevated levels of paxillin, as compared to low HER2 expressing cell lines or HER2 expression with undetectable HER3 level, paxillin expression dose not correlate well with HER1 expression.

Here, we report that HRG stimulation of noninvasive breast cancer MCF-7 cells resulted in the up-regulation of paxillin mRNA and protein.

a(CHEBI:"trichostatin A") -> r(HGNC:CPA3)

Trichostatin A, a potent and specific inhibitor of histone deacetylase, also induced CPA3 mRNA expression, suggesting that CPA3 gene induction is mediated by histone hyperacetylation.

p(MGI:Cdkn1a) -> complex(p(MGI:Ccnd1),p(MGI:Cdk4))

In a later complementary study, Cheng et al. (1999) observed that assembly of cyclin D1/D2-CDK4 complexes was impaired in primary mouse embryo fibroblast (MEF) strains taken from animals lacking the p21 gene, the p27 gene, or both.

p(MGI:Cdkn1b) -> complex(p(MGI:Ccnd2),p(MGI:Cdk4))

complex(p(HGNC:CCND1),p(HGNC:CDK4)) =| (p(HGNC:CDKN1B) =| kin(p(HGNC:CDK2)))

Titration of unbound p27Kip1 and p21Cip1 molecules into higher order complexes with assembling cyclin D-dependent kinases relieves cyclin E-CDK2 from Cip/Kip constraint, thereby facilitating cyclin E-CDK2 activation later in G1 phase.

Basic FGF and NGF treatment of macrophages and microglia significantly increased the levels of cathepsin S, B, and L mRNAs

kin(p(HGNC:ABL1)) => p(HGNC:TP73,pmod(P,Y,99))

p(HGNC:MAP2K6) -> kin(p(PFH:"MAPK p38 Family"))

expression of MKK6b(E), a constitutive activator of p38(MAPK), significantly reduced LDL receptor promoter activity.

p(MGI:Pawr) -| tscript(complex(NCM:"Nfkb Complex"))

NF-kappaB activation by tumor necrosis factor alpha (TNFalpha) provides a survival signal that impairs the TNFalpha-induced apoptotic response. We show here that expression of Par-4 inhibits the TNFalpha-induced nuclear translocation of p65 as well as the kappaB-dependent promoter activity.

p(MGI:Tnf) -> tscript(complex(NCM:"Nfkb Complex"))

p(MGI:Tnf) -> tloc(p(MGI:Rela),GOCCACC:"GO:0005737",GOCCACC:"GO:0005634")

p(MGI:Pawr) -| (p(MGI:Tnf) -> tscript(complex(NCM:"Nfkb Complex")))

Of potential functional relevance, the expression of Par-4 allows TNFalpha to induce apoptosis in NIH-3T3 cells. In addition, the down-regulation of Par-4 levels by oncogenic Ras sensitizes cells to TNFalpha-induced NF-kappaB activation.

Furthermore, thrombin increased expression of p47(phox) and Rac2

gtp(p(RGD:Rac2)) -> cat(complex(NCR:"NADPH Oxidase Complex"))

we examined whether the cytosolic components of the phagocytic NAD(P)H oxidase were present in VSMC. p47(phox) and Rac2 were present in VSMC

It was increased in mammary carcinoma MCF-7 cells treated by retinoids and by the anti-estrogen ICI 182,780 but not by 4-hydroxytamoxifen.

kin(p(PFH:"PRKC Family")) -> r(HGNC:NDRG1)

These antibodies revealed a protein with the expected 43 kDa molecular mass, up-regulated by phorbol ester, retinoids and 1,25-(OH)2 vitamin D3 in U937 cells.

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:PTPRO)

PTP-RO mRNA and protein expression are upregulated upon phorbol 12-myristate 13-acetate (PMA) treatment of the megakaryocytic cell lines CMS, CMK, and Dami.

cat(p(HGNC:GSN)) -> bp(MESHPP:Apoptosis)

Caspase-3 also cleaves and activates gelsolin, a protein that regulates actin dynamics. Interestingly, activated gelsolin promotes both cytoplasmic and nuclear apoptosis, including DNA fragmentation.

Ca2+ increased the levels of involucrin and transgultaminase mRNA in human keratinocytes.

kin(p(HGNC:PTK2)) -> p(HGNC:AKT1,pmod(P,S))

a(CHEBI:"okadaic acid") -| tloc(p(MGI:Ptpn14),GOCCACC:"GO:0005856",GOCCACC:"GO:0005737")

On the contrary, when the dephosphorylation of PTP36 was inhibited by okadaic acid, no translocation of PTP36 was induced by the cell detachment

a(CHEBI:staurosporine) -> tloc(p(MGI:Ptpn14),GOCCACC:"GO:0005737",GOCCACC:"GO:0005856")

Staurosporine and ML-9, which inhibited the phosphorylation of PTP36 in vivo, induced the translocation of PTP36 too.

phos(p(MGI:Ptpn14)) -| bp(GO:"cell adhesion")

Summary: The dephosphorylated form of PTPN14 translocates to the cell membrane associated cytoskeleton where it dephosphorylates proteins of the adherens junction, causing cellular detachment. Phosphorylation of PTPN14 induces it's sequestration in the cytoplasm.

a(SCHEM:"Sodium Salicylate") -| kin(p(PFH:"IkappaB Kinase Family"))

Aspirin and sodium salicylate inhibit activation of NF-KB by blocking IkappaB kinase, a key enzyme in NF-kappaB activation.

a(CHEBI:glucocorticoid) -> r(HGNC:NFKBIA)

Glucocorticoids suppress expression of inflammatory genes by binding glucocorticoid receptor with NF-kappaB, and increasing expression of inhibitory protein of NF-kappaB, IkappaBalpha

A431 cells expressing annexin VI are defective in their ability to sustain elevated levels of cytosolic Ca(2+) following stimulation with EGF.

kin(p(MGI:Prkcz)) -> p(MGI:Twf2,pmod(P,S))

A6rp was found to be expressed at the mRNA and the protein levels in all cells and tissues investigated. GST-A6rp was phosphorylated by PKCzeta but not significantly by other PKC isoenzymes.

AR protein levels, AR activity, sorbitol production, and PKCalpha protein content were also greater in the MCGT1 cells

kin(p(PFR:"Akt Family")) => p(RGD:Bad,pmod(P,S))

Akt directly links growth factor signaling to the central pathways controlling programmed cell death by phosphorylating the Bcl-2 family member BAD

cat(p(RGD:Bcl2)) -| bp(MESHPP:Apoptosis)

Bcl-2 or Bcl-xL to function as inhibitors of apoptosis

a(SCHEM:"LY 294002") -> bp(MESHPP:Apoptosis)

Similar results were obtained in both Rat-1 and Rat-1/B-Raf cells when apoptosis was induced by treatment with the PI 3-kinase inhibitor LY294002 in the presence of serum

p(HGNC:CSF3) -> complex(p(HGNC:CSF3R),p(HGNC:IL6ST))

HepG2 cells were transfected with expression vector for G-gp130 (WT) and Myc SHP-2CS or SHP-2-Myc and then were treated for 15 minutes with G-CSF, showed that gp130-recruited SHP-2 serves as a major mediator to the ERK pathway and that this function requires the carboxy-terminal half but not the phosphatase activity of the SHP-2 protein.

kin(p(HGNC:MAP3K5)) -> bp(MESHPP:Apoptosis)

Here we report that ASK1 proapoptotic activity is antagonized by association with 14-3-3 proteins.

Only NGF slightly increased fractalkine message expression in hypothalamic neurons.

In contrast, estrogen treatment decreased the expression of interleukin-6 (IL-6) (39%), carbonic anhydrase II (CA II) (36%), and osteopontin (OP) (37%)

a(SCHEM:"CP-24879") -| a(CHEBI:"arachidonic acid")

CP-24879 inhibited combined delta 6 and delta 5 desaturase activities and caused partial depletion of AA in liver.

p(MGI:Fads2) -> bp(GO:"inflammatory response")

Inadequate delta 6 desaturase activity has been correlated with chronic inflammatory disease...inhibition of delta 6 desaturase activity by SC-26196 caused a dose dependent increase in total fatty acid content and accompanying lipidosis in mouse liver.

tscript(complex(NCR:"Nfkb Complex")) -> r(RGD:Tnc)

mechanical strain increases tenascin-C gene transcription by activating nuclear factor-kappaB through reactive oxygen species.

a(SCHEM:"Concanavalin A") -> cat(p(HGNC:MMP14))

Specific antibodies against the subunits of alpha2beta1 integrins, the major collagen I receptor, induced partial inhibition of MMP2 activation. Treatment of cells with concanavalin A resulted in a marked activation of MMP2 that correlated with the proteolytic processing of MT1-MMP, the MMP2 activator, from a Mr=60 kd toward a Mr=43 kd polypeptide.

complex(p(MGI:Il4),p(MGI:Il4ra)) -> p(MGI:Jak3,pmod(P,Y))

However, disruption of a membrane-proximal proline-rich sequence motif ('box1') in either subunit of the bipartite IL-4R abolished not only ligand-induced tyrosine phosphorylation of Janus kinases JAK1 and JAK3, but also IL-4-triggered activation of STAT5 and concomitant cell proliferation

kin(p(MGI:Ikbke)) -> p(MGI:Nfkbia,pmod(P,S,32))

Overexpression of wild-type IKK-i phosphorylated serine residues Ser32 and Ser36 of IkappaB-alpha (preferentially Ser36), and significantly stimulated NF-kappaB activation.

The cyclooxygenase inhibitor indomethacin inhibited prostaglandin E2 production, and further enhanced thapsigargin-induced tumor necrosis factor-alpha production in parallel with further increase in cell-associated PAF production.

bp(GO:"response to oxidative stress") -> p(RGD:Serpinf1)

Levels above normal were seen for alpha(2)-antiplasmin and factor X at 48 h, normalizing at 72 h

bp(GO:"response to oxidative stress") -> cat(p(RGD:Plg))

The sequential changes over time indicate that kallikrein - kinin activation, and plasminogen activation are probably early events in cerulein-induced AP in rats

complex(p(HGNC:HIF1A),p(HGNC:ARNT)) => tscript(p(HGNC:ARNT))

Hypoxia inducible factor-1 (HIF-1) is a transcription factor composed of two subunits, HIF-1alpha and ARNT, which is activated under hypoxia.

tscript(p(HGNC:ARNT)) => complex(p(HGNC:HIF1A),p(HGNC:ARNT))

p(HGNC:PRL) -> tloc(p(HGNC:STAT5B),GOCCACC:"GO:0005737",GOCCACC:"GO:0005634")

Following prolactin activation, both STAT5A and STAT5B were rapidly translocated into the nucleus and displayed a detergent-resistant, punctate nuclear staining pattern.

Similar to prolactin induction, src activation resulted in tyrosine phosphorylation and DNA binding of both STAT5A and STAT5B. However, nuclear translocation of only STAT5B but not STAT5A was observed.

kin(p(HGNC:SRC)) -> tloc(p(HGNC:STAT5B),GOCCACC:"GO:0005737",GOCCACC:"GO:0005634")

a(CHEBI:"prostaglandin H2") -> path(MESHD:Ischemia)

We conclude that hypoxia-reoxygenation elicits the formation of superoxide, which causes loss of the vasodilatory action of NO and at the same time yields peroxynitrite. Subsequently, peroxynitrite nitrates and inactivates PGI2 synthase, leaving unmetabolized prostaglandin H2, which causes vasospasm, platelet aggregation, and thrombus formation via the TxA2/prostaglandin H2 receptor

bp(GO:"smooth muscle contraction") -> bp(GO:vasoconstriction)

a(SCHEM:Diacylglycerol) -> kin(p(RGD:Prkce))

Finally, we show that calsequestrin is an epsilonprotein kinase C substrate in vitro and protein kinase C phosphorylation of calsequestrin leads to a decreased binding of epsilonprotein kinase C to calsequestrin.

kin(p(RGD:Prkce)) -> p(RGD:Casq2,pmod(P,S))

<E25> Sp1 and E2F binding sites are both essential for activation of the murine thymidine kinase promoter (Karlseder et al., 1996). The promoter was activated when the Sp1 and E2F sites were separated by 6 or 10 bp but not when they were separated by 20 bp. The DHFR promoter was strongly activated by Sp1 alone but hardly at all by E2F1 alone (cotransfection in insect cells) (Lin et al., 1996a). E2F1, however, enhanced the activating ability of Sp1, even in the absence of a functional E2F binding site on the promoter.

p(HGNC:RB1,pmod(P)) -| complex(p(HGNC:E2F3),p(HGNC:RB1))

<E2> Unphosphorylated (or hypophosphorylated) pRb can bind to DP complexes of E2F1?3 and to a lesser degree E2F4. Binding of pRb family members is mediated by a short, highly conserved domain in the C-terminal region of E2F proteins. The E2F-binding site is in the C-terminal region of pRb.

p(HGNC:RB1,pmod(P)) -| complex(p(PFH:"TFDP Family"),p(HGNC:E2F4),p(HGNC:RB1))

p(HGNC:RB1,pmod(P)) =| (p(HGNC:RB1) -| tscript(p(HGNC:E2F4)))

<E7> E2F-DP dimers, complexed with pRb, p107, or p130, can bind and inhibit E2 promoter elements (Dyson, 1998; Mayol and Grana, 1998). In quiescent cells, the predominant complexes contain E2F4 and p130. E2F1_DP:RB1-|taof(E2F1_DP) E2F2_DP:RB1-|taof(E2F2_DP) E2F3_DP:RB1-|taof(E2F3_DP) E2F4_DP:RB1-|taof(E2F4_DP) E2F1_DP:RBL1-|taof(E2F1_DP) E2F2_DP:RBL1-|taof(E2F2_DP) E2F3_DP:RBL1-|taof(E2F3_DP) E2F4_DP:RBL1-|taof(E2F4_DP) E2F1_DP:NOLC1-|taof(E2F1_DP) E2F2_DP:NOLC1-|taof(E2F2_DP) E2F3_DP:NOLC1-|taof(E2F3_DP) E2F4_DP:NOLC1-|taof(E2F4_DP)

p(HGNC:RBL1,pmod(P)) =| (p(HGNC:RBL1) -| tscript(p(HGNC:E2F3)))

complex(p(HGNC:NOLC1),p(HGNC:E2F1)) => (p(HGNC:NOLC1) -| tscript(p(HGNC:E2F1)))

complex(p(HGNC:RBL1),p(HGNC:E2F3)) => (p(HGNC:RBL1) -| tscript(p(HGNC:E2F3)))

tscript(p(HGNC:RB1)) =| tscript(p(HGNC:E2F1))

bp(GO:"histone acetylation") -> complex(p(HGNC:GADD45A),p(PFH:"Histone Family"))

Gadd45 binds to core histones in chromatin or nucleosomes whose structure has been loosened by acetylation or UV light (UV) radiation

cat(p(HGNC:CREBBP)) => bp(GO:"histone acetylation")

p300 and CBP have intrinsic histone acetyl transferase activity

complex(p(HGNC:TP53),p(HGNC:TP53),p(HGNC:TP53),p(HGNC:TP53)) -> tscript(p(HGNC:TP53))

<p17> Ser392 phosphorylation of P53 increases 10-fold the association constant for tetramerization, but this effect is reversed by Ser315 phosphorylation. The tetramerization activates P53 for specific DNA binding and transcription

<p29> mdm2 inhibits p53-mediated transactivation; it inhibits the expression of p53 dependent genes

<p35> Mdm2 binds with E2F1:TFDP1 - this enhances the transcriptional activity of E2F1:TFDP1

p(HGNC:EGF) -> p(PFH:"Histone H3 Family",pmod(P))

Rsk-2, a member of the pp90rsk family of kinases implicated in growth control, was required for epidermal growth factor (EGF)-stimulated phosphorylation of H3

a(CHEBI:"nitric oxide") -| tscript(p(HGNC:ELK1))

This inhibitory effect was further substantiated by the inhibition of NO on both the shear stress-induced transcriptional activity of Elk-1 (an ERK substrate)

cat(p(HGNC:NOS3)) -| tscript(p(HGNC:ELK1))

Treatment of ECs with an NO donor, S-nitroso-N-acetylpenicillamine (SNAP) or 3-morpholinosydnonimine (SIN-1), inhibited this shear stress-induced Egr-1 expression.

Furthermore, it has been shown that NGF induces cyclin D1 expression in PC12 cells ( 64 ).

Molecular mechanisms for the restricted induction of TRAIL expression on NK cells by IL-2 or IL-15 remain to be determined.

The combination of the inflammatory cytokines IL-1 beta, TNF-alpha, and IFN-gamma, synergized with Tat to promote the development of angioproliferative KS-like lesions in nude mice that are not observed with each factor alone. Injection of inflammatory cytokines IL-1beta, TNF-alpha and IFN-gamma was found to cause an increase in the expression of bFGF and VEGF. However, bFGF, but not VEGF, synergizes with Tat in vivo and induces endothelial cells to migrate, to adhere, and to grow in response to Tat in vitro. Tat angiogenic effects correlate with the expression of the alpha v beta 3 integrin that is induced by bFGF and binds the arginine-glycine-aspartic acid (RGD) region of Tat.

cat(complex(p(HGNC:ITGA6),p(HGNC:ITGB1))) -| p(HGNC:PXN)

Certain integrins may regulate proliferation by additional mechanisms. For example, the a6b1 integrin may in part promote exit from the cell cycle in myoblasts, because the cytoplasmic domain of a6 inhibits paxillin signaling (44).

FAK also combines with, and may activate, phosphoinositide 3-OH kinase (PI 3-kinase), either directly or through the Src kinase (13). Finally, there is evidence that Src phosphorylates FAK at Tyr925, creating a binding site for the complex of the adapter Grb2 and Ras guanosine 5'-triphosphate exchange factor mSOS (10). These interactions link FAK to signaling pathways that modify the cytoskeleton and activate mitogen-activated protein kinase (MAPK) cascades (Fig. 3A).

FAK appears to play a major role in conveying survival signals from the ECM (50, 51). Because FAK binds PI 3-kinase, the protective effect against anoikis may be the result of PI 3-kinase-mediated activation of protein kinase B/Akt (52). Akt promotes survival, at least in part, by phosphorylating and thereby inactivating two proapoptotic proteins, Bad and caspase-9 (53) (Fig. 4). Inhibition of p53 prevents FAKdeficient cells from undergoing anoikis when deprived of growth factors, suggesting that p53 mediates the death signal under FAK deficiency (51).

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -| bp(MESHPP:Apoptosis)

complex(p(HGNC:PTK2),p(HGNC:SRC)) => kin(p(HGNC:SRC))

FAK may be recruited to nascent focal adhesions because it interacts, either directly or through the cytoskeletal proteins talin and paxillin, with the cytoplasmic tail of integrin b subunits (8). Upon activation, FAK autophosphorylates Tyr397, creating a binding site for the Src homology 2 (SH2) domain of Src or Fyn (9, 10). The Src kinase then phosphorylates a number of focal adhesion components. The major targets include paxillin and tensin, two cytoskeletal proteins that may also have signaling functions, and p130CAS, a docking protein that recruits the adapter proteins Crk and Nck (11, 12).

gtp(p(HGNC:RAC1)) -> a(SCHEM:Lamellipodiae)

Integrins and receptors for soluble mitogens, such as lysophosphatidic acid and growth factors, regulate cell spreading and migration through activation of the Rho-family of small guanine nucleotide-binding proteins (57). Among the Rho-related guanosine triphosphatase, Cdc42 induces filopodia, Rac induces lamellipodia, and Rho induces focal adhesions and associated stress fibers.

bp(GO:"cell adhesion") -> bp(GO:"cell cycle")

Rac promotes cell cycle progression, an effect that correlates with its ability to organize the cytoskeleton and promote spreading, rather than with its ability to activate MAP kinases (63).

p(HGNC:FN1) => cat(complex(p(HGNC:ITGA5),p(HGNC:ITGB1)))

The a5b1 integrin, which binds to fibronectin, induces expression of the antiapoptotic protein Bcl-2, protecting cells from apoptosis from stresses such as the lack of growth factors (55). Other integrins, including another fibronectin receptor, avb1, do not provide this survival effect. The avb3 integrin promotes endothelial and melanoma cell survival; this effect correlates with suppression of the p53 pathway and activation of the nuclear factor kappa B transcription factor (56). The activation of Shc by a1b1, a5b1, and avb3 may also contribute to protection from apoptosis (4, 17). Thus, integrinmediated attachment to ECM is a general requirement for cell survival, but survival under special circumstances may require a particular integrin.

cat(complex(p(HGNC:ITGAV),p(HGNC:ITGB3))) -| (p(HGNC:TP53) -> bp(MESHPP:Apoptosis))

cat(complex(p(HGNC:ITGAV),p(HGNC:ITGB3))) -> tscript(complex(NCH:"Nfkb Complex"))

cat(complex(p(HGNC:ITGAV),p(HGNC:ITGB3))) -> kin(p(HGNC:FLT1))

The receptors for insulin, plateletderived growth factor (PDGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) are optimally activated by their ligands only under appropriate cell attachment conditions (24-28). Although a systematic analysis has not been conducted, certain integrins appear to be preferentially associated with specific growth factor receptors. Thus, the avb3 integrin can be immunoprecipitated in complexes with the insulin, PDGF, and VEGF receptors (26, 28), whereas a5b1 and perhaps other b1 integrins associate with the EGF receptor (25, 27).

Angiotensin II is an established regulator of vascular tone and smooth muscle cell (SMC) growth. However, there are little data about its effect on collagen synthesis by SMCs and none regarding the mechanism of such an effect. We studied the effect of angiotensin II on collagen production by human arterial SMCs, using uptake of [(3)H]proline into collagenase-digestible proteins, and by ribonuclease protection assay for mRNA encoding the proalpha1 chain of type I collagen, the major collagen in arteries. This revealed a dose-dependent increase in relative collagen synthesis rate and a dose-dependent increase in proalpha1(I) collagen mRNA abundance, with the half-maximal effect at 1.7 nmol/L. Angiotensin II-stimulated collagen expression was associated with a 6-fold increase in transforming growth factor-beta (TGF-beta) production and was inhibited by a neutralizing antibody to TGF-beta. Both collagen production and TGF-beta release were inhibited by the AT(1)-specific antagonist, losartan, but not by the AT(2) receptor antagonist, PD123319. To determined if tyrosine phosphorylation was functionally linked to collagen synthesis, we studied the effect of 2 mechanistically distinct inhibitors of tyrosine kinase, genistein, and tyrphostin A25. These inhibitors abrogated angiotensin II-mediated procollagen mRNA expression and angiotensin II-mediated TGF-beta production, whereas the inactive homolog tyrphostin A1 had no effect. We conclude that angiotensin II stimulates collagen production in human arterial SMCs via the AT(1) receptor and an autocrine loop of TGF-beta, induction of which requires tyrosine phosphorylation.

kin(p(PFH:"PRKA Family")) => p(HGNC:LCP1,pmod(P,S,11))

kin(p(HGNC:PRKCD)) -| tscript(p(HGNC:STAT3))

Finally, we showed that the phosphorylation of Stat3 by PKC delta led to a negative regulation of Stat3 DNA binding and transcriptional activity.

p(HGNC:IL6) -> complex(p(HGNC:PRKCD),p(HGNC:STAT3))

Here, we report that Stat3 was specifically associated with PKC delta in vivo in an IL-6-dependent manner in several cell types.

interleukin-17 induces time-dependent stimulation of tyrosine phosphorylation of JAK 1, 2 and 3, Tyk 2 and STAT 1, 2, 3 and 4 within 0.5 to 30 min

complex(p(HGNC:NCOA1),p(HGNC:PGR),a(CHEBI:progesterone)) -> bp(GO:"histone acetylation")

ncoa1 possesses intrinsic histone acetyltransferase activity recruitment of coactivator ncoa1 by the ligand-activated PR in vivo leads to chromatin remodeling through histone acetylation and recruitment/stabilization of the preinitiation complex

a(CHEBI:progesterone) -> (p(HGNC:NCOA1) -> tscript(p(HGNC:PGR)))

ncoa1 potentiated transcription by ligand-activated PGR, whereas it had no effect on transcription in the absence of ligands

In fa/fa compared to Fa/fa rats, (a) PDE2 activity was significantly increased, (b) Western blot analysis of PDE2 revealed two signals at 71 and 105 kDa, with changes in protein being in good parallelism with changes in activity, (c) the PDE2 mRNA concentration was also significantly increased.

M-CSF triggers the activation of extracellular signal-regulated protein kinases (ERK)-1/2.

Splenocytes of control animals proliferated vigorously in response to MOG peptide and produced significant amounts of Th1 (IL2) cytokine. By contrast, splenocytes from NF-KB-deficient (NFKB1) animals produced significantly less amounts of cytokine IL2, and proliferated poorly in response to MOG stimulation.

tscript(complex(NCH:"Nfkb Complex")) -| cat(p(HGNC:CASP8))

NF-kappaB activation suppresses the activation of caspase 8

bp(GO:gluconeogenesis) positiveCorrelation path(MESHD:Hyperglycemia)

Addition of a sulfonylurea to metformin therapy gives an additive glucose- lowering effect (102, 103,149). Similarly, addition of metformin to sulfonylurea therapy gives an additive response, both with respect to glucose-lowering (101, 103, 149-152) and lipid-lowering (91, 103) effects the elevated fasting plasma glucose level is caused by incomplete suppression of basal hepatic glucose production by sulfonylurea or metformin Figure 1. Pathogenesis of type 2 diabetes mellitus. Sites of action of oral agents are indicated. A negative sign indicates inhibition; a positive sign indicates stimulation.

The [Ca2+]i increase induced by ET-1 was inhibited by both BQ123, an ET(A)-receptor antagonist, and BQ788, an ET(B)-receptor antagonist, whereas that induced by ET-3 was inhibited by BQ788 but not by BQ123.

kin(p(PFH:"PRKC Family")) -> r(HGNC:PTGIS)

BK increased cPLA(2) mRNA eightfold by 15 min, and this increase was inhibited by pretreatment with the PKC inhibitors.

kin(p(PFH:"PRKC Family")) -> a(SCHEM:Calcium)

The PKC inhibitors GF109203X and H7 attenuated the BK-induced increase in [Ca(2+)](i) and inhibited the BK-induced PGI(2) synthesis. Phorbol 12-myristate 13-acetate increased cPLA(2) activity and PGI(2) synthesis but failed to alter [Ca(2+)](i).

kin(p(PFH:"PRKC Family")) -> cat(p(HGNC:PTGIS))

Furthermore, high oxygen levels induce S-phase arrest and increased expression of p53 and p21(WAF1/CIP1).

path(MESHD:Hyperoxia) -> a(SCHEM:"free radical")

Hyperoxia increases free radical production, leading to DNA damage.

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:CD69)

% Thus the PMA-induced expression of CD11b and CD69 in human PMN represents two separate processes

gtp(p(HGNC:ARF6)) -> (p(HGNC:INS) -> sec(p(HGNC:CFD)))

In contrast, the secretion of adipsin, a serine protease specifically expressed in adipocytes, was increased by the expression of wild-type ARF6 and was inhibited by the expression of D125N. These results indicate a requirement for ARF6 in basal and insulin-regulated adipsin secretion but not in glucose transport.

Ariadne: GRP58 is a major target for tyrosine phosphorylation by the Lyn kinase ( 76 ), a kinase that can be activated by IL-6 through gp130 signaling

kin(p(HGNC:LYN)) => p(HGNC:PDIA3,pmod(P,Y))

complex(NCR:"Ngf Complex") -> tscript(complex(NCR:"Nfkb Complex"))

In comparison, overexpression of atypical PKC-iota was by itself sufficient to activate NF-kappaB and shift the kinetics of NGF-induced kappaB activity.

a(CHEBI:epoxomicin) -| tscript(complex(NCH:"Nfkb Complex"))

Epoxomicin also effectively inhibits NF-kappaB activation in vitro and potently blocks in vivo inflammation in the murine ear edema assay.

Renal CD54 mRNA expression was markedly increased by 24 hours after exposure to cisplatin in mice.

cat(p(HGNC:CASP3)) -> bp(MESHPP:Apoptosis)

Also cathepsin L participates in cell apoptosis mediated by caspase III activation.

a(CHEBI:lipopolysaccharide) -> r(RGD:Cebpb)

Northern blot analysis showed an increased abundance of the mRNA for C/EBP beta in LPS-treated lungs and for C/EBP delta in Bleo-treated lungs

gtp(p(HGNC:RAC1)) => complex(p(HGNC:CDC42),p(HGNC:IQGAP1))

Guanosine 5'-(3-O-thio)triphosphate (GTPgammaS).glutathione S-transferase (GST)-Cdc42 and GTPgammaS. GST-Rac1 inhibited the binding of IQGAP1 to beta-catenin in a dose-dependent manner in vitro

tscript(p(HGNC:PPARG)) -| tscript(complex(NCH:"AP-1 Complex"))

These results indicate that both PPAR{alpha} and PPAR{gamma} interfere with AP-1 transcriptional activity in a manner independent of the promoter context.

Note that both panels are reprobes of the same blot. d, In vitro Akt activation using histone H2B as a substrate in lysates of sympathetic neurons treated for 15 min with increasing concentrations of NGF (ng/ml) or KCl (mM).

GRK2, -3, -5, -6a, and -6b inhibit the FSH-R-mediated signaling

kin(p(PFH:"PRKC Family")) -> p(HGNC:TFPI)

Northern blot analysis of TFPI mRNA also showed a decrease of the 1.4-kb transcript after 4 hours of incubation with UFH, followed by recovery and an increase over the control level after 24 hours. Incubation of ECs with phorbol ester (PMA) significantly enhanced the secretion of TFPI and increased its activity on the cell surface, probably by preventing invagination of caveolae.

kin(p(PFH:"PRKC Family")) -> sec(p(HGNC:TFPI))

Previous work has established that the melanocyte-specific tyrosinase-related protein-1 (TRP-1) promoter is regulated positively by the microphthalmia-associated transcription factor Mitf, acting through the conserved M box and negatively by the T-box factor Tbx2,

kin(p(HGNC:MAPK1)) -> kin(p(HGNC:RPS6KA3))

Its (RSK2) activation requires phosphorylation of the linker region at Ser(369), catalyzed by extracellular signal-regulated kinase (ERK)

path(SDIS:"tissue damage") -> r(MGI:Dsc2)

freshly excised human skin specimens.At all stages studied the entire set of desmosomal cadherins [desmogleins (Dsg) 1-3 and desmocollins (Dsc) 1-3] was detected, with Dsg3, Dsc2 and Dsc3 being the most prominent.

path(SDIS:"tissue damage") -> r(MGI:Dsg1a)

path(SDIS:"tissue damage") -> r(MGI:Dsg3)

a(CHEBI:"nitric oxide") -> p(MGI:Pln,pmod(P))

Also, in rat aorta, nitric oxide-induced relaxation via the cGMP kinase pathway was associated with phosphorylation of PLB

p(HGNC:TP53,sub(R,273,H)) =| tscript(p(HGNC:TP53))

TMPRSS2 as a gene exhibiting increased expression upon exposure to androgens

gtp(p(HGNC:RAC1)) -> a(CHEBI:"reactive oxygen species")

Upon stimulation, a functional NADPH oxidase is assembled when the cytosolic proteins, Rac, p67phox, p47phox, and possibly p40phox, associate with the gp91phox and p22phox transmembrane proteins.

phos(p(HGNC:PTPN6)) -| kin(p(HGNC:PIK3R1))

Wild-type but not catalytically inactive SHP-1 induced dephosphorylation of p85. Furthermore, expression of SHP-1 decreased PI3K enzyme activity in anti-phosphotyrosine immunoprecipitates and phosphorylation of serine 473 in Akt, a process dependent on PI3K activity.

p(HGNC:TXN) -> tscript(complex(NCH:"Nfkb Complex"))

In the cytoplasm, it interferes with the signals to IkappaB kinases and blocks the degradation of IkappaB. In the nucleus, however, TRX enhances NF-kappaB transcriptional activities by enhancing its ability to bind DNA.

complex(p(HGNC:CDC42EP3),p(HGNC:RHOQ)) -| gtp(p(HGNC:CDC42))

Borg1, Borg2, Borg4, and Borg5 bind both TC10 and Cdc42 in a GTP-dependent manner.

complex(p(HGNC:APPL1),p(HGNC:AKT2),p(HGNC:PIK3CA)) -> (kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> kin(p(HGNC:AKT2)))
kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> kin(p(HGNC:AKT2))

These data suggest that APPL is an adaptor that may tether inactive AKT2 to p110alpha in the cytoplasm and thereby may expedite recruitment of AKT2 and p110alpha to the cell membrane upon mitogenic stimulation.

TNF-alpha stimulates secretion of RANTES, MIP-1beta and MIP-1alpha by HIV-infected alveolar macrophages and peripheral blood monocytes.

kin(p(PFR:"Prkc Family")) -> r(RGD:Col1a1)

In addition, TGFbeta(1)- and BMP-2-induced increases in alpha1(I) collagen mRNA levels were both dependent on protein kinase C and protein tyrosine kinase activities.

a(CHEBI:"angiotensin II") -> r(MGI:Tgfbr2)

ANG II upregulates TGF-beta receptor type II expression on proximal tubular cells

Treatment of intact C3H10T1/2 cells or microsomes therefrom with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzanthracene (BA) enhanced CYP1B1 activity and CYP1B1 expression as revealed by elevations of CYP1B1-catalyzed DMBA metabolism, CYP1B1 apoprotein level and CYP1B1 gene expression. One hundred microM DHEA caused an 80-90% inhibition of cellular DMBA metabolism without inflicting cell death. Cytosolic glucose-6-phosphate dehydrogenase (G6PDH) was also inhibited in DHEA-treated cells, presumably due to the inhibition of NADP reduction. In contrast, neither DMBA metabolism nor CYP1B1 apoprotein was inhibited by DHEA in the microsomes isolated from these cells. DHEA (100 microM), TCDD (10 nM) and BA (10 microM) stimulated the activities and increased the apoprotein levels of two peroxisomal enzymes, namely, acyl CoA oxidase (ACOX) and acyl CoA hydrolase (ACH2) and also induced the expression of CYP1B1 and ACOX genes. Cytosolic fatty acyl-CoA beta-oxidation was also stimulated by DHEA, TCDD and BA. In corroboratory experiments, it was found that concomitant with the stimulation of the activity of a key enzyme regulator of fatty acid homeostasis, namely, glycerol-3-phosphate dehydrogenase (G3PDH), these agents enhanced arachidonic acid (AA) metabolism as judged by the release of [3H] from AA into the culture medium. Collectively, these data suggest that DHEA mediates the regulation of CYP1B1 and inhibits BA and TCDD-induced CYP1B1-catalyzed carcinogen (DMBA) activation in 10T1/2 cells through metabolic interactions that involve the activation of the peroxisomal and fatty acid beta-oxidation signaling pathways. These results also present evidence for the first time, for the possible peroxisomal effects of TCDD and BA which are similar to those of DHEA in this mouse embryo fibroblast cell line.

complex(p(RGD:Npy1r),p(RGD:Npy)) -> path(SDIS:"food intake")

The results showed that intracerebroventricular administration of NPY stimulated feeding and increased immunostaining of c-Fos, a product of the immediate early gene c-fos

Ability of huIL18bp to inhibit IFNgamma induction was shown by incubating human KG-1 monocytic cells with IL-18. MC53L and MC54L blocked IFNgamma production at nanogram levels in a dose dependent manner.

cGMP concentrations were increased significantly in penile tissue of rats transfected with AdCMVeNOS compared with control.

On the other hand, TGF-beta stimulated the expression of both MCP-I and GM-CSF, but suppressed M-CSF expression.

BMP6 induced the phosphorylation of Smad5 and Smad1 in C2C12 cells and MC3T3-E1 cells.

Dietary fenofibrate had no effect on the ALD and P70R genes, but strongly increased expression of the ALDR and PMP70 genes in mouse liver.

Engrailed, Hoxa-5, and Hoxc-8 regulate BPAG1e promoter activity

The glypican- antisense transfected clones displayed markedly reduced glypican- protein levels and a marked attenuation of the mitogenic responses to heparin-binding growth factors that are commonly overexpressed in pancreatic cancer: fibroblast growth factor-2 (FGF2), heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), and hepatocyte growth factor (HGF)

complex(p(HGNC:HGF),p(HGNC:GPC1)) -> bp(GO:"cell growth")

# sentences for pubmedID=10506130: # Ariadne: Results showed that forskolin also inhibited the expression of alkaline phosphatase, bone sialoprotein, osteopontin, and osteocalcin genes (Fig. 2 C ). [Expression]

a(SCHEM:"cyclic AMP") -| tscript(p(HGNC:RUNX2))

In the osteoblastic cell line, MC3T3-E1, continuous treatment with cAMP elevating agents inhibited both osteoblastic differentiation based on alkaline phosphatase assay and DNA binding ability of Cbfa1 based on a gel retardation assay. Cbfa1 inhibition was paralleled by an inhibitory effect of forskolin on Cbfa1-regulated genes. Northern and Western blot analyses suggested that the inhibition of Cbfa1 by forskolin was mainly at the protein level.

kin(p(HGNC:CDK2)) -> phos(p(HGNC:PPP1CA))

In this study, we examined the cell cycle-dependent phosphorylation of PP1alpha in vivo using three different antibodies. PP1alpha was phosphorylated at Thr-320 during M-phase and again in late G(1)- through early S-phase. Inhibition of Cdk2 led to a small increase in PP1 activity and also prevented PP1alpha phosphorylation. In vitro, PP1alpha was a substrate for Cdk2 but not Cdk4.

path(MESHD:Ischemia) -> a(CHEBI:peroxynitrite)

These changes lead to the activation of five damaging events, termed perpetrators. These are the damaging actions of free radicals and their product peroxynitrite,

path(MESHD:Ischemia) -> bp(GO:"pH reduction")

bp(GO:"replicative cell aging") -| r(HGNC:ALDH1A1)

Figure 2. Differential gene expression at senesence.

As shown in Fig. 3, Northern blot analysis showed that the HGF levels were slightly increased in the CCl4-treated livers of the mock- and AxCALacZ-infected rats compared with those of normal rat livers. In contrast, a dramatic increase in HGF expression was observed in the rat liver infected with HNF3gamma (1.5×109 pfu).

Fig. 4 shows the results of the Northern blot analysis, which indicate that endogenous HNF-3? mRNA (indicated with an arrow) was decreased 50% in the CCl4-injured liver compared with the normal rat. However, the transduced HNF-3gamma mRNA (indicated with an arrowhead) was increased dose-dependently by the AxCAHNF3gamma infection in spite of CCl4 treatment. HNF-3alpha and HNF-3beta were up-regulated in the CCl4-treated livers of mock- and AxCALacZ-infected rats. Conversely, These mRNAs in the AxCAHNF3gamma-infected liver were not observed to be induced by CCl4 treatment.

We conclude that glucose increases AII production by mesangial cells, which results in stimulation of TGF-beta1 secretion, decreased matrix degradation, and increased matrix accumulation. These effects of AII are mediated by the AT1 receptor. Collagenase activity in cell medium was determined using three methods: 1) zymography; 2) quantitative assay using fluoresceinated gelatin as substrate; and 3) a new enzyme-linked immunosorbent assay (ELISA) that specifically measures 72-kDa collagenase (MMP-2), the principal collagenase synthesized by mesangial cells.

tscript(p(PFH:"TCF/LEF Family")) -> r(HGNC:MMP7)

Here we report the identification of the matrix metalloproteinase MMP-7 as another target gene of beta-catenin/TCF-4. MMP-7 is overexpressed in 80% of human colorectal cancers and known to be an important factor for early tumor growth, with a potential function also for later progression steps, like invasion and metastasis.

gtp(p(PFH:"RAS Family")) -| r(HGNC:PAWR)

Oncogenic Ras induces the transcription activity of NF-kappaB that confers cell survival. Oncogenic Ras also down-modulates the expression of Par-4, a transcriptional repressor protein, that is essential but not sufficient on its own to induce apoptosis. Here we show that reintroduction of Par-4 by transient transfection leads to apoptosis in cells expressing oncogenic Ras but not in those that lack oncogenic Ras expression. Par-4 abrogates oncogenic Ras-inducible NF-kappaB transcription activity

gtp(p(HGNC:HRAS)) -> tscript(complex(NCH:"Nfkb Complex"))
tscript(p(HGNC:PAWR)) -| (gtp(p(HGNC:HRAS)) -> tscript(complex(NCH:"Nfkb Complex")))

tscript(complex(NCH:"AP-1 Complex")) => r(HGNC:GCLC)

ECV304 cells transiently transfected with a plasmid containing the gamma-GCS promoter-luciferase construct showed increased luciferase activity when treated with melatonin. The melatonin-dependent luciferase activity was found in the gamma-GCS promoter containing AP-1 site

By contrast, G-protein inhibition by pertussis toxin, or transfection with a dominant negative mutant of Ha-Ras strongly increased fibronectin-induced MMP-2 and MMP-9. Inhibition of PI3 kinase, MAPkinase (MEK1), or p38 MAPkinase by wortmannin, PD 98059, or SB 202190, respectively, strongly promoted fibronectin-induced MMP2 and MMP-9

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -| r(HGNC:MMP2)

a(CHEBI:"reactive oxygen species") -> r(MGI:Prdx1)

Using differential screening, we cloned two novel proteins designated MSP23 and A170 that are induced in the cells by low levels of reactive oxygen species, electrophilic agents and other oxidative stress agents

cat(p(PFM:"Hdac Family")) -> (p(MGI:Trp53) -> bp(MESHPP:Apoptosis))

Significantly, inhibition of p53-mediated transcriptional repression with TSA markedly inhibits apoptosis induction by p53.

cat(p(PFM:"Hdac Family")) -| r(MGI:Stmn1)

We report that trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), abrogates the ability of p53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin.

tscript(p(MGI:Trp53)) -> (cat(p(PFM:"Hdac Family")) -| r(MGI:Stmn1))

kin(p(HGNC:MAPK1)) => p(HGNC:STAT3,pmod(P,S,727))

Recently, serine phosphorylation of Stat3 on Ser-727 by ERK has been identified in response to epidermal growth factor (EGF).

kin(p(PFH:"MAPK JNK Family")) -| p(HGNC:STAT3,pmod(P,Y,705))

We further demonstrate that JNK1, activated by its upstream kinase MKK7, negatively regulated the tyrosine phosphorylation and DNA binding and transcriptional activities of Stat3 stimulated by EGF.

p(MGI:Ccr2) -> path(SDIS:"Atherosclerotic lesion")

In addition, in recent in vivo studies, targeted disruption of the genes for MCP-1, CCR2, and CXCR2 significantly decreased atherosclerotic lesion formation and lipid deposition when the disrupted gene was bred or transferred into mouse strains prone to develop atherosclerotic-like lesions (36, 37, 29).

In vitro experiments supported these results and showed that IL-1beta, TNF-alpha, and CD40 ligand potentiated IP-10 expression from IFN-gamma-stimulated ECs.

We report here that the Ca(2+) ionophore A23187 substantially stimulated Cap43 gene expression. In addition, we found that BAPTA-AM, a specific chelator of free intracellular Ca(2+), consistently attenuated the induction of Cap43, indicating that elevation of intracellular Ca(2+) was essential for this response

kin(p(PFH:"PRKC Family")) => p(HGNC:CYTH2,pmod(P,S,392))

In PC12 cells, nerve growth factor induces neuronal differentiation and repressed expression of nrg-1.

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(EGID:305843)

Insulin inhibited the stimulatory effect of a high level of glucose (25 mM) and phorbol 12-myristate 13-acetate, an activator of protein kinase C) on the secretion of ANG and the expression of the ANG messenger RNA in IRPTC.

a(SCHEM:"serum glucose") -> sec(p(EGID:305843))

a(SCHEM:"serum glucose") -> r(EGID:305843)

kin(p(PFR:"Prkc Family")) -> sec(p(EGID:305843))

kin(p(PFR:"Prkc Family")) -> r(EGID:305843)

sodium butyrate enhanced TNF-alpha-induced C3 secretion, but suppressed TNF-alpha-induced factor B and IL-8 secretion.

p(HGNC:IL10) -| tscript(complex(NCH:"Nfkb Complex"))

In this study, we show that IL-10 functions to block NF-kappaB activity at two levels: 1) through the suppression of IKK activity and 2) through the inhibition of NF-kappaB DNA binding activity.

Okadaic acid and calyculin A had no effect on pRB phosphatase activity even though PP2A was completely inhibited. The decrease in pRB phosphorylation correlated with inhibitor-induced suppression of G(1) cyclin-dependent kinases including CDK2, CDK4, and CDK6. The inhibitors also caused decreases in the levels of cyclin D2 and cyclin E, and induction of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1).

cat(p(HGNC:DAB2IP)) =| gtp(p(PFH:"RAS Family"))

After activating Ras using EGF The presence of EGF increased the reporter gene activity at least 5-fold. However, DIP1/2 could inhibit the reporter gene activity in a dose-dependent manner.

complex(p(PFH:"RAS Family"),a(SCHEM:"Guanosine triphosphate")) => gtp(p(PFH:"RAS Family"))

Because Raf binds tightly to the GTP-bound form of Ras but not to the GDP-bound form, such differential affinity can be used to determine the GTP-bound status of Ras.

gtp(p(PFH:"RAS Family")) => kin(p(PFH:"RAF Family"))

cat(p(PFH:"SOS Family")) => gtp(p(PFH:"RAS Family"))

DOC-2/DAB2 and DIP1/2 complex represent a negative feedback machinery for several exogenous stimuli-elicited signal cascade. PKC can phosphorylate the N-terminal domain of DOC-2/DAB2 (serine 24) that recruits DIP1/2 to inactivate Ras protein. On the other hand, shortly after the treatment of peptide growth factors, the C terminus of DOC-2/DAB2 (proline-rich domain) competes with SOS for Grb 2 binding, which leads to the inactivation of the MAP pathway.

kin(p(HGNC:PRKCB)) => p(HGNC:DAB2,pmod(P,S,24))

DOC-2/DAB2, a novel phosphoprotein with signal-transducing capability, inhibits human prostatic cancer cells (Tseng, C.-P., Ely, B. D., Li, Y., Pong, R.-C., and Hsieh, J.-T. (1998) Endocrinology 139, 3542-3553). However, its mechanism of action is not understood completely. This study delineates the functional significance of DOC-2/DAB2 protein phosphorylation and demonstrates that in vivo activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) induces DOC-2/DAB2 phosphorylation, including a serine residue at position 24. Mutation of Ser(24) to Ala reduced DOC-2/DAB2 phosphorylation by PKC. Using a synthetic Ser(24) peptide (APS(24)KKEKKKGSEKTD) or recombinant DOC-2/DAB2 as substrates, PKCbetaII, PKCgamma, and PKCdelta (but not casein kinase II) directly phosphorylated Ser(24) in vitro. This indicates that DOC-2/DAB2 is a PKC-specific substrate. Since expression of wild-type DOC-2/DAB2, but not the S24A mutant, inhibited TPA-induced AP-1 activity in prostatic epithelial cells, phosphorylation of Ser(24) appears to play a critical role in modulating TPA-induced AP-1 activity. Taken together, these data suggest that PKC-regulated phosphorylation of DOC-2/DAB2 protein may help its growth inhibitory function.

kin(p(PFH:"PRKC Family")) => p(HGNC:DAB2,pmod(P,S,24))

activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) induces DOC-2/DAB2 phosphorylation, including a serine residue at position 24

Angiotensin II induces the tyrosine and serine phosphorylation of Stat1 and Stat3. Under High Glucose condition both the extent and the duration of phosphorylation of Stat1 and Stat3 was increased.

Androgen-independent sublines emerged 80-400 days after androgen withdrawal, and these sublines had variable growth phenotypes but were associated with mdm2 protein overexpression and increased expression of cyclin D1.

Established tumors in nude athymic BALB/c mice were sampled at various times after androgen withdrawal and after the development of androgen independence. Changes in the expression of cell cycle regulators were categorized into early and mid-to-late events. RESULTS and CONCLUSIONS: Early events included a decrease in androgen receptor expression, followed by a short-term increase in expression of the p53 and p21/WAF1 proteins and a marked decrease in the Ki67 proliferative index.

Mid-to-late events included progressive and sustained increases in p27 and p16 protein expression, a decrease in retinoblastoma protein expression, and an increase in the transcription factor E2F1

p(HGNC:S100A9) -> bp(GO:"cell adhesion")

Recently, Newton and Hogg showed that S100A9 stimulates neutrophil adhesion, and S100A8 reversed the stimulatory effect probably by the formation of the heterodimer.

a(SCHEM:Calcium) -> complex(p(HGNC:S100A8),p(HGNC:S100A9),a(CHEBI:"arachidonic acid"))

fatty acid binding was dependent on the calcium concentration;

cat(p(MGI:Tnfrsf12a)) -| bp(GO:"cell growth")

These experiments revealed that Fn14 expression decreased cellular adhesion to the extracellular matrix proteins fibronectin and vitronectin and also reduced serum-stimulated cell growth and migration

a(CHEBI:glucocorticoid) -> r(EGID:113902)

Results indicated that the CEH gene has two complex glucocorticoid response units in distal portions of the promoter corresponding to consensus glucocorticoid regulatory sequences as well as putative thyroid hormone response elements.

a(CHEBI:ethanol) -| (p(HGNC:PDGFA) -> p(HGNC:PDGFRA,pmod(P)))

Ethanol inhibited both PDGF-AA- and PDGF-BB-mediated phosphorylation of PDGFalphar

a(CHEBI:ethanol) -| (p(HGNC:PDGFB) -> p(HGNC:PDGFRA,pmod(P)))

p(HGNC:CDKN1B,pmod(P,T,187)) -| p(HGNC:CDKN1B)

The ubiquitination and subsequent degradation of p27 depend on its phosphorylation by cyclin-CDK complexes.

kin(p(PFH:"PRKA Family")) => p(HGNC:PTPN7,pmod(P,S,44))

kin(p(PFH:"PRKA Family")) -| complex(p(HGNC:PTPN7),p(HGNC:MAP2K1))

This modification reduces binding of MAP kinases to the KIM, an effect that is prevented by mutation of serine 23 to alanine.

kin(p(PFH:"PRKA Family")) -| complex(p(HGNC:PTPN7),p(HGNC:MAPK3))

a(SCHEM:"Tetradecanoylphorbol acetate") -> (kin(p(PFH:"MAPK Erk1/3 Family")) -| kin(p(HGNC:GSK3A)))
kin(p(PFH:"MAPK Erk1/3 Family")) -| kin(p(HGNC:GSK3A))

PKB alone mediates the IGF1-induced inhibition of GSK3alpha, while the MAPK cascade mediates the inhibition of GSK3alpha by PMA.

p(HGNC:EGF) -> (kin(p(PFH:"MAPK Erk1/3 Family")) -| kin(p(HGNC:GSK3A)))

protein kinase B (PKB) plays a key role in mediating EGF-induced inhibition of GSK3alpha and that the classical MAP kinase (MAPK) cascade has two functions in this process. Firstly, it makes a transient contribution to EGF-induced inhibition of GSK3alpha

Whole cell extract of wild-type K562 cells, a transformant cell line of K562 expressing HSF2 and HeLa cells expressing HSF2 transfected with the reporter construct of Ccte gene was found to bind the HSE sequence of Ccte gene, thus activating the Cct gene transcription.

Whole cell extract of wild-type K562 cells, a transformant cell line of K562 expressing HSF2 and HeLa cells expressing HSF2 transfected with the reporter construct of Cctz-1 gene was found to bind the HSE sequence of Cctz-1 gene, thus activating the Cct gene transcription.

TNF-alpha and IFN-gamma synthesis was suppressed by IL-10 and TGF-beta

p(HGNC:TRIM24) -> bp(GO:"gene silencing")

The silencing activity of TIF1alpha appears to result chiefly from histone deacetylation, whereas that of TIF1beta may be mediated via both HP1 binding and histone deacetylation.

cat(p(PFH:"HDAC Family")) -> (p(HGNC:TRIM28) -> bp(GO:"gene silencing"))
p(HGNC:TRIM28) -> bp(GO:"gene silencing")

kin(p(MGI:Acvr1)) -> tscript(p(MGI:Smad1))

kin(p(MGI:Acvrl1)) -> tscript(p(MGI:Smad1))

kin(p(MGI:Bmpr1a)) -> tscript(p(MGI:Smad5))

kin(p(MGI:Src)) -> p(PFM:"Plcg Family",pmod(P))

cat(p(HGNC:PPP1R12A)) -| bp(GO:"muscle contraction")

It is shown here that cGKIalpha is targeted to the smooth muscle cell contractile apparatus by a leucine zipper interaction with the myosin-binding subunit (MBS) of myosin phosphatase. Uncoupling of the cGKIalpha-MBS interaction prevents cGMP-dependent dephosphorylation of myosin light chain, demonstrating that this interaction is essential to the regulation of vascular smooth muscle cell tone.

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> r(HGNC:PIK3R1)

In addition, overexpression of a constitutively active protein kinase B increased p85alphaPI 3-K mRNA levels. These results indicate that the phosphatidylinositol 3-kinase/PKB/p70S6 kinase pathway is required for the stimulation by insulin of p85alphaPI 3-K gene expression in human muscle cells.

Three highly homologous acyl-CoA thioesterase genes, Cte1, Mte1, and Pte1, are located within a narrow cluster on chromosone 12. All four thioesterases are differentially expressed in tissues examined, but all are inducible at mRNA level by treatment with the peroxisome proliferator clofibrate, or during the physiological condition of fasting, both conditions causing a perturbation in overall lipid homeostasis.

kin(p(MGI:Abl1)) -> path(SDIS:"oncogenic transformation")

DOKL and p62(dok) bind through their PTB domains to the Abelson tyrosine kinase in a kinase-dependent manner in both yeast and mammalian cells. DOKL is phosphorylated by the Abl tyrosine kinase in vivo. In contrast to p62(dok), DOKL lacks YxxP motifs in the C terminus and does not bind to Ras GTPase-activating protein (RasGAP) upon phosphorylation. Overexpression of DOKL, but not p62(dok), suppresses v-Abl-induced mitogen-activated protein (MAP) kinase activation but has no effect on constitutively activated Ras- and epidermal growth factor-induced MAP kinase activation. T

deltaEF1 has a second mechanism of transrepression recruiting CtBP1 or CtBP2 as its corepressor

p(HGNC:APOE) -| complex(p(HGNC:RELN),p(HGNC:LRP8))

Reelin binds directly to lipoprotein receptors, preferably the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Binding requires calcium, and it is inhibited in the presence of apoE.

a(CHEBI:"arachidonic acid") -> r(HGNC:EDN1)

Arachidonic acid-induced production of ET-1 is dependent on lipoxygenase products of arachidonate metabolism.

tscript(p(HGNC:KLF10)) -> a(CHEBI:"reactive oxygen species")

TIEG1 induces apoptosis by a mechanism involving the formation of reactive oxygen species

kin(p(HGNC:ROCK1)) => p(PFH:"MYL Regulatory Family",pmod(P,S,20))

Rho-kinase, an effector of Rho, regulates integrin-mediated cell-substratum adhesion (focal adhesion) by regulating the phosphorylation state of myosin light chain (MLC):

kin(p(HGNC:LYN)) -> p(HGNC:PTPN6,pmod(P,Y,564))

The results show that Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity.

kin(p(HGNC:ROCK1)) -> p(HGNC:DES,pmod(P,T,16))

treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin. We also found that an antibody, which specifically recognizes vimentin phosphorylated at Ser-71 by Rho kinase, became immunoreactive after calyculin A treatment.

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:FAS)

We further show that anti-CD3 mAb, phorbol 12-myristate 13-acetate, and phorbol 12-myristate 13-acetate/ionomycin strongly activated promoters carrying multiple copies of the Fas enhancer, and mutation of either the GABP or AP-1 binding site severely reduced transcriptional activity.

tport(p(HGNC:SCARB1)) => a(SCHEM:"Oxidized High Density Lipoprotein")

Scavenger receptors bind and internalize modified low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Because the expression of scavenger receptors is not down-regulated by cholesterol, macrophages (Mphi) expressing scavenger receptors can internalize substantial quantities of cholesteryl ester from oxidized LDL and HDL, leading to foam cell formation

tloc(p(HGNC:AKT3),GOCCACC:"GO:0005737",GOCCACC:"GO:0005886") -> kin(p(HGNC:AKT3))

A consequence of Akt binding to phospholipids is the translocation of Akt from the cytoplasm to the inner surface of the plasma membrane, where PI3K-generated 3'-phosphorylated phospholipids reside Relocalization of Akt to the plasma membrane brings Akt in proximity to regulatory kinases that phosphorylate and activate Akt.

Treatment with Synthetic Androgen (R1881) resulted in a consistent downregulation of mRNA expression of Peg3 mRNA in LNCaP cells. Combined addition of androgen and actinomycin D revealed no change in the stability of Peg3 mRNA suggesting that androgens decrease Peg3 expression by inhibiting the rate of transcription

a(CHEBI:"trichostatin A") -> r(HGNC:CDKN1A)

\"IGF-II enhances trichostatin A-induced TGFbeta1 and p21(Waf1,Cip1, sdi1) expression in Hep3B cells.\"

Gel mobility-shift assays performed with in vitro-translated ADD1, Id2 or Id3 proteins and a fatty acid synthase (FAS) promoter oligonucleotide showed evidence for a marked inhibition of the formation of DNA-ADD1 complexes by Id2 or Id3 proteins.

We here demonstrated that there was a dramatic rise of Id2 and Id3 mRNA levels when 3T3-L1 adipocytes or isolated rat fat cells were exposed to lipolytic and anti-lipogenic agents, forskolin and isoproterenol.

Stimulation of microglial cell lysates with CD40L led to an increase in p42/44MAPK activity. However CD40-CD40L did not induce phosphorylation of p38 MAPK.

a(CHEBI:calcitriol) -> surf(p(HGNC:ITGAM))

1alpha,25-dihydroxyvitamin D(3) (D(3)) promotes the maturation of myeloid cells and surface expressions of CD14 and CD11b, markers of cell differentiation in response to D(3).

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> r(HGNC:CD14)

Furthermore, induction of CD14 expression in response to D(3) was abrogated by (a) the PI 3-kinase inhibitors LY294002 and wortmannin; (b) antisense oligonucleotides to mRNA for the p110 catalytic subunit of PI 3-kinase; and (c) a dominant negative mutant of PI 3-kinase.

Vasopressin cell stimulation caused a biphasic increase of PDE4 activity

a(SCHEM:"Tetradecanoylphorbol acetate") -> p(HGNC:SYK,pmod(P,Y))

PMA at 100 nmol/L strongly potentiated adhesion and tyrosine phosphorylation of p125(FAK) and p72(syk)

kin(p(PFH:"PRKC Family")) -> p(HGNC:PTK2,pmod(P,Y))

Cyclin D1 was elevated to a smaller extent on overexpression of ornithine decarboxylase. Histone or Rb-associated kinase activities of cyclin complexes was elevated.

kin(p(MGI:Cdk2)) => p(MGI:Mybl2,pmod(P,T,267))

kin(p(MGI:Cdk2)) => p(MGI:Mybl2,pmod(P,T,408))

bp(GO:"response to UV-B") -> bp(MESHPP:Apoptosis)
p(HGNC:NGF) -| (bp(GO:"response to UV-B") -> bp(MESHPP:Apoptosis))

nerve growth factor overexpressing keratinocytes were partially resistant to apoptosis induced by increasing doses of ultraviolet B

bp(GO:"response to UV-B") -| r(HGNC:NGF)

ultraviolet B radiation downregulated nerve growth factor mRNA and protein

gtp(p(HGNC:HRAS)) -> p(HGNC:BAD,pmod(P))

kin(p(PFR:"Prka Family")) -> p(RGD:Creb1,pmod(P))

The present work provides evidence that cAMP, through PKA-mediated CREB phosphorylation, and phenobarbital induce ALA-S expression at the transcriptional level, while heme represses it.

cat(p(HGNC:RASGRF1)) -> gtp(p(HGNC:HRAS))

Site-directed mutagenesis replaced each of the serine residues within this region with alanine and demonstrated that serine 916 is a major site of in vivo phosphorylation of Ras-GRF1 in both COS-7 cells and NIH-3T3 fibroblasts.

a(SCHEM:Calcium) -> cat(p(HGNC:RASGRF1))

The activity of Ras-GRF1 is regulated by increases in intracellular calcium and the release of Gbetagamma subunits from heterotrimeric G-proteins.

a(SCHEM:"Concanavalin A") -> r(HGNC:IL4)

Interleukin 4 production by concanavalin A (Con A)-stimulated mesenteric lymph node cells (MLNC) was induced preferentially in infected +/+ mice.

kin(p(HGNC:ATM)) => p(HGNC:LIG4,pmod(P,S,199))

tscript(complex(NCM:"AP-1 Complex")) => r(MGI:Mmp13)

AP-1-dependent genes, such as collagenase (MMP-13) and stromelysin (MMP-3)

cat(p(HGNC:SLC25A4)) -> bp(MESHPP:Apoptosis)

Here, we describe the isolation of adenine nucleotide translocase-1 (ANT-1) in a screen for dominant, apoptosis-inducing genes.

cat(p(RGD:Xdh)) -> a(CHEBI:"reactive oxygen species")

The increased expression of P-selectin appears to be triggered by a mechanism dependent on free radicals generated by xanthine oxidase released by the damaged pancreas.

All five cell lines did not express FADD by immunoblot analysis and were completely resistant to Fas-induced death. Complementation of the FADD mutant cell lines with wild-type FADD restored Fas-mediated apoptosis. Fas activation of caspase-2, caspase-3, caspase-7, and caspase-8 and the proteolytic cleavage of substrates such as BID, protein kinase Cdelta, and poly(ADP-ribose) polymerase were completely defective in the FADD mutant cell lines. In addition, Fas activation of the stress kinases p38 and c-Jun NH2 kinase and the generation of ceramide in response to Fas ligation were blocked in the FADD mutant cell lines

tscript(complex(NCR:"Nfkb Complex")) -> tscript(p(RGD:Stat3))

We report that TNF induces DNA replication in growth-arrested LE6 cells and that its effect involves the activation of NFkappaB and STAT3 and an increase in c-myc and IL-6 mRNAs. We conclude that NFkappaB is an essential component of the TNF proliferative pathway and that TNF-induced changes in IL-6 mRNA, STAT3, and c-myc mRNA are dependent on NFkappaB activation.

The proto-oncogene product Cbl has emerged as a negative regulator of a number of protein-tyrosine kinases, including the ZAP-70/Syk tyrosine kinases that are critical for signaling in hematopoietic cells.

a(SCHEM:"LY 294002") -| p(HGNC:RAC1,pmod(P))

Akt kinase activity and Rac1 peptide phosphorylation were down-regulated by the treatment of SK-MEL28 cells with wortmannin or LY294002 (a phosphoinositide 3-kinase inhibitor), but JNK/SAPK kinase activity was up-regulated.

a(CHEBI:wortmannin) -> kin(p(HGNC:MAPK8))

Actinomycin D, but not cycloheximide, inhibited the p53 dependent DDA3 induction, suggesting that the activation is through transcriptional regulation and does not require de novo protein synthesis.

complex(p(HGNC:PRKCZ),p(HGNC:RAF1),p(HGNC:YWHAQ)) -> (kin(p(HGNC:PRKCZ)) => p(HGNC:RAF1,pmod(P)))
kin(p(HGNC:PRKCZ)) => p(HGNC:RAF1,pmod(P))

Together, the results suggest that 14-3-3 binds both PKC-zeta (at phospho-Ser-186) and Raf-1 in a ternary complex. Phosphorylation of 14-3-3beta by PKC-zeta negatively regulated their physical association. 14-3-3beta with its putative PKC-zeta phosphorylation sites mutated enhanced co-precipitation between PKC-zeta and Raf-1, suggesting that phosphorylation of 14-3-3 by PKC-zeta weakens the complex in vivo. We conclude that 14-3-3 facilitates coupling of PKC-zeta to Raf-1 in an isotype-specific and phosphorylation-dependent manner. We suggest that 14-3-3 is a transient mediator of Raf-1 phosphorylation and activation by PKC-zeta.

kin(p(HGNC:PRKCZ)) => p(HGNC:YWHAQ,pmod(P))

tscript(p(HGNC:"NKX2-5")) -> r(HGNC:IRX4)

These studies demonstrate that GATA6 is a direct target gene for Nkx2.5 in the developing heart and reveal a mutually reinforcing regulatory network of Nkx2.5 and GATA transcription factors during cardiogenesis.

bp(GO:"myoblast differentiation") -> r(HGNC:HSPB3)

The expressions of MKBP/HSPB2 and HSPB3 are induced during muscle differentiation under the control of MyoD, suggesting that the sHSP oligomer comprising MKBP/HSPB2 and HSPB3 represents an additional system closely related to muscle function.

tscript(p(HGNC:STAT3)) -| bp(MESHPP:Apoptosis)

The activation of STAT3 by the cytokine receptor gp130 is required for both the G1 to S cell cycle transition and antiapoptosis. #[JL] IL6ST is gp130

In transient cotransfection assays using CV1 cells with full-length human AR and a mouse mammary tumor virus luciferase reporter vector, there was an androgen-dependent 3- to 5-fold greater increase in luciferase activity with PIAS1 over that obtained with an equal amount of control antisense cDNA or mutant PIAS1

binding of L-glutamate to the class II metabotropic glutamate receptor, norepinephrine (NE)-dependent formation of cAMP was inhibited, resulting in decreased serotonin-N-acetyltransferase (NAT) activity and melatonin output.

Treatment of osteoblasts cells with 100 U/ml of TNF-alpha for 72 hours results in enhanced basal IL-11 production.

a(SCHEM:"Low Density Lipoprotein") -> r(HGNC:UBE2K)

we isolated the genes specifically induced by agLDL by using a subtraction-based cloning strategy. One of the cloned genes, termed low density lipoprotein (LDL)-inducible gene (LIG), encodes a human homologue of bovine ubiquitin-conjugating enzyme E2-25K. Although LIG mRNA was ubiquitously expressed among human tissues, including hematopoietic cells, the abundance of transcripts was markedly increased by agLDL treatment in activated monocytes.

kin(p(MGI:Fyn)) -> gtp(p(PFM:"Ras Family"))

In Fyn-/- fibroblasts, activation of Ras by H(2)O(2) was significantly attenuated.

phos(complex(NCM:"Calcineurin Complex")) -| p(MGI:Nfatc4,pmod(P))

Activation of the Adss1 gene involves the calcineurin-mediated dephosphorylation of NFAT3, allowing its translocation to the nucleus, where it can directly participate in Adss1 gene activation.

phos(complex(NCM:"Calcineurin Complex")) -> tscript(p(MGI:Nfatc4))

tscript(p(HGNC:MEF2C)) -> r(HGNC:ADSSL1)

cat(p(HGNC:GLRX3)) -| tscript(p(HGNC:FOS))

overexpression of full-length PICOT (but not its N- or C-terminal fragments) in T cells inhibited the activation of c-Jun N-terminal kinase and the transcription factors AP-1 or NF-kappaB.

a(CHEBI:"nitric oxide") -> a(SCHEM:"Cyclic GMP")

1) in endothelial cells PDE4 inhibition may up-regulate basal production of NO, this effect being potentiated by PDE2 inhibition; 2) in smooth muscle cGMP produced by NO inhibits PDE3 and increases cAMP level

cat(p(PFH:"PDE4 Family")) -| a(CHEBI:"nitric oxide")

cat(p(HGNC:PDE3A)) -| kin(p(HGNC:PRKG1))

3) protein kinase G mediates the relaxing effects of PDE3 or PDE4 inhibition

a(CHEBI:"nitric oxide") -| cat(p(PFH:"PDE4 Family"))

4) DNIC inhibits non competitively PDE4B indicating a direct effect of NO on PDE4 which could explain an additive vasodilatory effect of NO

tscript(p(HGNC:NCOR2)) -> cat(p(PFH:"HDAC Family"))

The transcriptional corepressor SMRT functions by mediating the repressive effect of transcription factors involved in diverse signaling pathways. Taken together, our results provide the first evidence that SMRT-mediated repression is promoted by class I and class II histone deacetylases and that SMRT can recruit class II histone deacetylases

Reduction in the expression levels of Nscl1 (dorsal -specific neuronal marker) was observed in the dorsal and medial telencephalic preplate of Ngn2 mutant at E12.5 as compared to wild-type. These results demonstrate that Ngn2 plays an important role in the upregulation of dorsal postmitotic markers leading to dorsal neuron specification.

The cytokine TGF-beta inhibits basal expression of Fas as well as cytokine-mediated Fas expression by microglia

cat(p(EGID:81638)) -> bp(GO:"cell adhesion")

Ang II induces integrin and alpha-actinin expression in cardiac fibroblasts that is associated with adhesion and left ventricular hypertrophy and blocked through inhibition of the AT(1) receptor.

path(SDIS:"mechanical stress") -> kin(p(HGNC:PTK2))

FAK is activated by the mechanical stretch of muscle (28, 57, 62). Interestingly, stretch activation of FAK and paxillin in smooth muscle is not dependent on tension development but only sensitive to muscle length changes (62).

Stretch has been shown to activate FAK in cardiac myocytes (57), smooth muscle (62), and skeletal muscle (28).

kin(p(PFH:"PRKA Family")) -> p(HGNC:STK11,pmod(P,S,431))

The predicted LKB1 protein sequence terminates with a conserved prenylation motif (Cys(433)-Lys-Gln-Gln(436)) directly downstream from a consensus cAMP-dependent protein kinase (PKA) phosphorylation site (Arg(428)-Arg-Leu-Ser(431)).

complex(p(HGNC:OMD),p(HGNC:ITGAV),p(HGNC:ITGB3)) -> bp(GO:"cell adhesion")

# Ariadne: It has been demonstrated that osteoadherin can mediate cell attachment via binding by alpha v eta 3 integrin in vitro ( 45 ). [Regulation]

path(SDIS:"mechanical stress") -> r(MGI:Hdgf)

Sequencing identified 4 differentially expressed genes enhanced by tracheal ligation: hepatoma-derived growth factor (HDGF), ribosomal protein S24, stathmin, and parathyroid hormone (PTH).

path(SDIS:"mechanical stress") -> r(MGI:Rps24)

path(SDIS:"mechanical stress") -> r(MGI:Stmn1)

phos(p(HGNC:PTEN)) -| complex(p(HGNC:EGF),p(HGNC:EGFR),p(HGNC:GAB1))

expression of the gene for the lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4, 5)P3, inhibits EGF signaling and translocation of Gab1 to the plasma membrane.

ER stress led to a twofold increase in JNK activity in wild-type fibroblasts, whereas in the IRE1alpha-^sup 1^- fibroblasts JNK activity was decreased by ER stress (Fig. 2B).

cat(p(HGNC:HSD11B1)) -> deg(a(SCHEM:Hydrocortisone))

Observations in obese men suggest enhanced inactivation of cortisol by 5alpha-reductase and altered reactivation of cortisone to cortisol by 11betahydroxysteroid dehydrogenase type 1 (11betaHSD1

cat(p(HGNC:SRD5A1)) -| a(CHEBI:glucocorticoid)

We conclude that greater inactivation of glucocorticoids by 5alpha-reductase in liver and 11betaHSD2 in kidney combined with impaired reactivation of glucocorticoids by 11betaHSD1 in liver may increase the MCR of glucocorticoids and decrease local glucocorticoid concentrations at these sites.

cat(p(HGNC:HSD11B1)) -> tscript(p(HGNC:NR3C1))

enhanced 11betaHSD1 in omental adipose tissue may increase local glucocorticoid receptor activation and promote obesity.

In myometrial SMC, both isoforms of the progesterone receptor, PR-B and PR-A, caused a ligand-dependent activation of PGDH-2368/luc3. Transcriptional activity of PR-B was further enhanced by the addition of 8-bromo-cAMP

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:HPGD)

PGDH promoter was strongly induced by phorbol ester

TR and the other two [13-cis-retinoic acid/isotretinoin and all trans-retinoic acid] retinoids dose-dependently induced tenascin-C expression in the fibroblasts.

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -| r(HGNC:ESR1)

Protein kinase A and phosphatidylinositol 3-kinase inhibitors blocked the IGF-I effects on ER-alpha expression and activity, suggesting that these kinases may be involved in the cross-talk between the IGF-I and ER-alpha pathways.

complex(p(HGNC:PTPN11),p(HGNC:EPHA2)) => phos(p(HGNC:PTPN11))

tscript(p(HGNC:MYBL2)) -> bp(GO:"DNA replication")

B-Myb is a transcription factor belonging to the myb family, whose activity has been associated with augmented DNA synthesis and cell cycle progression.

complex(p(HGNC:CDK9),p(HGNC:CCNT1)) -| (complex(p(HGNC:CDK9),p(HGNC:MYBL2)) -| tscript(p(HGNC:MYBL2)))
complex(p(HGNC:CDK9),p(HGNC:MYBL2)) -| tscript(p(HGNC:MYBL2))

Cyclin T1 restores B-Myb transactivating activity when co-transfected along with CDK9, suggesting that the down-regulatory effect observed on B-Myb is specifically due to CDK9 alone.

At the time of disease onset (day 7), a 2 to 5-fold increase in expression of CCR2 was observed. In GL3-treated mice, reduced levels of CCR2 was observed on day 6 and remained lower than in the EAE controls on day 7.

bp(GO:"muscle contraction") -> r(HGNC:GYG1)

For the first time, we report that a single bout of exercise is sufficient to cause upregulation of GLUT-4 and glycogenin gene expression in human skeletal muscle.

a(SCHEM:Sirolimus) -| (a(SCHEM:Sirolimus) -| p(HGNC:STAT3,pmod(P,S,727)))
a(SCHEM:Sirolimus) -| p(HGNC:STAT3,pmod(P,S,727))

We found that CNTF-induced phosphorylation of Ser727 was inhibited by the mTOR inhibitor rapamycin, but not by inhibitors of MAPK and protein kinase C (PKC) activation.

p(HGNC:NCOA1,pmod(P,S)) -> p(HGNC:NCOA1)

All the sites contained consensus sequences for the serine/threonine-proline-directed family of protein kinases, and two sites (serine 395 and threonine 1179) contained a perfect consensus sequence for the mitogen-activated protein kinase family (Erk-1 and Erk-2). % Erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro,

kin(p(HGNC:MAPK1)) => p(HGNC:NCOA1,pmod(P,S,395))

Despite appearing overtly normal, Vegfb(-/-) hearts are reduced in size and display vascular dysfunction after coronary occlusion and impaired recovery from experimentally induced myocardial ischemia.

cat(p(HGNC:PTGDS)) -> a(CHEBI:"prostaglandin D2")

Prostaglandin (PG) D synthase catalyzes the isomerization of PGH2, a common precursor of various prostanoids, to produce PGD2

cat(p(HGNC:MSR1)) -> bp(GO:"cell adhesion")

SRA has been shown to be important in the inflammatory response in host defense, cellular activation, adhesion, and cell-cell interaction. Given the importance of these processes in atherogenesis, these latter functions may prove to make the SRA a multifunctional player in the atherosclerotic process

TNF-alpha induced rapid biphasic increase in ERK1/2 phosphorylation which was detected as early as 2 minutes after addition of TNF-alpha and reached a maximum after 15 mins.

gtp(p(HGNC:RAC1)) -> tloc(p(HGNC:TWF1),GOCCACC:"GO:0005737",GOCCACC:"GO:0005634")

Furthermore, expression of the activated Rac1(V12) in NIH 3T3 cells leads to an increased A6/twinfilin localization to nucleus and cell cortex, whereas a dominant negative form of Rac1(V12,N17) induces A6/twinfilin localization to cytoplasm.

kin(p(MGI:Prkg1)) => complex(p(MGI:Gkap1),p(MGI:Prkg1))

Although both cGK-Ialpha and -Ibeta, but not cAMP-dependent protein kinase, phosphorylated GKAP42 in vitro, GKAP42 was a good substrate only for cGK-Ialpha in intact cells

Three DNA-protein complexes (C1, C3 and C4) were detected in control extracts and 4 complexes (C1, C2, C3 and C4) were detected in oncostatin M (OM)-treated nuclear extracts using a P32-labeled oligonucleotide probe (TATA1+2) containing LDLR promoter sequence -25 to +5. EMSA studies demonstrated that the C1 complex was completely supershifted by anti-c-Jun antibodies but none of these antibodies affected the C2 complex. The data suggest that the C1 complex may be a heterodimer of ATF and c-Jun; c-Jun is not present in the C2 complex. Additional gel shift assays using control extract showed a weaker supershift band with anti-c-Jun antibodies compared to the OM-treated extract, suggesting that OM stimulation may increase the c-Jun DNA-binding activity.

complex(p(HGNC:RBMS1),p(HGNC:MYC),p(HGNC:MAX)) -| tscript(p(HGNC:MYC))

^ MSSP, c-Myc and Max formed a ternary complex in vivo, although MSSP did not directly associate with Max.

p(HGNC:IL6) -> bp(GO:"lymphocyte differentiation")

Cultures of the myeloid leukemia cell line M1 were induced to terminally differentiate by treatment with interleukin-6 (IL-6).

# Ariadne: Other orphan receptors including RORalpha2, RORgamma and COUP-TFI are also potentiated by CaMKIV. [Regulation]

a(SCHEM:Calcium) -> tscript(p(HGNC:RORA))

Retinoid-related receptor alpha (RORalpha) is an orphan nuclear receptor that constitutively activates transcription from its cognate response element. We show that RORalpha is Ca(2+ )responsive, and a Ca(2+)/calmodulin-independent form of Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) potentiates RORalpha-dependent transcription 20- to 30-fold.

a(CHEBI:paclitaxel) -> p(HGNC:BCL2,pmod(P,S,87))

we have previously mapped taxol induced phosphorylation sites to be Ser-70 and 87 residues of Bcl2 protein

Moreover, the expression of Drg-1 is controlled by several known cell differentiation reagents, such as ligands of peroxisome proliferator-activated receptor gamma (troglitazone and BRL46593) and of retinoid X receptor (LG268), and histone deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and tributyrin).

kin(p(MGI:Mapk3)) => p(MGI:Bcl2,pmod(P,S,70))

p44MAPK/extracellular signal-regulated kinase 1 (ERK1) and p42 MAPK/ERK2 are activated by IL-3, colocalize with mitochondrial Bcl2, and can directly phosphorylate Bcl2 on Ser-70 in a stauro-resistant manner both in vitro and in vivo

Adrenomedullin inhibits angiotensin II stimulated aldosterone production in vitro and in vivo in experimental animals. Adrenomedullin selectively inhibits angiotensin II-stimulated aldosterone production.

a(SCHEM:Dinoprostone) -| bp(MESHPP:Apoptosis)

COX-2 synthesizes prostaglandin E2 (PGE2) which stimulates bcl-2 and inhibits apoptosis, and induces interleukin-6 (IL-6) which enhances haptoglobin synthesis. PGE2 is associated with tumor metastases, IL-6 with cancer cell invasion, and haptoglobin with implantation and angiogenesis

bp(GO:"response to oxidative stress") -> r(HGNC:PTGS2)

Dexamethasone, antioxidants, and tumor-suppressor protein p53 suppress COX-2 expression.

% Jubilant: IL-1beta upon inducing its own production in an autocrine/paracrine fashion, in turn, up-regulates IL-18 production at the protein level.

The Nos2 immunoreactivity in the CNS of IFN-gamma -/- mice or IFN-gamma-receptor-/- mice with EAE was barely detectable, whereas in SJL/J mice infiltrates were strongly stained for Nos2 during EAE.

p(HGNC:EGF) -> complex(p(HGNC:CBL),p(HGNC:SH3KBP1))

The CIN85-c-Cbl association was enhanced shortly after stimulation of 293 cells with epidermal growth factor (EGF) and gradually diminished to a basal level, which correlated with a tyrosine phosphorylation level of c-Cbl.

cat(p(MGI:Prdx5)) -| (tscript(p(MGI:Trp53)) -> bp(MESHPP:Apoptosis))
tscript(p(MGI:Trp53)) -> bp(MESHPP:Apoptosis)

Pubmed:gene: Mouse peroxiredoxin V is a thioredoxin peroxidase that inhibits p53-induced apoptosis.

kin(p(RGD:Prkcz)) -> (p(RGD:Fgf2) -> p(RGD:Gja1,pmod(P)))

We conclude that PKC mediates the FGF-2-induced effects on cardiac GJs and that PKCepsilon likely interacts with and phosphorylates cardiac Cx43 at sites of intercellular contact.

After 48 h of culture, parathyroid hormone, forskolin, dibutyryl cAMP, 8-bromo cAMP, and phorbol myristate acetate inhibited transgene activity, while the calcium ionophore ionomycin had no effect. These data show that the inhibitory effect of parathyroid hormone on Col1a1 expression in mouse calvariae is mediated mainly by the cAMP signaling pathway.

complex(p(HGNC:IL12A),p(HGNC:IL12B)) -| (p(HGNC:IL1B) -> a(SCHEM:Dinoprostone))

Consistent with these observations, IL-12, a known inducer of IFN-gamma, augmented IL-1beta-induced IFN-gamma but suppressed IL-1beta-induced PGE(2) by 75%.

complex(p(HGNC:IL12A),p(HGNC:IL12B)) -> p(HGNC:IFNG)

In the same cultures, IL-1beta induced a 12-fold increase in PGE(2). Although IL-1beta-induced IL-8 synthesis was augmented 3-fold by IL-18, IL-18 suppressed IL-1beta-induced PGE(2) production by 40%.

The suppressive effect of IL-18 on PGE(2) production was mediated by interferon (IFN)-gamma because anti-human IFN-gamma-antibody prevented IL-18-induced reduction in PGE(2).

kin(p(HGNC:PRKG1)) => p(HGNC:CRIP2,pmod(P,S,104))

5PC-12 cells stimulated with 100 ng per ml NGF showed increase in Ras activation after 5 minutes, which was maintained after 45 minutes of NGF stimulation

a(CHEBI:"reactive oxygen species") -> cat(p(HGNC:ALOX5))

Generation of endogenous ROS from mitochondria by antimycin A also lead to a threefold upregulation of 5-LO activity in B-cells

kin(p(PFH:"MAPK Erk1/3 Family")) => p(HGNC:SH2D3C,pmod(P,S))

treatment of cells with epidermal growth factor or nerve growth factor increased the phosphorylation level of Chat, phosphorylation of Chat by MAP kinase

tscript(complex(NCH:"Nfkb Complex")) -> bp(MESHPP:Apoptosis)

Administration of a LacZ-expressing adenoviral vector induces NFkB DNA and correlates with the up-regulation of Fas (CD95) mRNA

a(SCHEM:"Tetradecanoylphorbol acetate") -> kin(p(PFH:"PRKC Family"))

Phorbol-12-myristate-13-acetate, a PKC activator, robustly increased RGS2. This signal was attenuated by the PKC inhibitor GF 109203X (50 +/- 4%) and by phorbol-12, 13-dibutyrate-mediated down-regulation of PKC

a(CHEBI:"okadaic acid") -| (kin(p(PFR:"Prka Family")) -> r(RGD:Hmox1))
kin(p(PFR:"Prka Family")) -> r(RGD:Hmox1)

Simultaneous treatment with OA plus dibutyryl cAMP caused a synergistic up-regulation of steady-state levels of HO-1 mRNA, and the specific protein kinase A inhibitor KT5720 markedly reduced the OA-dependent HO-1 mRNA induction.

complex(p(MGI:Npy1r),p(MGI:Npy)) -> path(SDIS:"food intake")

The icv NPY-induced food intake was remarkably reduced in Y1-/- mice The Y1 receptor therefore plays a dominant role in NPY-induced feeding

CRH KO mice had significantly lower plasma epinephrine and higher norepinephrine than WT mice at baseline, and delayed epinephrine secretion during restraint.

a(SCHEM:Stanolone) -| bp(GO:"cell growth")

Exposure to high dose dihydrotestosterone (DHT) inhibits population growth of the human prostate carcinoma cell line, LNCaP.

kin(p(HGNC:PDPK1)) => kin(p(PFH:"PRKA Family"))

PDK1 has now been shown to play a central role in activating many of the AGC subfamily members (reviewed in [150,151]). Apart from phosphorylating PKB on Thr308, PDK1 phosphorylates the equivalent residues on PKC isoforms [48,152,153], p70-S6K [32,154], the three isoforms of SGK [27,28,155] and PKA [156] (Figure 6).

kin(p(HGNC:PDPK1)) => kin(p(PFH:"PRKC Family"))

a(CHEBI:"reactive oxygen species") -> bp(GO:"response to oxidative stress")

Free radicals and other ROS are generated by all aerobic cells and are known to participate in a wide variety of deleterious reactions [1]. A number of studies have also demonstrated that bursts of oxidant production as well as dramatic changes in the activities of various antioxidant defenses are closely associated with alterations in gene expression in a variety of tissues from phylogenetically diverse organisms [1-3]. Free radical reactions have been observed to influence molecular and biochemical processes and to directly cause some of the changes observed in cells during differentiation, aging, and transformation [3-9]. These observations have been interpreted to suggest that cells evolved strategies to utilize ROS as biological stimuli [2,8 -11]. Furthermore, ROS and antioxidants are known to influence the expression of a number of genes and signal transduction pathways [1,12-17] and are thought to act as subcellular messengers for certain growth factors [11,13,18,19]. Indeed, the last decade has seen rapid if not explosive growth in the number of genes shown to be influenced by redox changes as well in as those that exert downstream effects through increased ROS formation. This review article is intended to provide a convenient summary of known redox effects on gene expression. Because nearly half of the effects discussed involve members of the MAP kinase and NF-kB signaling pathways or genes regulated by these pathways, a detailed discussion of these signal transduction pathways is also presented. Although we have intentionally kept our overview brief, we include a short discussion of the various species and tissue-specific differences in redox effects that are known to exist as well a summary of the molecular basis of some of these differences. Cell state transitions leading to transformation, differentiation, and senescence tend to cause large changes in cellular redox state. Our discussion concludes with a brief overview of potential consequences of redox changes for signaling pathways during the cellular transitions. OXIDANTS AND ANTIOXIDANTS MODULATE GENE EXPRESSION A number of genes and cellular pathways are now thought to be regulated by variations in cellular redox status. Identification of redox-sensitive genes and pathways has culminated from a number of independent studies and multiple strategies of detection. Changes in cellular redox state can modulate transcriptional activation of collagen [20] and collagenase [21], post-transcriptional control of ferritin [22,23], and activation of transcription factors such as Myb [24] and Egr-1 [25] as well as the binding activity of the fos/jun (AP-1) protein conjugate [9,26]. Several proto-oncogenes are known to be transcriptionally activated by increased cellular oxidation. For example, exposure of both normal and transformed cells to UV radiation or to H2O2 stimulates increased expression of jun-B, jun-D, c-fos, and fos-B [27-34]. Extensive analysis of this effect by several laboratories has revealed that the influence of H2O2 treatment on c-fos as well as on other early response genes such as c-jun and c-myc is to some extent mediated by PKC [27,29,30,32,35,36]. Presently, the exact sequence of events leading to induction of c-fos transcription after an oxidizing stimulus remains unclear. H2O2 has been used frequently as an oxidative stimulus to identify redox-sensitive genes. For example, Crawford and his colleagues [37-40] used differential display to isolate a number of oxidation-sensitive genes (the so-called 'adapt genes') from hamster fibroblasts treated with H2O2. Although the identity of some of these genes remains unknown, adapt 66 was found to be a homologue of mafG [38], adapt 73 is homologous with a cardiac shock response gene (PigHep3) [41], and adapt 78 is a critical gene associated with Down's syndrome [40]. A specific protein tyrosine-phosphatase has been isolated from H2O2-stimulated human cells...

TAK1, a member of the mitogen-activated kinase kinase kinase family, is activated in vivo by various cytokines, including interleukin-1 (IL-1), or when ectopically expressed together with the TAK1-binding protein TAB1. However, this molecular mechanism of activation is not yet understood. We show here that endogenous TAK1 is constitutively associated with TAB1 and phosphorylated following IL-1 stimulation. Furthermore, TAK1 is constitutively phosphorylated when ectopically overexpressed with TAB1. In both cases, dephosphorylation of TAK1 renders it inactive, but it can be reactivated by preincubation with ATP. A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192.

p(PFR:"Plcg Family") -> kin(p(PFR:"Prkc Family"))

PC12-E2 cells were treated with the specific PKC inhibitor Calphostin C (400 nM). This treatment led to an inhibition of NCAM-dependent neurite outgrowth. These results confirm that NCAM signaling involves the FGF receptor and PLCgamma and indicate a thus far unrecognized role for PKC in NCAM stimulated outgrowth.

In contrast, GATA4 expression was enhanced after Noggin treatment.

After 24 h of exposure of T47-D cells to either 1 or 10 microM progesterone, we observed a marked down-regulation of protooncogene bcl-2 protein and mRNA levels.

a(CHEBI:progesterone) -| bp(GO:"cell proliferation")

Progesterone inhibits the proliferation of normal breast epithelial cells in vivo, as well as breast cancer cells in vitro.

a(CHEBI:progesterone) -> bp(MESHPP:Apoptosis)

progesterone at relative high physiological concentrations, but comparable to those seen in plasma during the third trimester of human pregnancy, exhibited a strong antiproliferative effect on breast cancer cells and induced apoptosis.

Interleukin 1alpha (IL-1alpha), IL-1beta, IL-3, IL-6, IL-8, tumour necrosis factor (TNF-alpha) and SCF (both at 10 ng/ml) stimulate LIF production.

tscript(p(HGNC:"NKX2-5")) -> r(HGNC:NAB2)

tBH treatment of hRPE cells resulted in increased expression of FasL and Fas. Glutathione and NAC completely abrogated tBH-induced increase in FasL and Fas expression

p(MGI:Lif) -> bp(GO:"macrophage chemotaxis")

Leukaemia inhibitory factor is required for normal inflammatory responses to injury in the peripheral and central nervous systems in vivo and is chemotactic for macrophages

kin(p(HGNC:ATM)) => p(HGNC:EIF4EBP1,pmod(P,S,11))

complex(p(HGNC:CD44),p(HGNC:FGF4)) => p(HGNC:FGF4)

# Ariadne: In addition, CD44 HSPG isoforms identified in the embryonic mouse apical ectodermal ridge have been shown to bind and present FGF-4 and FGF-8 during limb bud development in embryonic mice ( 22 ) and CD44 HSPGs from tumor cells have been shown to present hepatocyte growth factor as a mechanism to increase tumor cell dissemination ( 23 ). [Binding]

complex(p(HGNC:CD44),p(HGNC:FGF2)) -> kin(p(HGNC:FGFR1))

Furthermore, we show these isoforms are preferentially modified with heparan rather than chondroitin sulfate, bind the macrophage-derived growth factors FGF-2, vascular endothelial growth factor, and heparin-binding epidermal growth factor with varying affinities (K(d) 25-330 nM) and in the case of FGF-2, can stimulate productive binding to the high affinity tyrosine kinase FGF receptor 1 (FGFR1).

kin(p(HGNC:MAP2K4)) -> (kin(p(HGNC:MAP2K7)) -> kin(p(HGNC:MAPK10)))
kin(p(HGNC:MAP2K7)) -> kin(p(HGNC:MAPK10))

Measuring catalysis under Vmax conditions showed MKK4 + MKK7-activated JNK3 alpha 1 had Vmax 715-fold greater than nonactivated JNK3 alpha 1 and MKK7-activated JNK3 alpha 1 had Vmax 250-fold greater than nonactivated JNK3 alpha 1

kin(p(HGNC:MAP2K7)) -> p(HGNC:MAPK10,pmod(P,T))

These data suggest that MKK7 was largely responsible for JNK3 alpha 1 activation and that a single threonine phosphorylation may be all that is needed for JNK3 alpha 1 to be active

a(CHEBI:"trichostatin A") -| bp(GO:"G1/S transition of mitotic cell cycle")

Butyrate blocked cells mainly in the G(1) phase of the cell cycle, whereas trichostatin A was inhibitory in both G(1) and G(2) phases.

a(CHEBI:"trichostatin A") -| r(HGNC:CCND1)

Trichostatin A showed similar effects on cyclin D1 and D3. Butyrate and trichostatin A stimulated p21 expression both at the mRNA and protein levels

Microinjection studies show that Fgd3 stimulates fibroblasts to form filopodia, actin microspikes formed upon the stimulation of Cdc42

Serine 307 is a major site of JNK phosphorylation in IRS-1. Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function.

p(HGNC:ATF1,pmod(P)) => tscript(p(HGNC:ATF1))

ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinase. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.

kin(p(HGNC:MAPK1)) => p(HGNC:ELK4,pmod(P))

We further find that the FAP1 site binds ATF1 and CREB from HeLa nuclear extracts and that the phosphorylation of these factors is induced by TPA. ATF1 and CREB can be phosphorylated by Rsk2(RPS6KA3) which is a protein kinase directly activated by Erk (MAPK1) MAP kinases. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.

In clones of REF/Myc ectopically expressing eIF4E, resistance to apoptosis paralleled steady state levels of cyclin D1.

p(RGD:Ccnd1) -> bp(GO:"cell proliferation")

a(CHEBI:"nitric oxide") -> r(RGD:Akr1b1)

Spontaneous NO donors, S-nitroso-N-acetylpenicillamine (SNAP) and 3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamin e, elicited a dose-dependent increase in AR mRNA to a maximum of 7-fold in 12 h.

a(CHEBI:"hydrogen peroxide") -> complex(p(RGD:Egfr),p(RGD:Shc1),p(RGD:Grb2),p(RGD:Sos1))

H2O2 induced the phosphorylation of the EGF receptor and the formation of a receptor complex comprising Shc, Grb2, Sos, and the EGF receptor

NGF induces transcription of the RA-synthesizing enzyme RALDH-2, as well as detectable release of newly synthesized all- trans -RA.

p(HGNC:IL6) -> a(SCHEM:"1-Alkyl-2-acetyl-sn-glycero-3-phosphocholine")

Cells and organs producing PAF in response to exogenous stimulations Neutrophils Human IL-6 Human GM-CSF and zymosan Eosinophils Human IgG, IL-5, PMA Monocytes Human LPS [361] Human HIV infection Peritoneal macrophages Mouse HGF, TNF-a Lung mast cells Human Anti-IgE [363] Bone marrow mast cells Mouse Monoclonal IgE and antigen

cat(p(HGNC:TLR4)) -> a(SCHEM:"1-Alkyl-2-acetyl-sn-glycero-3-phosphocholine")

# Jubilant: PERP is a direct target of 53, involved in p53-dependent apoptosis. High level PERP expression correlated with the induction of cell death, with 21 percent of cells undergoing apoptosis by 16 hours. Accumulation of high levels of PERP gene expression is dependent on p53, E1A and DNA damage which are all essential for E1A-induced apoptosis in mouse endothelial fibroblasts.

To investigate the regulation of the CCR1 chemokine receptor, a rat basophilic leukemia (RBL-2H3) cell line was modified to stably express epitope-tagged receptor. These cells responded to RANTES (regulated upon activation normal T expressed and secreted), macrophage inflammatory protein-1alpha, and monocyte chemotactic protein-2 to mediate phospholipase C activation, intracellular Ca(2+) mobilization and exocytosis.

NAB2 overexpression blocked NGF-dependent differentiation and prevented NGF induction of TGF-beta1, MMP3 and p21waf1

tscript(p(PFH:"E2F Family")) -> r(HGNC:CDKN2A)

a feedback loop exists through which ARF levels are negatively regulated by p53. Significantly, ARF expression is positively regulated by members of the E2F family of transcription factors

a(CHEBI:"carbon monoxide") -| r(HGNC:IL1B)

Both in vivo and in vitro, carbon monoxide at low concentrations differentially and selectively inhibited the expression of lipopolysaccharide-induced pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-1beta and increased the lipopolysaccharide-induced expression of the anti-inflammatory cytokine interleukin-10.

a(CHEBI:"reactive oxygen species") -> kin(p(RGD:Syk))

These data indicate that endogenous reactive oxygen species are necessary for the activation of p56(Hck), p72(Syk), and p77(Btk) by spores; they also indicate that some species of spores are capable of activating tyrosine kinases independent of superoxide anion.

a(SCHEM:"serum leptin") -| r(HGNC:TMED9)

By using this process we have identified five genes (POMC, PC2, prolactin, HSGP25L2G, and one novel) that are both abnormally expressed in the pituitaries of obese mice and are sensitive to the effects of leptin POMC, PC2 and HSGP25L2G expressions were decreased in response to leptin and prolactin expression was increased

a(SCHEM:fibrate) => tscript(p(HGNC:PPARA))

Fibrates are widely used hypolipidemic drugs that regulate the expression of many genes involved in lipid metabolism by activating the peroxisome proliferator-activated receptor alpha (PPARalpha)

cat(p(RGD:Adora1)) -| a(SCHEM:"serum leptin")

Rats were treated with the A1AR agonist N6-cyclopentyladenosine (CPA), and changes in circulating levels of leptin and leptin gene expression were examined. Serum leptin levels rose 2- to 10-fold, with peak increases seen 8-16 h after injection of CPA (P < 0.05)

a(CHEBI:"trichostatin A") -| r(HGNC:TAF9)

trichostatin A (TSA), an inhibitor of histone deacetylases Complex hybridization of cDNA arrays revealed repression of Bcl-xL, CRAB2 and TFIID/TAFII31 as well as induction of p21waf1/cip1, GATA-2, hsp86, ID1, ID2 and ID3 mRNA expression, which could be verified by Northern blotting.

a(CHEBI:"trichostatin A") -> r(HGNC:ID2)

a(CHEBI:"trichostatin A") -> r(HGNC:ID3)

tyrosine phosphorylation of STAT3, JAK1, and JAK2 was increased upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected with the respective STAT or JAK expression vector.

p(HGNC:TNF) -> kin(complex(NCH:"CK II Complex"))

Here we demonstrate that the stress signaling agents anisomycin, arsenite, and tumor necrosis factor-alpha stimulate the specific enzyme activity of CK2 in the human cervical carcinoma HeLa cells by up to 8-fold, and this could be blocked by the p38 MAP kinase inhibitor SB203580.

tscript(p(MGI:Cebpb)) -| path(SDIS:"muscle insulin receptor signaling pathway")

These results demonstrate that C/EBPbeta deletion decreases plasma FFA levels and increases insulin signal transduction specifically in skeletal muscle, and both contribute to increased whole-body insulin sensitivity.

tscript(complex(NCM:"AP-1 Complex")) -> r(MGI:Trp53)

ability of v-Maf to activate p53 expression

DNA binding assays and cell transfection experiments revealed that the bipartite core sequence of FPB (5'-ATCAATCA-3') binds the PBX1/2, PREP1, and HOXB1 proteins, and this in turn leads to promoter transactivation.

tscript(p(HGNC:PKNOX1)) => r(HGNC:COL5A2)

tscript(p(HGNC:ZNF202)) =| r(HGNC:APOC3)

Additional fragments derived from the promoters of phospholipid transfer protein and hepatic nuclear factor-4 (HNF4) and the apoCIII enhancer that had been shown to bind GST.ZF3-8 in vitro were also used in reporter assays. Transcriptional repression in the presence of ZNF202 was similar to the one observed for the apoE and apoAIV promoters (Table I)

tscript(p(HGNC:ZNF202)) =| r(HGNC:APOA4)

Fig. 6. Repression of apoAIV and apoE promoters by ZNF202 m1 in HepG2 cells. ......we used several reporter constructs containing portions of the apoE and apoAIV genes; these fragments all had been shown to bind ZNF202 in gel shift experiments.

In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IkappaB kinases (IKKs) and JNK. Consequently, IL-17-induced IL-6 and intercellular adhesion molecule 1 expression in the TRAF6-deficient cells was abolished.

p(MGI:Traf6) -> (p(MGI:Il17a) -> p(MGI:Icam1))

p(MGI:Il17a) -> kin(p(PFM:"Mapk JNK Family"))
p(MGI:Traf6) -> (p(MGI:Il17a) -> kin(p(PFM:"Mapk JNK Family")))

phosphorylation of extracellular signal-regulated kinase (ERK), but not of c-Jun NH2-terminal kinase or p38, was induced by cross-linking of Fas

p(MGI:Irs1) -> bp(GO:"cell differentiation")

osteoblasts from homozygous deficient mice treated with insulin or IGF1 failed to induce tyrosine phosphorylation of cellular proteins and showed reduced proliferation and differentiation

p(MGI:Irs1) -> bp(GO:"cell proliferation")

Administration of norepinephrine to rats and isoproterenol to mice stimulated MT and UCP1 expression in BAT, implying a sympathetically mediated pathway for MT induction.

Both RGS3 and RGS3T bound to endogenous Galpha(q/11) and inhibited endothelin-1-stimulated calcium mobilization and mitogen-activated protein kinase activity to a similar extent.

cat(p(HGNC:EDNRA)) -> kin(p(PFH:"MAPK Erk1/3 Family"))

The sequences of the other cDNA fragments were identical to those of contrapsin, transketolase, and vanin-3. The latter two were up-regulated, whereas contrapsin was down-regulated in neonatal MT-null mice.

We observed that several other focal adhesion components, including focal adhesion kinase (FAK) and the adaptor molecules Crk and Crk-L, are phosphorylated on SDF-1alpha stimulation.

kin(p(HGNC:MET)) -> a(SCHEM:"Guanine-nucleotide-releasing factor")

The results presented here delineate a novel signaling pathway from HGF to the GTPase Rap1 which depends on the interaction of the adapter protein CRKL with the exchange factor C3G and could be linked to cell migration.

kin(p(PFH:"AKT Family")) -> cat(p(HGNC:BAD))

IL-4-producing CD30+ clones also produced high levels of IL-10. The production of IL-10 by CD30+ clones was much higher in early than in late Rheumatoid Arthritis.

tscript(p(PFM:"Nfat Family")) -> tscript(p(MGI:Egr2))

The transcription factors Egr2 and Egr3 are potent activators of FasL expression

tscript(p(PFM:"Nfat Family")) -> tscript(p(MGI:Egr3))

Similar responses are observed for the serum and glucocorticoid-regulated kinase and channel-inducing factor genes. All four genes show clear and rapid up-regulation of their mRNA levels by aldosterone, which is paralleled by GR-mediated up-regulation of expression.

bp(GO:"histone deacetylation") -| r(MGI:Mat2a)

evaluated Mat1a and Mat2a methylation in liver and in other tissues, such as kidney Mat1a is hypomethylated in liver and hypermethylated in non-expressing tissues the opposite situation is found in Mat2a histones associated to Mat1a and Mat2a genes showed enhanced levels of acetylation in expressing tissues

# Jubilant: It was proved that Reactive oxygen species generation was dependent on P22-PHOX subunit of NADPHoxidase. Transfection with antisense P22-PHOX oligonucleotides reduced the Angiotensin induced Reactive oxygen species induction

cat(p(RGD:Agtr1b)) -> (cat(p(RGD:Cyba)) -> kin(p(RGD:Mapk14)))

Ang II also induced the rapid formation of ROS, which could be inhibited by a specific antibody as well as by antisense against the p22phox subunit of the NAD(P)H oxidase. JNK and p38 MAPK, but not ERK, activation was inhibited by an inhibitor of NAD(P)H oxidase. Antisense against p22phox also solely inhibited p38 MAPK but did not affect ERK.

cat(p(RGD:Agtr2)) -> (cat(p(RGD:Cyba)) -> kin(p(RGD:Mapk14)))

a dominant-negative mutant of nuclear factor-kappaB-inducing kinase also promoted TNFalpha- and Fas-mediated apoptosis. Expression of either crmA or a dominant-negative mutant of the Fas-associated death domain protein prevented TNFalpha- and Fas-mediated apoptosis. In addition, the caspase inhibitors, DEVD-cho and IETD-fmk, inhibited TNFalpha- and Fas-mediated apoptosis. In Ad5IkappaB-infected hepatocytes, caspases-3 and -8 were activated within 2 h after treatment with anti-Fas antibody or within 6 h after TNFalpha treatment

p(MGI:Cftr) -> sec(a(SCHEM:"Chloride(1-)"))

1. The isoflavone genistein may either stimulate or inhibit cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels. To investigate how genistein inhibits CFTR, we studied CFTR Cl- channels in excised inside-out membrane patches from cells expressing wild-type human CFTR. 2. Addition of genistein (100 microM) to the intracellular solution caused a small decrease in single-channel current amplitude (i), but a large reduction in open probability (Po). 3. Single-channel analysis of channel block suggested that genistein (100 microM) may inhibit CFTR by two mechanisms: first, it may slow the rate of channel opening and second, it may block open channels. 4. Acidification of the intracellular solution relieved channel block, suggesting that the anionic form of genistein may inhibit CFTR. 5. Genistein inhibition of CFTR Cl- currents was weakly voltage dependent and unaffected by changes in the extracellular Cl- concentration. 6. Channel block was relieved by pyrophosphate (5 mM) and ATP (5 mM), two agents that interact with the nucleotide-binding domains (NBDs) of CFTR to greatly stimulate channel activity. 7. ATP (5 mM) prevented the genistein-induced decrease in Po, but was without effect on the genistein-induced decrease in i. 8. The genistein-induced decrease in i was voltage dependent, whereas the genistein-induced decrease in Po was voltage independent. 9. The data suggest that genistein may inhibit CFTR by two mechanisms. First, it may interact with NBD1 to potently inhibit channel opening. Second, it may bind within the CFTR pore to weakly block Cl- permeation.

a(CHEBI:troglitazone) -| r(HGNC:SERPINE1)

By contrast, in human aortic smooth muscle cells, 3 microg/mL troglitazone decreased basal PAI-1 expression by 23% (P = 0.037) and decreased transforming growth factor-beta-induced expression by 34% (P = 0.026).

Cullin-1, a component of SCF, is modified by ubiquitin-like protein Nedd8. The modification site of cullin-1 was shown to be K696 because the K696R mutant was not modified. When the effect of the Nedd8 modification on the SCF(skp2) activity toward p27(kip1) was investigated, the activity was markedly decreased by using the Nedd8-unmodified mutant cullin-1 (K696R), indicating that the modification may play an important role on the SCF(skp2) activity toward p27(kip1).

tscript(p(HGNC:NR2F2)) -| bp(GO:"cell growth")

Introduction of COUP-TFII to MDA-MB-435 cells resulted in reduced growth and plating efficiency. Interestingly, COUP-TFII increased the expression of cyclin D1 and p21(WAF1/CIP1) in MDA-MB-435 cells

Putative binding sites for the erythroid-specific nuclear factors GATA-1, NF-E2, and EKLF were identified within the first 300bp region of the mouse ALAS2 5'-flanking region

Treatment with TNFalpha at concentrations of 0.1-10 ng/ml resulted in a dose dependent increase in 11beta-HSD1 reductase activity from 1.5 to 10-fold. Insulin (0.1-100 nM) had no effect under basal conditions, but inhibited the stimulatory effects of TNFalpha (5 ng/ml) on 11beta-HSD1 reductase activity in a dose dependent fashion (8-66%) inhibition).

In addition, B1 receptor activation by des-Arg(10)-kallidin induced a rise in cytosolic Ca(2+) that is consistent with B1 receptor pharmacology.

phos(p(MGI:Pten)) -| kin(p(PFM:"Akt Family"))

a(CHEBI:glucocorticoid) -| r(RGD:Atp2b1)

PMCA1 was repressed approximately 33% after a high, but not a low dose of the GC, corticosterone (B), suggesting glucocorticoid (but not mineralocorticoid) receptor-mediated repression.

p(HGNC:IKBKB,pmod(P,S,181)) => kin(p(HGNC:IKBKB))

Phosphorylation of two closely spaced serine residues in this domain, at positions 176 and 180 in IKK? and positions 177 and 181 in IKK?, has been shown to be important for IKK kinase activity (22).

kin(p(HGNC:CHUK)) => p(HGNC:NFKBIA,pmod(P,S))

Two related kinases, IkappaB kinase alpha (IKKalpha) and IKKbeta, phosphorylate the IkappaB proteins, leading to their degradation and the subsequent activation of gene expression by NF-kappaB

UGT2B7 promoter activity with the HNF1/AT-rich element was stimulated by cotransfection with HNF1alpha.

This study determined that the guanosine diphosphate (GDP)-dissociation inhibitor RhoGDI is overexpressed at the protein level in patients' neutrophils and that overexpression is a result of G-CSF treatment.

tscript(p(HGNC:EP300)) => tscript(p(HGNC:AR))

p300 and p300/cAMP-response element-binding protein acetylated the AR at a highly conserved lysine-rich motif carboxyl-terminal to the zinc finger DNA-binding domain. [(14)C]acetate-labeling experiments demonstrated that AR acetylation by p300 in cultured cells requires the same residues identified in vitro. Point mutation of the AR acetylation site (K632A/K633A) abrogated dihydrotestosterone-dependent transactivation of the AR in cultured cells.

cat(p(HGNC:F2)) -> bp(GO:"platelet activation")

Stimulation of human platelets with thrombin or thrombin receptor agonist peptide (TRAP/ Ser-Phe-Leu-Leu-Arg-Asn) resulted in phosphorylation of the protease-activated receptor 1 (PAR1)

The transfection of the TOPK gene to COS-7 cells up-regulated a phosphorylation of p38 MAPK but not ERK1/2 or SAPK/JNK.

PA28 is an interferon-gamma inducible modulator of proteasome function composed of two subunits, i.e. PA28alpha and PA28beta.

tscript(p(HGNC:SMAD7)) -| tscript(p(HGNC:SMAD3))

Smad7 was recently shown to antagonize TGF-beta-induced activation of signal-transducing Smad2 and Smad3 proteins

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:CSF2)

GM-CSF promoter constructs were cloned and stably transfected into A549 cells (Figure 5A). All three constructs gave rise to similar levels of inducibility (Figures 5B and 6A–6C). Induction of these constructs by IL-1b was only 1.5- to 2-fold and induction by PMA was 3- to 6-fold (Figure 5),

we demonstrate that two of the early events after Fas ligation are the release of cytochrome c from the mitochondria and activation of caspase-9

p(MGI:Ifng) -> sec(p(PFM:"Txnrd Family"))

we analyzed the expression of TrxR in peripheral blood cells, tumor-transformed leukemia, and melanoma cells and found, in addition to abundant plasma membrane localization, that TrxR was released from these cells. The release was inducible, and physiological stimulation of human monocytes by IFN-gamma, lipopolysaccharide, and interleukin 1alpha significantly increased the number of TrxR-secreting cells

path(SDIS:"laminar shear stress") -| complex(NCH:"NADH Dehydrogenase Complex")

path(SDIS:"laminar shear stress") -> r(HGNC:EGR1)

path(SDIS:"laminar shear stress") -> r(HGNC:F3)

path(SDIS:"laminar shear stress") -> r(HGNC:HMOX1)

cat(p(HGNC:SERPINB9)) -| (cat(p(HGNC:CASP1)) -> p(HGNC:IL18))

We report here that the serine proteinase inhibitor (serpin) PI-9 accounts for the endogenous caspase-1 inhibitory activity in human SMCs and prevents processing of the enzyme's natural substrates, IL-1beta and IL-18 precursor.

p(MGI:Cabin1) -| phos(complex(NCM:"Calcineurin Complex"))

differentiation is inhibited at the commitment stage by either treatment with the calcineurin inhibitor cyclosporine A (CSA) or expression of CAIN, a physiological inhibitor of calcineurin.

a(CHEBI:heparin) -> (p(HGNC:IFNG) -> bp(GO:"inflammatory response"))
p(HGNC:IFNG) -> bp(GO:"inflammatory response")

It is known that IFN-gamma can bind cell surface and extracellular heparan sulphate. Furthermore, soluble heparin can inhibit the function of this cytokine, presumably by competitive displacement from the cell surface

a(CHEBI:"vitamin E") -| cat(p(PFR:"Pla2 Family"))

At the posttranslational level, alpha-tocopherol inhibits protein kinase C, 5-lipoxygenase and phospholipase A2 and activates protein phosphatase 2A and diacylglycerol kinase

cat(p(HGNC:CASP1)) -> cat(p(HGNC:CASP8))

These results demonstrate an additional and novel function for caspase-1 in which Pro-C1 acts to enhance Fas-mediated apoptosis, most probably through facilitation of the activation of caspase-8

kin(p(PFH:"PRKC Family")) -> r(HGNC:COL1A2)

# Ariadne: On the other hand, previous studies have shown that acetaldehyde induces the levels of c-Jun through a PKC-dependent mechanism and enhances murine alpha2(I) collagen promoter mediated by PKC activation ( 46 , 47 ). [Expression]

VEGF production induced by IL-1beta, TNF-alpha, and TGF-beta was further increased when CD40L+ L cells were coincubated, by factors of 5.9, 5.5, and 9.6, respectively, which indicated that these cytokines had an additive effect on VEGF production driven by CD40L.

tscript(complex(NCM:"AP-1 Complex")) -> (a(SCHEM:Dinoprostone) -> r(MGI:Cd14))

# Ariadne: Therefore, the present study demonstrates that PGE 2 has the ability to stimulate AP-1-mediated expression of CD14 in mouse macrophages via cAMP-dependent protein kinase A. [Expression] # Ariadne: PGE 2 -stimulated expression of CD14 was inhibited by antisense c- fos and c- jun oligonucleotides, but not by their sense oligonucleotides. [Expression]

kin(p(PFM:"Prka Family")) -> (a(SCHEM:Dinoprostone) -> r(MGI:Cd14))

Protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5- isoquinolinesulfonamide (H-89), but not protein kinase C inhibitor 3-(1-[3- (dimethylamino)propyl]-1H- indol-3-yl)-4-(1H-indol-3-yl)-1H-py rrole-2,5-dione (GF109203X), abolished the stimulated expression of CD14.

we investigated the effect of PG on CD14 expression in mouse macrophages. PGE1, PGE2, and PGA1 among the PGs tested strongly stimulated the expression of the CD14 gene in the cells.

a(CHEBI:"prostaglandin A1") -> r(MGI:Cd14)

cat(p(HGNC:PLAU)) -> bp(GO:"DNA replication")
tloc(p(HGNC:PLAU),GOCCACC:"GO:0005886",GOCCACC:"GO:0005737") -> (cat(p(HGNC:PLAU)) -> bp(GO:"DNA replication"))

PAs mitogenic stimulation of serum-starved cells was associated with the internalization of their molecules

kin(p(PFH:"PRKC Family")) -> r(HGNC:JUN)

The biological activity of u-PA, t-PA, as well as that of limiting concentration of FCS (1%), was mediated by PTK and PKC.

kin(p(PFH:"PRKC Family")) -> r(HGNC:MYC)

cat(p(HGNC:EP300)) -> tport(p(HGNC:KPNA2))

Using an antibody raised against an acetylated Rch1 peptide, we show that Rch1 was acetylated at Lys22 in vivo and that CBP or p300 could mediate this reaction Acetylation of Lys22 promoted interaction with importin-beta in vitro

Factor XII deficiency has been postulated to be a risk factor for thrombosis suggesting that factor XII is an antithrombotic protein. The biochemical mechanism leading to this clinical observation is unknown. We have previously reported high molecular weight kininogen (HK) inhibition of thrombin-induced platelet aggregation by binding to the platelet glycoprotein (GP) Ib-IX-V complex. Although factor XII will bind to the intact platelet through GP Ibalpha (glycocalicin) without activation, we now report that factor XIIa (0. 37 microm), but not factor XII zymogen, is required for the inhibition of thrombin-induced platelet aggregation. Factor XIIa had no significant effect on SFLLRN-induced platelet aggregation. Moreover, an antibody to the thrombin site on protease-activated receptor-1 failed to block factor XII binding to platelets. Inhibition of thrombin-induced platelet aggregation was demonstrated with factor XIIa but not with factor XII zymogen or factor XIIf, indicating that the conformational exposure of the heavy chain following proteolytic activation is required for inhibition. However, inactivation of the catalytic activity of factor XIIa did not affect the inhibition of thrombin-induced platelet aggregation. Factor XII showed displacement of biotin-labeled HK (30 nm) binding to gel-filtered platelets and, at concentrations of 50 nm, was able to block 50% of the HK binding, suggesting involvement of the GP Ib complex. Antibodies to GP Ib and GP IX, which inhibited HK binding to platelets, did not block factor XII binding. However, using a biosensor, which monitors protein-protein interactions, both HK and factor XII bind to GP Ibalpha. Factor XII may serve to regulate thrombin binding to the GP Ib receptor by co-localizing with HK, to control the extent of platelet aggregation in vivo.

its immunoreactivity with RS-11 is up-regulated by malignant transformation or stimulation with either epidermal growth factor or transforming growth factor alpha.
kin(p(HGNC:MAPK14)) => p(HGNC:MEF2C,pmod(P,T,293))
# Ariadne: Collectively, these results support the concept that p38 kinase targets MEF2C at a unique site (Thr293), whose phosphorylation is required to stimulate MEF2- dependent transcription during muscle differentiation. [MolTransport]
p(HGNC:IL10) -| bp(GO:"macrophage activation")
Interleukin (IL)-10 suppresses macrophage activation and down-regulates proinflammatory cytokine production
p(HGNC:INSR,pmod(P,Y)) => kin(p(HGNC:INSR))
PTPN1 binding is required for the physiological effects of PTPN1 on IR signaling transduction (dephosphorylation)
a(SCHEM:"SF 2370") -| (a(SCHEM:"Tetradecanoylphorbol acetate") -> p(MGI:Optn,pmod(P)))
a(SCHEM:"Tetradecanoylphorbol acetate") -> p(MGI:Optn,pmod(P))
This phosphorylation event could only be inhibited by K-252a and stauroporin.
p(HGNC:HRAS) -| gtp(p(PFH:"RAC Family"))
Oncogenic Ras decreases Rac activity through sustained Raf/MAP kinase signaling, which causes transcriptional downregulation of Tiam1, an activator of Rac in epithelial cells.
a(SCHEM:Calcium) -> complex(p(HGNC:CALM1),p(HGNC:EDF1))
Under basal conditions, calcium-free CaM binds to other proteins termed CaM-binding proteins. Here we report that (i) EDF-1 binds CaM in vitro and in vivo;
histamine suppresses gene expression and synthesis of tumor necrosis factor alpha (TNF-alpha) induced by lipopolysaccharide (LPS)
p(HGNC:MAPK8,pmod(P)) => kin(p(HGNC:MAPK8))
Expression of active PTPH1 also reduced receptor-induced activation of Erk2 MAP kinase, its upstream activator, Mek, and the Jnk kinases.
complex(p(HGNC:SOCS3),p(HGNC:INSR)) -| (kin(p(HGNC:INSR)) -> p(HGNC:STAT5B,pmod(P,Y)))
kin(p(HGNC:INSR)) -> p(HGNC:STAT5B,pmod(P,Y))
First, using a yeast two-hybrid system, we show that SOCS-3 binds to the insulin receptor at phosphotyrosine 960, which is precisely where Stat5B binds.
p(HGNC:SOCS3) -| (kin(p(HGNC:INSR)) -> p(HGNC:STAT5B,pmod(P,Y)))
Once induced, SOCS-3 inhibits insulin activation of Stat5B without modifying the insulin receptor tyrosine kinase activity.
Second, using confocal microscopy, we show that insulin induces translocation of SOCS-3 from an intracellular compartment to the cell membrane, leading to colocalization of SOCS-3 with the insulin receptor. This colocalization is dependent upon phosphorylation of insulin receptor tyrosine 960.
p(HGNC:STAT5B,pmod(P,Y)) => tscript(p(HGNC:STAT5B))
Using transfection of COS-7 cells, we show that insulin induction of SOCS-3 is enhanced upon Stat5B expression. Moreover, Stat5B from insulin-stimulated cells binds directly to a Stat element present in the SOCS-3 promoter.
a(SCHEM:"serum insulin") -> r(HGNC:SOCS3)
insulin induction of SOCS3 is enhanced upon Stat5B expression
Using peritoneal macrophages from Nrf2-deficient mice, we show here that Nrf2 also controls the expression of a group of electrophile- and oxidative stress-inducible proteins and activities, which includes heme oxygenase-1, A170, peroxiredoxin MSP23, and cystine membrane transport (system x(c)(-)) activity.
p(PFH:"FGF Family") -> kin(p(PFH:"MAPK Erk1/3 Family"))
phos(p(HGNC:PTPRF)) -| (p(PFH:"FGF Family") -> kin(p(PFH:"MAPK Erk1/3 Family")))
We found that although both EGF and FGF induce activation of mitogen-activated protein kinase (MAPK), LAR only inhibits FGF-induced MAPK activation.
kin(p(PFH:"PRKC Family")) => p(HGNC:ADD3,pmod(P,S,662))
Loss of alpha -Adducin from Adherens Junctions Is Associated with Increased Phosphorylation of Ser726-- Phosphorylation of alpha - and gamma -adducin at Ser726 and Ser660 precedes loss of both alpha - and gamma -adducin from adherens junctions after treatment of RPTE cells with the phorbol ester phorbol 12,13-dibutyrate (41, 58) [activates PKC].
kin(p(PFH:"PRKC Family")) => p(HGNC:GRM1,pmod(P,T,695))
cat(p(HGNC:HDAC4)) =| (tscript(p(PFH:"MEF2 Family")) => r(HGNC:NR4A1))
tscript(p(PFH:"MEF2 Family")) => r(HGNC:NR4A1)
# Ariadne: It is thus somewhat surprising that the minimal MEF2-binding domain of HDAC4, which lacks histone deacetylase catalytic domain, is still able to inhibit MEF2-dependent activation of the minimal Nur77 promoter (Fig. 3 ) ( 23 ). [Expression]
cat(p(HGNC:HDAC4)) =| tscript(p(PFH:"MEF2 Family"))
MEF2 has been reported to be associated with several distinct repressors including Cabin1(cain), MEF2-interacting transcriptional repressor (MITR), and HDAC4.
IL-2-mediated phosphorylation of Jak3 and Stat5a
kin(p(HGNC:SYK)) -> tscript(p(HGNC:STAT5A))
We first observed that in the absence of Jak3, both Lck and Syk had the capacity to phosphorylate Stat3 and Stat5a.
p(HGNC:CGB5) -> bp(GO:"cell proliferation")
Treatment with HCG significantly increased cell proliferation in both myometrial and leiomyomal cells
complex(p(HGNC:NCOA2),a(CHEBI:calcitriol),p(HGNC:VDR)) => tscript(p(HGNC:VDR))
The vitamin D receptor (VDR) is the nuclear receptor for 1, 25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] that acts as a ligand-dependent transcription factor via combined contact with coactivator proteins (steroid receptor coactivator-1, transcriptional intermediary factor 2, and receptor associated coactivator 3) and specific DNA binding sites [vitamin D response elements (VDREs)].
p(HGNC:MAPK3,pmod(P)) => kin(p(HGNC:MAPK3))
insulin significantly increased MAP kinase [isoforms p42(MAPK) and p44(MAPK) (ERK1 and ERK2)] phosphorylation and activity, and the activity of its upstream activator MEK1. Insulin also increased the activity of the MAP kinase downstream substrate, the p90 ribosomal S6 kinase 2 (RSK2) almost twofold
a(SCHEM:"serum insulin") -> p(HGNC:MAPK3,pmod(P))
a(SCHEM:"serum insulin") -> kin(p(PFH:"RPS6KA Family"))
bp(GO:"response to heat") -> r(RGD:Nfkbib)
Expression of full-length rat IkappaB-beta, but not a carboxyl-terminal truncated form, inhibited NOS2 induction and potentiation by lactacystin. Lactacystin increased IkappaB-beta expression in the absence of NOS2 inducers, as well as expression of heat shock protein 70, and the heat shock response due to hyperthermia increased IkappaB-beta expression
Moreover, Rac1 and Cdc42Hs extinction in normal cells activates endogenous p53.
a(CHEBI:cholesterol) -> a(SCHEM:Corticosteroids)
Corticosteroids are synthesized from cholesterol which may arise from de novo synthesis or from the uptake of low or high density lipoproteins (LDL or HDL)
a(SCHEM:"High Density Lipoprotein") -> a(SCHEM:Corticosteroids)
a(SCHEM:"Low Density Lipoprotein") -> a(SCHEM:Corticosteroids)
accumulation of both LDL receptor and CLA-1 mRNAs was upregulated by ACTH in a dose- and time-dependent manner, with an earlier induction of LDL receptor than CLA-1 mRNA expression. (Bu)(2)cAMP also increased the levels of these two mRNAs.
p(MGI:Mesp1) -> bp(GO:"mesoderm formation")
Thus, expression patterns of these bHLH genes, together with that of an additional bHLH gene in the mouse, Paraxis, collectively define discrete but highly dynamic prepatterned subdomains of the paraxial mesoderm. In functional assays, we show that pMesogenin1 from either mouse or frog can efficiently drive nonmesodermal cells to assume a phenotype with molecular and cellular characteristics of early paraxial mesoderm. Based on our results and results from prior studies of related bHLH genes, we propose that pMesogenin1 and its closest known relatives, MesP1/2 (in mouse) and Thylacine1/2 (in Xenopus), comprise a bHLH subfamily devoted to formation and segmentation of paraxial mesoderm.
activation of the human H(2) receptor (hH(2)R) leads to an increase in c-fos transcription and cell proliferation
cat(p(HGNC:HRH2)) -> bp(GO:"cell proliferation")
a(CHEBI:staurosporine) -| kin(p(PFH:"PRKC Family"))
protein kinase C (PKC) inhibitors staurosporine and GF-109203X (10(-6) M) significantly inhibited histamine-stimulated c-fos mRNA while not altering c-jun expression
Heterologous expression of PSD-95 enhanced NRG activation of ErbB4 and MAP kinase.
Interestingly, the transcription of egr1 in PC12 cells is also activated by both NGF ( 23 ) and by TPA ( 24 ) with typical immediate early kinetics.
kin(p(PFH:"MAPK p38 Family")) -> r(HGNC:SGK1)
Treatment with pharmacological inhibitors of p38 MAPK or with a dominant negative form of MKK3, an upstream regulator of p38 MAPK, significantly reduced or ablated the sorbitol induction of sgk promoter activity
a(CHEBI:"reactive oxygen species") -> r(HGNC:TXNIP)
When cells were treated with various stress stimuli such as H2O2 and heat shock, mVDUP1 was significantly induced.
Sp1 interacts physically with distinct regions in the mouse Smad7 promoter.
tscript(p(HGNC:NCOA6)) -> tscript(p(HGNC:SRF))
complex(p(MGI:Clock),p(MGI:Arntl)) -> (tscript(p(MGI:Dbp)) -> r(MGI:Per1))
The mPer1 promoter is cooperatively activated by DBP and CLOCK-BMAL1.
tscript(p(PFH:"ETS Family")) => r(HGNC:FGF1)
These results link signaling pathways previously shown to be associated with cell proliferation (18) and cytoskeletal organization (29, 30) to growth factor gene activation and identify a cis element in FGF1 promoter 1D that can be defined as an SRE. This SRE is comprised of Ets and CArG sites. These sites are targets of regulation by divergent signaling pathways; Ets site target of Ras, Rac1, and Cdc42 regulation; and the CArG site target of de novo protein synthesis-independent cascade.
kin(p(HGNC:MAPK7)) -> (tscript(p(HGNC:MEF2C)) -> r(HGNC:JUN))
# Ariadne: We have previously shown that BMK1 regulates c- jun gene expression through direct phosphorylation and activation of transcription factor MEF2C. [Regulation]
p(HGNC:MEF2A,pmod(P,S,355)) => tscript(p(HGNC:MEF2A))
Here, we demonstrate that, in addition to MEF2C, BMK1 phosphorylates and activates MEF2A and MEF2D but not MEF2B. The blocking of BMK1 signaling inhibits the epidermal growth factor-dependent activation of these three MEF2 transcription factors. The sites phosphorylated by activated BMK1 were mapped to Ser-355, Thr-312, and Thr-319 of MEF2A and Ser-179 of MEF2D both in vitro and in vivo.
p(HGNC:MEF2A,pmod(P,T,312)) => tscript(p(HGNC:MEF2A))
p(HGNC:MEF2A,pmod(P,T,319)) => tscript(p(HGNC:MEF2A))
kin(p(HGNC:MAPK7)) => tscript(p(HGNC:MEF2A))
cat(p(MGI:Il2rb)) => tscript(p(MGI:Stat5b))
kin(p(MGI:Jak1)) => (cat(p(MGI:Il2rb)) => tscript(p(MGI:Stat5b)))
Stat5 proteins activated by IL-2. The phosphorylated tyrosines on IL-2Rbeta can then serve as docking sites for signaling molecules that otherwise cannot associate with IL-2Rbeta, including the adaptor protein Shc, Stat5a, and Stat5b (Figure 2). For example, only phosphorylated (but not non-phosphorylated) peptides spanning either Tyr-392 or Tyr-510 of IL-2Rbeta can efficiently compete with IL-2-induced Stat5 DNA binding to a GAS motif IL-2-mediated hetero-dimerization of its receptor triggers a rapid increase in the recruitment of Jak3 and activation of both Jak1 and Jak3 (Johnston et al., 1994; Witthuhn et al., 1994). These kinases phosphorylate the receptor as well as each other, and activate other signaling molecules associated with the receptor. The phosphorylated tyrosines on IL-2Rbeta can then serve as docking sites for signaling molecules that otherwise cannot associate with IL-2Rbeta, including the adaptor protein Shc, Stat5a, and Stat5b
Like sodium butyrate, trichostatin A enhanced TNF-alpha-induced C3 secretion, but suppressed TNF-alpha-induced factor B secretion. These effects were also observed at the level of mRNA. Trichostatin A modulated TNF-alpha-induced C3 and factor B secretion in a manner similar to that induced by sodium butyrate, suggesting that both sodium butyrate and trichostatin A exert certain counter-regulatory effects associated with histone hyperacetylation
cat(p(HGNC:MYD88)) -> kin(p(HGNC:IRAK1))
Tollip is present in a complex with IRAK, and that recruitment of Tollip-IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs). As overexpression of Tollip results in impaired NF-kappaB activation, we conclude that Tollip is an important constituent of the IL-1R signalling pathway.
a(SCHEM:Acetaminophen) -| cat(p(HGNC:NOS2))
Recent studies have shown that PAK3 can function as a Raf kinase, thus contributing to the activation of Raf by growth factors and other stimuli
indicating that local IL-4 inhibits the formation of osteoclast-like cells. Messenger RNA levels of IL-17, IL-12, and cathepsin K in the synovial tissue were suppressed, as were IL-6 and IL-12 protein production.
a(SCHEM:"Tetradecanoylphorbol acetate") -> tscript(p(HGNC:JUN))
tscript(p(HGNC:RARB)) -| (a(SCHEM:"Tetradecanoylphorbol acetate") -> tscript(p(HGNC:JUN)))
all three RAR subtypes, RARalpha, RARbeta, and RARgamma, could effectively inhibit phorbol ester 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 activity and the activity of oncogenes c-Jun and c-Fos on AP-1 containing reporter genes in the presence of retinoic acid (RA)
The addition of all-trans retinoic acid (ATRA) in combination with basic fibroblast growth factor (bFGF) to human fibroblasts results in a synergistic induction of tissue inhibitor of metalloproteinases-1 (TIMP-1) protein production...An incubation of 10 min to 12 h with bFGF alone followed by ATRA gave a similar synergistic induction of TIMP-1 protein to that seen with both agents together. Treatment of cells with ATRA first followed by bFGF was ineffective.
a(CHEBI:"cholic acid") -| a(SCHEM:"High Density Lipoprotein")
Dietary CA reduced plasma HDL levels by 35% in NTg and 250% in apoAI-Tg mice, independent of the fat or cholesterol content of the diet
Hepatic apoA-I mRNA decreased 30% in NTg and 180% in apoAI-Tg mice. Hepatic apoA-I synthesis and apoA-I mRNA transcription rates also decreased in parallel with apoA-I mRNA levels, suggesting that the CA-induced decreases in plasma apoA-I levels occurred primarily via decreasing apoA-I mRNA transcription rates
Tst-1 Activates the sst1 Gene Promoter by Binding to the fp2b DNA Region
kin(p(PFH:"PRKC Family")) => p(HGNC:PRKD1,pmod(P,S,249))
Therefore, SP-A signals through PI3 kinase to increase SP-B transcription in type II pneumocytes by enhancing TTF-1 and HNF-3 activation of the SP-B promoter.
kin(p(PFR:"Akt Family")) -| kin(p(RGD:Braf))
\"Negative regulation of the serine/threonine kinase B-Raf by Akt.\"
p(RGD:Braf,pmod(P,S,364)) =| kin(p(RGD:Braf))
One site, Ser(364), is conserved with c-Raf but two additional sites, Ser(428) and Thr(439), are unique to B-Raf.
MSSP possesses versatile functions, including stimulation of DNA replication, transcriptional regulation, apoptosis induction, and cell transformation coordinated by c-Myc.
Using the appropriate 'kinase inactive' mutant receptors, we show that ligand-induced activation of Met results in transphosphorylation of Ron, and vice versa. Transphosphorylation is direct, as it occurs in Met or Ron receptors lacking the docking sites for signal transducers. Phosphate groups are transferred to the tyrosine phosphorylation sites responsible both for kinase up-regulation (Met: Y1234/Y1235 and Ron: Y1238/Y1239) and for generation of signal transducer docking sites (Met: Y1349/Y1356 and Ron Y1353/Y1360).
kin(p(HGNC:MET)) => p(HGNC:MST1R,pmod(P,Y,1239))
kin(p(HGNC:MET)) => p(HGNC:MST1R,pmod(P,Y,1353))
p(HGNC:GADD45A) -> tscript(p(HGNC:RXRA))
Gadd45 family proteins interact with several nuclear hormone receptors including RXR alpha, RAR alpha, ER alpha, PPAR alpha, PPAR beta, and PPAR gamma2 in vitro. Interaction between Gadd45 family proteins and nuclear hormone receptors resulted in modest activation of transactivating function of nuclear hormone receptors in reporter systems.
TNF alpha, IFN gamma and IL1 beta induced the tyrosine and threonine phosphorylation of ERK MAP kinases. Treatment with PD98059, an inhibitor of MEK1 and MEK2 kinase inhibited ERK MAP kinase phosphorylation by IFN gamma, TNF alpha and IL1 beta.
TNF alpha induced the expression of mRNAs encoding c-fos and c-jun after 30 min of stimulation. Induction of c-fos mRNA reached maximum at 60 min and of c-jun reached a maximum level at 45 min of TNFA stimulation.
The expression of PMEPA1 in LNCaP cells was induced by androgen in a time-and dose-specific manner
a(SCHEM:"serum insulin") -| pep(p(NCH:"Proteasome Complex"))
\"Insulin inhibits the ubiquitin-dependent degrading activity of the 26S proteasome.\"
complex(p(HGNC:RPA2),p(HGNC:STAT3)) -> tscript(p(HGNC:STAT3))
We also show that STAT3 binds to RPA p32 in vivo by conducting co-precipitation experiments. As the SH2 domain is highly involved in the tyrosine phosphorylation and the transcriptional activity of STAT3, over-expression of RPA p32 correspondingly augmented growth factor-stimulated tyrosine phosphorylation and transcription activities of STAT3.
Deletion and mutation analysis of the promoter identified a single HOXA5-binding site required for transactivation of the PR gene by HOXA5. HOXA5 binds directly to this site in the PR promoter.
Previously we have reported that the intracellular effectors of TGF-beta, Smad3 and Smad4, functionally cooperate with Sp1 to activate the human p21 promoter in hepatoma HepG2 cells.
Transforming growth factor-beta (TGF-beta) inhibits cell cycle progression, in part through up-regulation of gene expression of the p21(WAF1/Cip1) (p21) cell cycle inhibitor
kin(p(HGNC:SRC)) => p(HGNC:DAPP1,pmod(P,Y,139))
Src, Lyn and Lck tyrosine kinases phosphorylate DAPP1 at Tyr(139) in vitro at similar rates in the presence or absence of PtdIns(3,4,5)P(3), and overexpression of these kinases in HEK-293 cells induces the phosphorylation of Tyr(139). co-expression of DAPP1 with Src, Lyn or Lck induced a very high level of phosphorylation of DAPP1 at Tyr139, even in unstimulated cells, which was not increased further by agonist stimulation of cells. As Src-family kinases activate the PI 3-kinase pathway in many cells [1], it is possible that the overexpression of Src, Lyn or Lck in HEK-293 cells induces the activation of PI 3-kinase, thereby promoting DAPP1 phosphorylation in unstimulated cells. As Src-family tyrosine kinases are located at the plasma membrane by virtue of myristoylation and palmitoylation of their N-termini [26], it is likely that the role of PtdIns(3,4,5)P3 is to recruit DAPP1 to the cell membrane, where it can be phosphorylated with Src-family tyrosine kinases.
kin(p(HGNC:INSR)) -> p(HGNC:DAPP1,pmod(P,Y,139))
in HEK-293 cells, the agonists insulin, insulin-like growth factor-1 and epidermal growth factor induce the phosphorylation of DAPP1 at Tyr(139).
cat(p(HGNC:TLR2)) -> (p(HGNC:MYD88) -> tscript(complex(NCH:"Nfkb Complex")))
p(HGNC:MYD88) -> tscript(complex(NCH:"Nfkb Complex"))
Bacterial lipoproteins (BLPs), which are expressed by all bacteria, are potent activators of Toll-like receptor-2 (TLR2). Here we show that the adaptor molecule, myeloid differentiation factor 88 (MyD88), mediates both apoptosis and nuclear factor-kappaB (NF-kappaB) activation by BLP-stimulated TLR2.
cat(p(HGNC:TLR2)) -> (p(HGNC:MYD88) -> cat(p(HGNC:CASP8)))
Inhibition of the NF-kappaB pathway downstream of MyD88 potentiates apoptosis, indicating that these two pathways bifurcate at the level of MyD88. TLR2 signals for apoptosis through MyD88 via a pathway involving Fas-associated death domain protein (FADD) and caspase 8.
Interestingly, BLP also activates caspase 1 through TLR2, resulting in proteolysis and secretion of mature IL-1beta.
These data indicate that TLR2 is a novel 'death receptor' that engages the apoptotic machinery without a conventional cytoplasmic death domain. Through TLR2, BLP induces the synthesis of the precursor of the pro-inflammatory cytokine interleukin-1beta (IL-1beta).
a(SCHEM:Corticosteroids) -| (bp(GO:"inflammatory response") -> r(HGNC:MMP2))
bp(GO:"inflammatory response") -> r(HGNC:MMP2)
These observations strongly suggest an involvement of MMP-2 and MMP-9 in acute inflammatory processes. Moreover, we have shown in mice that LPS-induced acute inflammation could be reduced by corticosteroid treatment, as observed by inhibition of inflammatory cell infiltration (mainly neutrophils) and reduction of MMP-2 and MMP-9 activity
a(SCHEM:Corticosteroids) -| (bp(GO:"inflammatory response") -> r(HGNC:MMP9))
bp(GO:"inflammatory response") -> r(HGNC:MMP9)
kin(p(HGNC:CHUK)) => p(HGNC:NFKBIA,pmod(P,S,36))
This led to the identification of a high molecular weight IkBalpha kinase complex capable of phosphorylating IkBalpha specifically on serines 32 and 36. Subsequently, the same complex was isolated from TNFalpha-induced HeLa cells and found to contain two IkBalpha kinases, designated IKKalpha and IKKbeta (or IKK1 and IKK2). These kinases were cloned and shown to be activated by TNFalpha, IL-1, and PMA.
kin(p(HGNC:IKBKB)) => p(HGNC:NFKBIA,pmod(P,S,32))
As expected, mRNA levels for LPL were reduced in fld white adipose tissue, as were those of adipsin. We also found that uncoupling protein 1 mRNA in brown adipose tissue from fld mice was reduced.
As previously described, white adipose tissue from fld mice expresses substantially reduced levels of lipoprotein lipase (LPL) activity ( 2 ), which may contribute to the reduced lipid accumulation in these cells.
Preliminary studies to examine levels of apolipoproteins A-I, A-II, A-IV and E revealed slightly higher apo A-I and apo A-II levels in plasma of fld mice
The lack of lipid accumulation in fld/fld adipose tissue could be attributed, in part, to a failure to induce expression of lipoprotein lipase and enzymes involved in fatty acid synthesis, such as fatty acid synthase and acetyl-CoA carboxylase.
FIG. 7. Lyn induces SAPK activation by an MKK7- and MEKK1-dependent, SEK1-independent mechanism.
p(HGNC:ITGB1,pmod(P,Y,783)) -> kin(p(HGNC:PTK2))
Focal adhesion kinase (FAK) tyrosine phosphorylation and activation were severely impaired in response to beta1-dependent adhesion in GD25-beta1A(Y783/795F) cells compared to that in wild-type GD25-beta1A or mutants in which only a single tyrosine was altered (beta1A(Y783F) or beta1A(Y795F)).
a(CHEBI:ciprofibrate) -| p(MGI:Selenbp2)
Treatment of mice with 0.025% ciprofibrate resulted in the more basic of this pair of proteins being decreased to 30% of control abundance while the acidic protein was decreased to 7% of the control amount.
kin(p(HGNC:ABL1)) => p(HGNC:ROBO1,pmod(P,Y))
Both Abl and Ena can directly bind to Robo's cytoplasmic domain. A mutant form of Robo that interferes with Ena binding is partially impaired in Robo function, while a mutation in a conserved cytoplasmic tyrosine that can be phosphorylated by Abl generates a hyperactive Robo receptor.
In vitro sumoylation of Mdm2 abrogates its self-ubiquitination and increases its ubiquitin ligase activity toward p53
AND-34 displays GEF activity on RalA, Rap1A, and R-Ras but not Ha-Ras GTPases in cells
Addition of FGF-2 to osteoblast cultures revealed an up-regulation in FGFR4 mRNA and protein levels.
complex(p(MGI:Fgf2),p(MGI:Fgfr1)) => kin(p(MGI:Fgfr1))
FGF-2 (/=10(-12) m) also increased cathepsin K and MMP-9 mRNA levels in mouse and rabbit osteoclasts. FGF-2 acts directly on mature osteoclasts through activation of FGFR1 and p42/p44 MAP kinase, causing the stimulation of bone resorption at physiological or pathological concentrations.
Ariadne: Both IL-1 and IL-18 activate IRAK (Robinson et al. 1997 ), NF-kappaB in Th1 cells (Matsumoto et al. 1997 ; Robinson et al. 1997 ), and TRAF6 (Kojima et al. 1998 ). [Regulation]
complex(p(MGI:Ep300),p(MGI:Mitf)) => tscript(p(MGI:Mitf))
E1A acting to partition CBP p300 from Mitf and thereby reduce its ability to activate transcription.
a(SCHEM:Diacylglycerol) -> kin(p(HGNC:PRKCE))
An increase in fatty acyl CoAs can lead to increased diacylglycerol (DAG) concentrations. DAG, in turn, activates many isoforms of protein kinase C (PKC), including PKCepsilon and PKCtheta.
a(SCHEM:"Fatty acyl CoA") -| kin(p(PFH:"AKT Family"))
a(CHEBI:lipid) -| cat(p(PFH:"GYS Family"))
glucose oxidation was increased in leg muscle of type 2 diabetic subjects studied postabsorptively under conditions of fasting, hyperglycemia. lipid infusion did produce a decrease in insulin-stimulated glucose oxidation that was associated with decreased PDH activity (22), there was a greater decrease in glycogen synthesis associated with decreased glycogen synthase activity
p(PFH:"RAS Family") => kin(complex(NCH:"p85/p110 PI3Kinase Complex"))
Ras thus binds PI3 kinase and potentiates its activation
kin(p(HGNC:DYRK1B)) => p(HGNC:DYRK1B,pmod(P,Y,271))
we have demonstrated that PP1, a pharmacological inhibitor of Src kinases, blocked SCF-mediated activation of mitogen-activated protein (MAP) kinase, but it also inhibited Kit activation.
p(HGNC:SOCS1) -| path(SDIS:"thrombopoietin activity")
In addition, a dominant negative version of STAT3 inhibits the induction of SOCS1 mRNA in response to IL-6 or LIF in M1 cells
The expression of early adipogenic gene markers, such as lipoprotein lipase, peroxisome proliferator-activated receptor-gamma, and adipocyte-specific fatty acid binding protein 2, was enhanced by aldosterone, confirming activation of the differentiation process.
a(SCHEM:Calcium) -> complex(p(HGNC:S100B),p(HGNC:S100A11))
Furthermore, co-immunoprecipitation experiments demonstrated that Ca(2+)/Zn(2+) stabilizes S100B-S100A6 and S100B-S100A11 heterocomplexes
# Ariadne: RhoB also has cell cycle inhibitory roles and is upregulated during stress responses ( 14 , 15 ) and by the inhibitory growth factor transforming growth factor beta ( 12 ). [Regulation]
kin(p(HGNC:NTRK1)) -| bp(MESHPP:Apoptosis)
we show that triggering of the high-affinity NGF receptor TrkA with agonists protects monocytes from apoptosis
p(HGNC:SREBF1,pmod(P,S)) => tscript(p(HGNC:SREBF1))
ERK1, and ERK2 phosphorylates and activates to SREBP1
kin(p(HGNC:FGFR1)) -> p(HGNC:PLCG1,pmod(P,Y))
Mutation of Lys650-->Glu in the activation loop of the FGFR3 kinase domain causes the lethal human skeletal disorder thanatophoric dysplasia type II (TDII) and is also found in patients with multiple myeloma, bladder and cervical carcinomas. This mutation leads to constitutive activation of FGFR3. We show that the kinase domains of FGFR1, FGFR3, and FGFR4 containing the activation loop mutation, when targeted to the plasma membrane by a myristylation signal, can transform NIH3T3 cells and induce neurite outgrowth in PC12 cells. Phosphorylation of Shp2, PLC-gamma, and MAPK was also stimulated by all three 'TDII-like' FGFR derivatives. Additionally, activation of Stat1 and Stat3 was observed in cells expressing the activated FGFR derivatives. Finally, we demonstrate that FGFR1, FGFR3, and FGFR4 derivatives can stimulate PI-3 kinase activity.
kin(p(HGNC:FGFR1)) -> tscript(p(HGNC:STAT1))
p(HGNC:IFNA1) -| bp(GO:"cell proliferation")
antiproliferative effects of IFN-beta than of IFN-alpha
complex(p(HGNC:MAP3K7),p(HGNC:TRAF6)) -> tscript(complex(NCH:"Nfkb Complex"))
Here we report that ASK 1 binds to TAK 1 and dissociates TAK 1 from TNF receptor-associated factor 6 (TRAF 6), and inhibits TAK 1- and TRAF 6-, but not NF-kappa B-inducing kinase (NIK)-induced NF-kappa B activation
kin(p(HGNC:GSK3B)) -> p(HGNC:CTNNB1,pmod(P))
beta-Catenin is efficiently phosphorylated by glycogen synthase kinase-3beta in the Axin complex in the cytoplasm, resulting in the down-regulation.
bp(GO:"cell differentiation") -> r(RGD:Plekhb1)
we have identified a novel gene, KPL1, induced in rat tracheal epithelial (RTE) cells grown under conditions which stimulate ciliogenesis. Andrews et al. (2000) found that Kpl1 expression increased in rat tracheal epithelial cells that underwent mucociliary differentiation in response to retinoic acid.
a(CHEBI:"hydrogen peroxide") -> tscript(complex(NCH:"AP-1 Complex"))
a(CHEBI:acetylcysteine) -| (a(CHEBI:"hydrogen peroxide") -> tscript(complex(NCH:"AP-1 Complex")))
Also, EGTA and NAC regulated H2O2- or ionomycininduced AP-1 binding activity in the same pattern (Fig. 6B).
p(HGNC:CAT) -| (p(HGNC:TGFB1) -> a(SCHEM:Calcium))
Antioxidants such as NAC and catalase abolished TGF-b1-induced [Ca21] level successfully, indicating that ROS generation is required for TGF-b1-mediated [Ca21] increase in HLF cells.
Fig. 5D showed that TGF-b1 treatment increased [Ca21] level rapidly
a(CHEBI:"hydrogen peroxide") -> a(SCHEM:Calcium)
In addition, when HLF cells were treated with H2O2, [Ca21] was elevated ;3-fold (Fig. 6C)
p(HGNC:MMP12) -> deg(a(SCHEM:Fibrinogen))
Our data demonstrate that the catalytic domains of MMP-8, MMP-12, MMP-13, and MMP-14 can proteolytically process fibrinogen and, with the exception of MMP-8, also inactivate Factor XII (Hageman factor).
p(HGNC:SFPQ) -> bp(GO:"strand invasion")
More important, the protein promotes the incorporation of a ss oligonucleotide into a homologous superhelical dsDNA, D-loop formation. A D-loop is the first heteroduplex DNA intermediate generated between recombining DNA molecules.
p(HGNC:SFPQ,pmod(P,S)) -> (p(HGNC:SFPQ) -> bp(GO:"strand invasion"))
Significantly, phosphorylation of hPOMp100/PSF by protein kinase C inhibits its binding to RNA but stimulates its binding to DNA and D-loop formation and may represent a regulatory mechanism to direct this multifunctional protein to DNA metabolic pathways.
kin(p(PFH:"PRKA Family")) -> p(HGNC:TEAD1,pmod(P,S,102))
. TEF-1 is phosphorylated by PK-A at residue serine-102.
p(MGI:Slc2a4) -> (a(SCHEM:"serum insulin") -> path(SDIS:"muscle glucose import"))
Insulin-stimulated glucose transport was abolished in muscle-G4KO muscles, and was partially reduced in Het KO muscles .
gtp(p(HGNC:RAC1)) -> bp(GO:phagocytosis)
Furthermore, Iba1 colocalized with a small GTPase Rac in the membrane ruffles and the phagocytic cups. The Iba1 mutants also suppressed membrane ruffling induced by dominant active Rac1V12
complex(NCH:"Follicle Stimulating Hormone Complex") -> r(HGNC:JUN)
JunB, c-Jun, c-Fos, and Fra2 were rapidly but transiently induced by FSH in immature granulosa cells.
phos(p(HGNC:PPM1A)) -| kin(p(HGNC:CDK2))
Moreover, purified recombinant PP2C alpha and PP2C beta 2 proteins efficiently dephosphorylated monomeric Cdk2/Cdk6 in vitro.
a(CHEBI:"nitric oxide") -> a(CHEBI:adenosine)
We found that exposure to nitric oxide increased intracellular adenosine to 125 +/- 18% of control values (p consistent with the possibility that in our system the inhibition of adenosine kinase is related to an increase in intracellular adenosine, and that the effect of nitric oxide on extracellular adenosine is significantly potentiated by substrate inhibition of adenosine kinase.
Thus, the GnRH proximal promoter is regulated by the Otx2 homeoprotein.
Quinidine-treated MCF-7 cells showed elevated p21(WAF1), hypophosphorylation and suppression of retinoblastoma protein, and down-regulation of cyclin D1, similar to the cell cycle response observed with cells induced to differentiate by histone deacetylase inhibitors, trichostatin A, and trapoxin.
When LNCaP cells were deprived of androgen cyclin D1 levels decreased.
p(HGNC:EPO) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))
EPO induced activation of STAT5 was inhibited by PI3K inhibitor LY294002.
Phosphorylation of Epor, Stat5 and Gab1 induced by Epo was inhibited by Jak2 inhibitor AG490.
kin(p(HGNC:LYN)) => p(HGNC:SLC4A1,pmod(P,Y,8))
In addition to reduced expression of the genes encoding insulin, glucose transporter-2, L-pyruvate kinase, aldolase B and 3-hydroxy-3-methylglutaryl coenzyme A reductase, induction of HNF1 alpha-P291fsinsC also significantly inhibits expression of mitochondrial 2-oxoglutarate dehydrogenase (OGDH) E1 subunit mRNA and protein. OGDH enzyme activity and [(14)C]pyruvate oxidation were also reduced. In contrast, the mRNA and protein levels of mitochondrial uncoupling protein-2 were dramatically increased by HNF1 alpha-P291fsinsC induction.
tscript(p(HGNC:HNF1A)) -| r(HGNC:SLC2A2)
PD098059, a specific inhibitor of p42/44(MAPK) phosphorylation, inhibited FGF-2-stimulated DNA synthesis, phosphorylation of p42/44(MAPK) and p90(RSK), and degradation of IkappaBbeta
kin(p(HGNC:GSK3B)) => p(HGNC:AXIN1,pmod(P))
p(HGNC:SENP2) -> (kin(p(HGNC:GSK3B)) => p(HGNC:AXIN1,pmod(P)))
Axam inhibited the complex formation of Dvl with Axin and the activity of Dvl to suppress GSK-3beta-dependent phosphorylation of Axin.
a(CHEBI:"hydrogen peroxide") -> bp(GO:"cell death")
p(MGI:Gstp1) -| (a(CHEBI:"hydrogen peroxide") -> bp(GO:"cell death"))
Treatment with 50 ?m H2O2 in the absence of GSTp expression led to the death of 35% of the cells after 24 h; this was reduced to 20% upon GSTp expression (Fig. 3 ? ).
kin(p(HGNC:MET)) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))
kin(p(HGNC:PAK1)) -> kin(p(HGNC:MAP2K2))
Consistent with the earlier results, p42/44 MAPK and its upstream kinase MEK1/2 were activated in a time-dependent manner by the induction of Pak1 (Fig. 3C).
p(PFH:"PDGF Family") -> p(HGNC:PRKCD,pmod(P,Y,187))
In response to PDGF, Fyn associated with PKCdelta via tyrosine 187. Finally, overexpression of dominant negative Fyn abrogated the decrease in GS expression and reduced the tyrosine phosphorylation of PKCdelta induced by PDGF. We conclude that the tyrosine phosphorylation of PKCdelta and its association with tyrosine kinases may be an important point of divergence in PKC signaling.
cat(p(HGNC:CASP8)) -> (p(HGNC:TGFB1) -> bp(MESHPP:Apoptosis))
Use of specific caspase inhibitors revealed that the induction of apoptosis is caspase 8 dependent, but caspase 3 independent.
We detected cleavage of caspases 2, 3, 7, 8, and 9 into their active subunits. Consistent with the involvement of these enzymes in TGF-beta-mediated apoptosis, the broad spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(Ome)-flouromethylketone (ZVAD-fmk) blocked TGF-beta-induced apoptosis
Ly-GDI, fibronectin-accelerated Ly-GDI cleavage, and fibronectin-accelerated apoptosis in TNF-alpha-treated PMN.
Interestingly, this factor had the structural features of a Ser/Thr kinase and actually exhibited protein kinase activity. TSF1 mRNA as well as its protein level were stimulated by TGF-beta treatment.
cat(p(MGI:Adra2b)) -| a(SCHEM:"cyclic AMP")
beta- and alpha 2-adrenergic receptors (ARs) couple positively and negatively, respectively, to adenylyl cyclase
cat(p(MGI:Adra2c)) -| a(SCHEM:"cyclic AMP")
increased alpha 2/beta-AR balance in adipocytes promotes obesity by stimulating adipocyte hyperplasia
p(HGNC:SOCS1) -| (p(HGNC:IL4) -> tscript(p(HGNC:STAT6)))
SOCS-1 and SOCS-3 inhibit interleukin (IL)-4-dependent signal transducer and activator of transcription 6 (Stat6) activation of and subsequent gene induction. By contrast, SOCS-2 and cytokine-inducible Src homology domain 2 (SH2)-containing protein up-regulate these processes
tscript(complex(NCM:"Nfy Complex")) -> r(MGI:Mybl1)
The CCAAT box efficiently binds the NF-Y complex and its mutation decreases basal promoter activity by 50%.
Metal response element-binding transcription factor (MTF)-1 mediates metal regulation of the metallothionein I gene. In vitro DNA-binding assays demonstrated that mouse MTF-1 can bind avidly to the two metal-response element sequences found in the ZnT1 promoter. Using mouse embryo fibroblasts with homozygous deletions of the MTF-1 gene, it was shown that this transcription factor is essential for basal as well as metal (zinc and cadmium) regulation of the ZnT1 gene in these cells.
kin(p(MGI:Egfr)) => p(MGI:Eps15,pmod(P,Y,850))
Elevated FFAs impair the ability of insulin to suppress hepatic glucose output and to stimulate glucose uptake into skeletal muscle, as well as to inhibit insulin secretion from pancreatic b cells.
path(SDIS:"Type II diabetes") negativeCorrelation r(HGNC:IRS1)
In adipocytes from obese humans with type 2 diabetes, IRS-1 expression is reduced, resulting in decreased IRS-1-associated PI3K activity, and IRS-2 becomes the main docking protein for PI3K (14).
path(SDIS:"Type II diabetes") negativeCorrelation kin(complex(NCH:"p85/p110 PI3Kinase Complex"))
In contrast, in skeletal muscle of obese, type 2 diabetic subjects, IRS-1 and IRS- 2 protein levels are normal but PI3K activity associated with both IRSs is impaired
Insulin promotes adipocyte triglyceride stores by a number of mechanisms, including fostering the differentiation of preadipocytes to adipocytes and, in mature adipocytes, stimulating glucose transport and triglyceride synthesis (lipogenesis), as well as inhibiting lipolysis
cat(p(HGNC:ADRB1)) -> path(SDIS:"adipose glucose import")
rodents or humans are treated with the b3 adrenergic agonist CL316,243 (25, 26). Since b3 adrenergic receptors are expressed almost exclusively in fat, effects of these agents would be expected to be initiated by alterations in fat. Treatment with CL316,243 results in enhanced sensitivity of both whole body glucose uptake and suppression of hepatic glucose production (25). Thus, increasing glucose uptake selectively in fat with b3 adrenergic receptor agonists may improve whole body glucose uptake, with the effects in fat indirectly resulting in increased insulin sensitivity in liver.
a(SCHEM:"L 663536") -| cat(p(HGNC:ALOX5))
The addition of cycloheximide inhibited the paclitaxel-induced increase in cdc2 protein level, further indicating that paclitaxel stimulates cdc2 synthesis.
kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> p(PFH:"AKT Family",pmod(P,T,308))
Reexpression of PTEN or treatment with the PI3K inhibitor LY294002 abolished the levels of both PtdIns(3, 4)P2 and PtdIns(3,4,5)P3, reduced phosphorylation of PKB on Thr308 and Ser473, and inhibited PKB activity.
p14ARF expression was able to greatly inhibit the MCF-7/Adr cell proliferation. Furthermore, p14ARF expression resulted in decrease of MDR-1 mRNA and P-glycoprotein production, which linked to the reducing resistance of MCF-7/Adr cells to doxorubicin.
kin(p(HGNC:BMX)) -> bp(MESHPP:Apoptosis)
p(HGNC:CSF3) -> (kin(p(HGNC:BMX)) -> bp(MESHPP:Apoptosis))
The expression of wild type Bmx in 32D myeloid progenitor cells resulted in apoptosis in the presence of G-CSF, while cells expressing a kinase dead mutant of Bmx differentiated into mature granulocytes.
Furthermore, expression of dominant negative Smad3 or Smad4 in cells decreased or abolished the stimulation of beta(5) promoter activity by TGF-beta. Smad4 mutant also inhibited the up-regulation of surface beta(5) level by TGF-beta. Thus, TGF-beta increases expression of the integrin beta(5) gene by mechanisms involving Sp1/Sp3 and Smad transcription factors.
TGF-beta increased cell adhesion to vitronectin and up-regulated the surface level of alpha(v)beta(5) via increasing beta(5) protein synthesis by a transcriptional mechanism.
p(MGI:Abl1,pmod(P,Y,412)) => kin(p(MGI:Abl1))
These results support a model where c-Abl is inhibited in part through an intramolecular Src homology 3-linker interaction and stimulated to full catalytic activity by sequential phosphorylation at Tyr-412 and Tyr-245.
kin(p(PFH:"PRKC Family")) -> r(HGNC:MSR1)
Furthermore, in MSR gene promoter-driven luciferase reporter assays with TNF, PKC activator increases, but antioxidant N-acetylcysteine, PK inhibitors, and dominant negative constructs decrease luciferase activity in MSR gene promoter-transfected cells
gtp(p(RGD:Rac1)) => complex(p(RGD:Rac1),p(RGD:Iqub))
WAVE proteins are members of the Wiskott-Aldrich syndrome protein (WASP) family of scaffolding proteins that coordinate actin reorganization by coupling Rho-related small molecular weight GTPases to the mobilization of the Arp2/3 complex.
a(SCHEM:"cyclic AMP") -> bp(GO:"fibroblast proliferation")
DBcAMP stimulated keratinocyte proliferation through increased interleukin (IL)-6 production by fibroblasts, and transiently enhanced production of transforming growth factor (TGF)-beta1 by fibroblasts at an early stage of incubation. DBcAMP also stimulated fibroblast proliferation, resulting in further increases in IL-6 and TGF-beta1
kin(p(MGI:Map3k3)) -> tscript(p(MGI:Mef2c))
# Ariadne: Thus, our findings provide support for a signaling pathway in which Mekk3 activity leads to the activation of p38 MAPK, which in turn regulates MEF2C. [Regulation]
kin(p(HGNC:ATM)) => p(HGNC:CHEK2,pmod(P,S,35))
kin(p(HGNC:SYK)) -> kin(p(PFH:"AKT Family"))
Phosphorylation of Akt is regulated positively by Btk and Syk and negatively by Lyn. Akt in turn can regulate positively the transcriptional activity of interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha promoters.
p(HGNC:KRAS,sub(G,12,C)) => gtp(p(HGNC:KRAS))
Tissue levels of IL-1b, TNF-a, and MIP-2 were significantly elevated in the lungs after administration of doses of HMG-1 as low as 1 mg/mouse (Fig. 2).
IL-10 at a concentration of 10ng/ml produced a modest 2 fold increase in CXCR4 expression on CD4 T cells after 48hours of incubation.
TGF-Beta3 at a concentration of 1ng/ml induced a 10-fold increase in the level of CXCR4 expressed on synovial CD4 T cells after 48 hours of incubation.
In addition, introduction of B-Raf enhances and sustains integrin-mediated activation of ERK in wild-type primary fibroblasts
a(CHEBI:estradiol) -| p(HGNC:BCL2L1,pmod(P))
kin(p(HGNC:EGFR)) => complex(p(HGNC:GAB1),p(HGNC:SYP))
Recently, we identified a similar cohort of tyrosine phosphorylation sites for the epidermal growth factor receptor (EGFR) with a predominant phosphorylation of tyrosine residue Y657 and binding of Syp [Lehr, S. et al. (1999) Biochemistry 38, 151-159].
CD40L-induced increased phosphorylation and activity of p44 and p42 are specific to the CD40-CD40L interaction.
Thrombopoetin (TPO) induced the phosphorylation of Jak2 in BaF3/mMpl cells. Pretreatment of BaF3/mMpl cells and mature megakaryocytes (MKs) with IFN-alpha for 4 hours before stimulation with TPO, inhibited the TPO-induced Jak2 phosphorylation. It is observed that Jak2 phosphorylation was blunted by IFN-alpha and is most consistent with the action of Socs-1 which appears responsible for impaired TPO signaling. Phosphorylation of Jak2 was reduced in the presence of TPO plus IFN-alpha to 45% than that seen in cells cultured in TPO alone. In primary murine MK cultured in TPO plus IFN-alpha, Jak2 phosphorylation was reduced to 75%, compared to cultures containing TPO alone.
kin(p(HGNC:MAPK3)) => p(HGNC:RPS6KA3,pmod(P,T,577))
Consistent with the physical interaction between ER81 and the coactivators CBP and p300, ER81 transcriptional activity was potentiated by CBP/p300 overexpression.
In combination with cell proliferative activities of c-myc and cyclin D1, MDR1 may initiate colorectal tumorigenesis by suppressing cell death pathways programmed in intestinal epithelial cells.
p(HGNC:MYC) -> bp(GO:"cell proliferation")
The mutational inactivation of a tumor suppressor gene, adenomatous polyposis coli (APC), results in the accumulation of cytoplasmic beta-catenin protein and the activation of T-cell factor (TCF)/lymphoid enhancer factor transcriptional factors.
cat(p(HGNC:APC)) -| tscript(p(PFH:"TCF/LEF Family"))
a(SCHEM:"Adenosine triphosphate") =| tport(p(HGNC:ABCC9))
p(HGNC:GNG2) -| (a(SCHEM:"Adenosine triphosphate") =| tport(p(HGNC:ABCC9)))
# Ariadne: On the other hand, the ATP-induced inhibition of Kir6.2/SUR2A channels was reduced by G ..gamma 2 in a concentration-dependent manner (Figure 2 B). [Regulation]
The phosphorylated residue is essential for efficient association with IRF-1 and thus for the repressor activity of ICSBP exerted on IRF-1.
kin(p(HGNC:MAPK1)) => p(HGNC:RGS19,pmod(P,S,151))
Induction of SAA by phorbol 12-myristate 13-acetate, a known agonist of protein kinase C (PKC), suggested a potential role of the PKC signaling pathway in the activation process.
kin(p(HGNC:IRAK1)) -> tscript(complex(NCH:"Nfkb Complex"))
Interleukin-1 receptor-associated kinase-1 (IRAK-1) has recently been shown to be involved in IL-18-stimulated activation of NF-kappaB and AP-1.
bp(GO:"macrophage activation") -> bp(GO:"macrophage chemotaxis")
DBP as a Chemotaxin for Phagocytic Cells DBP is reported to augment the chemotactic effect of C5a for macrophages and neutrophils64-66. This chemotactic activity requires binding of DBP to a cell surface site on leukocytes67,68 as part of the inflammatory response.
Studies of the DBP gene proximal promoter have identified three functional hepatocyte nuclear factor 1 (HNF1)-binding sites within 2 kb of the transcriptional start site. The activities of the two more distal HNF1-binding sites were found to be dependent upon the relative levels of the two isoforms of this transcription factor, HNF1a and HNF1b. This was because HNF1b acted as a trans-dominant inhibitor of HNF1amediated enhancer activity14. The relative levels of these HNF1 isoforms in liver and kidney may contribute to the differences in the observed levels of DBP mRNA in these two tissues (Fig. 2). In contrast to their opposing effects on the DBP promoter, HNF1a and HNF1b both display only strong enhancing activities on the AFP and ALB promoters.
a(SCHEM:"D-Glucose, anhydrous") -> r(HGNC:TGFB1)
In cultured mesangial cells, high glucose levels induce TGF-beta1 production
Treatment of cells with 5 ng/ml of recombinant TGF beta1 led to an increase in luciferase activity of PAI-1 promoter. Treatment of cells with a pan-specific neutralizing antibody to TGF beta prevented the activation of PAI-1 promoter by GFAT overexpression, suggesting that PAI-1 activity is TGF beta1 responsive.
In MCF-7, an increase in Bad and Bax protein expression and a decrease in Bcl-x(L) protein and Bcl-2 protein and mRNA were observed.
a(SCHEM:"NS 398") -| (p(HGNC:IL1B) -> cat(p(HGNC:PTGS2)))
Cultured myometrial cells expressed low levels of Cox-2 mRNA under baseline conditions, but interleukin-1beta (IL-1beta) caused a 17-fold induction of expression of the Cox-2 transcript after incubation for 6 h. IL-1beta also induced expression of biologically active Cox-2 protein, as detected by immunofluorescence, Western blot analysis, and measuring the conversion of arachidonic acid to prostanoids in the presence and absence of a Cox-2-selective inhibitor, NS-398.
Treatment of human femoral condyles cartilage chondrocytes, cultured with 0.75 mM L-NMA, with 50 ng/ml of IGF1 for 48 hours resulted in increased proteoglycan synthesis for two-fold.
a(CHEBI:"arachidonic acid") -> bp(MESHPP:Apoptosis)
% Exogenous arachidonic acid caused apoptosis in colon cancer and other cell lines, as did triacsin C, a FACL inhibitor. In addition, indomethacin and sulindac significantly enhanced the apoptosis-inducing effect of triacsin C.
kin(p(MGI:Ak1)) -> a(SCHEM:"Adenosine triphosphate")
However, under hypoxia AK1-deficient hearts, compared with the wild type, had a blunted AK-catalyzed phosphotransfer response, lowered intracellular ATP levels, increased P(i)/ATP ratio, and suppressed generation of adenosine
TGFbeta stimulates the gene coding for human alpha2(I)-collagen (COL1A2) by inducing binding of an Sp1-containing complex to an upstream promoter element (TGFbeta responsive element or TbRE) that contains a CAGA box. Here we report that the CAGA box of the TbRE is the binding site of the Smad3/Smad4 complex, and that the binding of the complex is required for TGFbeta-induced COL1A2 up-regulation. Recombinant Smad3 and Smad4 bind in vitro to the CAGA box of COL1A2; TGFbeta treatment of cultured fibroblasts induces Smad3/Smad4 binding to the TbRE; transient overexpression of Smad3 and Smad4 in fibroblasts transactivates TbRE-driven transcription;
kin(p(MGI:Map2k1)) -> (a(SCHEM:Tretinoin) -> r(MGI:Krt8))
the exogenous expression of dominant-negative MEK1 efficiently abrogated RA-mediated induction of the cytokeratins EndoA
TNF-alpha or IL-1beta induced both G-CSF and PTHrP production in the conditioned medium.
a(CHEBI:"nitric oxide") -| cat(p(HGNC:GLO1))
a(CHEBI:glutathione) -| (a(CHEBI:"nitric oxide") -| cat(p(HGNC:GLO1)))
Severe depletion of intracellular GSH prevents the inactivation of Glo I in response to NO
We previously found that glyoxalase I (Glo I) is inactivated upon exposure of human endothelial cells to extracellular nitric oxide (NO)
mRNA expression of fibrillin-1, emilin, and elastin was strong in quiescent mesangial cells; their gene expression was further up-regulated by transforming growth factor-beta1, while it was transiently reduced when cells were exposed to mitogenic 10% fetal calf serum and platelet-derived growth factor
In the nucleoprotein complex, Smad2 interacted through its C-domain with Sp1 and enhanced the DNA binding and transcriptional activity of Sp1
complex(p(HGNC:SP1),p(HGNC:SMAD2)) => tscript(p(HGNC:SP1))
The various AREs bind to a complex of nuclear proteins from cells of different origins (15-23, 25). Analysis of ARE-nuclear protein complexes have identified several nuclear transcription factors including c-Jun, Jun-B, Jun-D, c-Fos, Fra1, Nrf1, Nrf2, YABP, ARE-BP1, MafK, Ah (aromatic hydrocarbon) receptor, and the estrogen receptor (15-32). Among these transcription factors, Nrf1 and Nrf2 have been shown to heterodimerize with c-Jun and up-regulate the ARE-mediated expression and induction of NQO1 in response to antioxidants and xenobiotics (26, 31).
phos(p(HGNC:PTPN21)) -> tscript(p(HGNC:STAT3))
Furthermore, the Etk-PTPD1 interaction stimulated the kinase activity of Etk, resulting in an increased phosphotyrosine content in both factors. The Etk-PTPD1 interaction also increased Stat3 activation. In addition, Tec (but not Btk) kinase can also be activated by PTPD1.
tscript(complex(NCH:"AP-1 Complex")) =| r(HGNC:GNRHR)
2 potential AP-1 binding sites located at positions -1000 to -994 and -943 to -937 was identified in the 248-bp fragment of the gonadotropin releasing hormone receptor (Gnrhr). A decrease in human GnRHR promoter activity was observed after GnRHa (GnRH agonists) treatment. GnRHa- and TPA-mediated decrease in the human GnRHR promoter activity was reversed by a specific protein kinase C inhibitor. These findings indicate that the activation of the PKC pathway is important in regulating the human GnRHR gene expression. EMSA studies with alphaT3-1 cells transfected with the Gnrhr reporter construct using anti-c-jun antibody demonstrated the binding of c-jun to the AP-1 binding site of the Gnrhr promoter. It was also demonstrated that mutation of the AP-1 binding site at -1000 to -994 abolished the GnRHa (GnRH agonists) induced inhibition. Thus, AP-1-binding site located at -1000 to -994 of the human GnRHR5'-flanking region has been identified to be involved in mediating the down-regulatory effect.
a(SCHEM:Nitroarginine) -| a(CHEBI:"nitric oxide")
when administered intravenously, PAF is hypotensive in all species studied In animal species such as the rat, where platelets are insensitive to PAF action, no tachyphylaxis was observed action of PAF on the heart, peripheral vasculature, and microcirculation may account, at least in part, for the reduction of systemic blood pressure. PAF decreases the cardiac output through several mechanisms: 1) it reduces venous blood return as the consequence of peripheral vasodilatation or vasoconstriction and increased microvascular permeability; 2) it produces a right ventricular overload with an increased right atrial pressure and a reduced filling of left ventricle as the result of an increase in pulmonary vascular resistance; 3) it may impair cardiac function by a direct negative inotropic effect and by reduction of coronary blood flow (CBF); and 4) finally, PAF was shown to affect cardiac electrical activity and the conducting system. 3) it may impair cardiac function by a direct negative inotropic effect and by reduction of coronary blood flow (CBF); and 4) finally, PAF was shown to affect cardiac electrical activity and the conducting system. High doses of PAF, in contrast, produced a sustained decrease of cardiac index, tachycardic response, and transient fall followed by sustained increase of total peripheral resistances In the mesenteric district, a marked reduction of blood flow consequent to the increase in mesenteric resistance was observed (380). it was found that delayed and persistent but not early hypotension induced by PAF is inhibited by Nv-nitro-L-arginine, which inhibits the production of nitric oxide from endothelial cells, thus suggesting a role for the endothelium derived relaxing factor(406).
tscript(p(HGNC:ESR1)) -> bp(GO:"cell proliferation")
conducted using human breast cancer cells, BRCA1 protein inhibited ER-a-mediated transcriptional pathways related to cell proliferation. This finding suggests that in addition to maintaining genomic stability during periods of rapid cellular division and multiplication, BRCA1 may also suppress signaling initiated by estrogen-induced activation of ER-a... A loss of BRCA1 function leads to increased proliferation of malignant cells in cell culture (56, 57), and stable transfection of wild-type BRCA1 into these cells inhibits their growth (58). However, activation of BRCA1 seen during puberty and pregnancy does not seem to block proliferation occurring in the breast at these times.
cat(p(HGNC:GRB2)) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))
80 nM wortmannin reduced both ET-1 and EGF-induced Erk 2 activation. Quantitative densitometric analysis indicated that wortmannin caused a 32% reduction in the phosphorylated:unphosphorylated Erk 2 ratio in ET-1-stimulated cells. ET-1-induced Erk 2 phosphorylation was only partially blocked in the presence of both inhibitors. The degree of inhibition (36%) was similar to that caused by tryphostin AG1478 or wortmannin alone. These results indicate that the tryphostin AG1478-insensitive activation of Erk2 is only partially attributable to the contribution of a PI3K-dependent pathway.
Here, we report that BRCA1 interacts with androgen receptor (AR) and enhances AR target genes, such as p21((WAF1/CIP1)), that may result in the increase of androgen-induced cell death in prostate cancer cells.
a(CHEBI:fulvestrant) -| (a(CHEBI:estradiol) -> r(MGI:Krt19))
Stimulation by estradiol (E2) of K19 mRNA is rapid, with maximal increase at 3 h, and is not blocked by cycloheximide, suggesting that it is a primary response to the hormone. Increased accumulation of K19 protein is observable by 8 h after E2 and levels continue to increase at 24-48 h after E2 treatment. Suppression of E2-induced K19 gene expression by the antiestrogen ICI 182,780 suggests that ER mediates this regulation.
kin(p(MGI:Map2k1)) -> p(MGI:Elk1,pmod(P,S))
kin(p(PFM:"Akt Family")) => p(MGI:Ets2,pmod(P,T,72))
The transcription factor ets-2 was phosphorylated at residue threonine 72 in a colony-stimulating factor 1 (CSF-1)- and mitogen-activated protein kinase-independent manner in macrophages isolated from motheaten-viable (me-v) mice. The CSF-1 and ets-2 target genes coding for Bcl-x, urokinase plasminogen activator, and scavenger receptor were also expressed at high levels independent of CSF-1 addition to me-v cells. Akt (protein kinase B) was constitutively active in me-v macrophages, and an Akt immunoprecipitate catalyzed phosphorylation of ets-2 at threonine 72.
kin(p(HGNC:ERBB2)) -> p(HGNC:SMAD2,pmod(P,S,240))
A phosphopeptide antiserum raised against Smad2 phosphoserine-240 reacted with Smad2 in vivo when coexpressed with Cam kinase II and by activation of the platelet-derived growth factor receptor, the epidermal growth factor receptor, HER2 (c-erbB2), and the TGF-beta receptor.
p(PFH:"TGFB Family") -> complex(p(HGNC:SMAD2),p(HGNC:SMAD3))
Furthermore, Cam kinase II blocked nuclear accumulation of a Smad2 and induced Smad2-Smad4 hetero-oligomerization independently of TGF-beta receptor activation, while preventing TGF-beta-dependent Smad2-Smad3 interactions.
p(HGNC:SMAD2,pmod(P,S,260)) =| tscript(p(HGNC:SMAD2))
Here we report that Smad-TGF-beta-dependent transcriptional responses are prevented by expression of a constitutively activated Ca(2+)-calmodulin-dependent protein kinase II (Cam kinase II). Smad2 is a target substrate for Cam kinase II in vitro at serine-110, -240, and -260.
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Acly)
Table 1. Genes with decreased expression with obesity in each mouse strain
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Apoe)
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Cyc1)
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Echs1)
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Fmo1)
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Gbe1)
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Gpd2)
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Mccc1)
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Srebf1)
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Tshr)
bp(MESHPP:Obesity) negativeCorrelation r(MGI:Uck1)
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Ctsb)
Table 2. Genes with increased expression with obesity
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Dusp1)
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Fcgr3)
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Grn)
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Ifi30)
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Lbp)
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Mrc1)
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Pabpc1)
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Pld3)
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Selplg)
a(SCHEM:Estrogens) -> complex(p(HGNC:PIK3R1),p(HGNC:ESR1))
Here we show that the ER isoform, ER alpha, binds in a ligand-dependent manner to the p85alpha regulatory subunit of phosphatidylinositol-3-OH kinase (PI(3)K). Stimulation with oestrogen increases ER alpha-associated PI(3)K activity, leading to the activation of protein kinase B/Akt and endothelial nitric oxide synthase (eNOS).
p(HGNC:NRAS,sub(Q,61,K)) => gtp(p(HGNC:NRAS))
a(SCHEM:Tretinoin) -> complex(p(HGNC:CDKN2C),p(HGNC:CDK4))
We also showed that an increase in CDK2-bound p27 and CDK4-bound p18 are caused by treatment with ATRA and a decrease in CDK6-bound cyclin D3 is induced synergistically by treatment with both reagents.
tscript(p(MGI:Ncor1)) -> tscript(p(MGI:Rest))
Altered patterns of transcription in tissues and cells derived from N-CoR gene-deleted mice block at specific points in CNS, erythrocyte, and thymocyte development indicated that N-CoR was a required component of short-term active repression by nuclear receptors and MAD and of a subset of long-term repression events mediated by REST/NRSF
a(SCHEM:"Low Density Lipoprotein") -> p(RGD:Tnf)
Exposure of aortic smooth muscle cell to 50 micro gram/mL of human LDL for 6 hours resulted in a marked expression of TNF- alpha mRNA. Incubation of aortic smooth muscle cell with 50 micro gram/mL of LDL for 12 hours induced the release of TNF- alpha from the cell. Also, 6 mg of human LDL was found to activate vascular expression of TNF-alpha within 6-12 hours of stimulation.
Plating of serum-starved cells expressing ephrin-A5 on fibronectin induced phosphorylation of Mapk3. Similarly plating of cells on EphA5-Fc resulted in the phosphorylation of Mapk3, but the activation appeared more robust and prolonged. Preincubation of the cells with a function-blocking antibody specific for beta1 integrin before plating on EphA5-Fc slightly reduced the level of the phosphorylation. These results suggested that only a part of the Mapk3 activation seen in response to ephrin-A5 engagement was due to signalling cascade downstream of integrin beta1.
a(CHEBI:dopamine) -| tscript(complex(NCH:"Nfkb Complex"))
Although DA significantly reduced NF-kappaB binding activity, Grx2 could stimulate the binding of NF-kappaB to DNA by: (i) translocating NF-kappaB from the cytoplasm to the nucleus after promoting the phosphorylation and degradation of I-kappaBalpha, and (ii) activating the binding of pre existing nuclear NF-kappaB.
p(MGI:Tgfb1) -> complex(p(MGI:Nfkb1),p(MGI:Rela))
The TGF-beta1 pre-treatment synergistically stimulated activation and increased in nuclear levels of NF-kB, evoked by RANKL in monocyte/macrophage hemotopoietic cells, which is analyzed in presence of anti-p65 and anti-p50 anti-bodies of NF-kB.
p(RGD:Gsk3b,pmod(P,S,9)) =| kin(p(RGD:Gsk3b))
Consistent with the inhibitory effect of phosphorylation at serine 21 and 9 on GSK-3 activation (9?12), 8-Br-cAMP, forskolin, or isoproterenol dramatically inhibited GSK-3 kinase activity as shown in in vitro kinase assays in Rat1 (Fig. 1A) and HEK293 cells (data not shown).
complex(p(HGNC:SIRPA),p(HGNC:JAK2),p(HGNC:PTPN11)) -| p(HGNC:JAK2,pmod(P))
SIRP is a transmembrane protein that is now known to bind to integrin-associated protein. It appears to bind directly to JAK2 by a process that does not require tyrosyl phosphorylation, although is itself highly phosphorylated on tyrosines in response to GH. The phosphorylated SIRP recruits one or more molecules of the tyrosine phosphatase SHP2 that, in turn, de-phosphorylates SIRP and most likely JAK2.
kin(p(PFH:"MAPK Erk1/3 Family")) -> p(EGID:51776)
Here we have identified a novel MAP kinase kinase kinase (MAPKKK), termed MLTK (for MLK-like mitogen-activated protein triple kinase), whose expression is increased by activation of the ERK/MAPK pathway
results indicate that raising endogenous levels of Ado through inhibition of adenosine kinase can increase the expression of VEGF and stimulate endothelial cell proliferation during normoxic and hypoxic conditions.
We conclude that NFI binding to two NFI elements, at bp -264 to -153, positively regulates TTF-1 expression and controls constitutive TTF-1 levels.
a(CHEBI:dopamine) -| p(HGNC:PPP1R1B,pmod(P,T,75))
We report here that dopamine, in slices, and acute cocaine, in whole animals, decreases the state of phosphorylation of striatal DARPP-32 at Thr-75 and thereby removes this inhibitory constraint.
The pathophysiological response to thrombin is mediated by protease-activated receptor-1 (PAR-1), a seven-transmembrane G protein-coupled receptor expressed in the nervous system that is identical to the thrombin receptor in platelets, fibroblasts, and endothelial cells.
complex(p(MGI:Pdzk1),p(MGI:Cftr)) -> (p(MGI:Cftr) -> sec(a(SCHEM:"Chloride(1-)")))
We have identified a novel hydrophilic CFTR binding protein, CAP70, which is also concentrated on the apical surfaces.
RA stimulated gene expression in both cell types in a time- and dose-dependent manner
complex(complex(NCH:"Dystrophin Associated Glycoprotein Complex"),p(HGNC:AGRN)) -> bp(GO:"cell adhesion")
# Pubmed:gene: Syncoilin, a novel member of the intermediate filament superfamily that interacts with alpha-dystrobrevin in skeletal muscle.
On the other hand, inactivation of phosphorylase by insulin is mediated through the PI-3 kinase pathway involving a rapamycin-sensitive p70(s6k) and PP-1G.
kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -| cat(p(HGNC:PYGM))
In mouse myocyte cultures, triiodothyronine (T3), norepinephrine (NE) through a beta-adrenergic receptor, and leukemia inhibitory factor induced hypertrophy by a 20% to 30% increase in [(3)H]phenylalanine-labeled protein content.
An ELISA assay was used to quantitatively evaluate eotaxin protein expression. This analysis demonstrated marked induction of eotaxin protein expression by aortic smooth muscle cells after treatment with TNF-a, whereas untreated control cells did not show eotaxin protein expression (P,0.001) (Figure 1).
kin(p(HGNC:TGFBR1)) -> complex(p(HGNC:SMAD2),p(HGNC:KAT2B))
Moreover, Smad2 and Smad3 interacted with P/CAF upon TGF-beta type I receptor activation in cultured mammalian cells.
kin(p(HGNC:TGFBR1)) => tscript(p(HGNC:SMAD3))
p(HGNC:KAT2B) -> (kin(p(HGNC:TGFBR1)) => tscript(p(HGNC:SMAD3)))
P/CAF potentiated the transcriptional activity of heterologous Gal4-Smad2 and Gal4-Smad3 fusion proteins. In addition, P/CAF potentiated the TGF-beta/Smad3-induced transcriptional responses, which could be further enhanced by co-activators p300 and Smad4.
tscript(p(HGNC:KAT2B)) -| bp(GO:"cell proliferation")
indicate a direct physical and functional interplay between two negative regulators of cell proliferation, Smad3 and P/CAF.
p(MGI:Ambp) -| bp(GO:"inflammatory response")
It is most abundant at interfaces between the cells of the body and the environment, such as in lungs, intestine, kidneys and placenta. alpha(1)-Microglobulin inhibits immunological functions of white blood cells in vitro, and its distribution is consistent with an anti-inflammatory and protective role in vivo.
kin(p(HGNC:PDPK1)) -> (kin(p(HGNC:PRKCZ)) -> tscript(p(HGNC:SP1)))
kin(p(HGNC:PRKCZ)) -> tscript(p(HGNC:SP1))
In the presence of PDK-1, a major activating kinase for PKC, the Ras-mediated activation of VPF/VEGF promoter through PKCzeta was further increased, suggesting that PKCzeta can serve as an effector for both Ras and PDK-1.
kin(p(HGNC:MAP2K7)) => p(HGNC:MAPK9,pmod(P,T,183))
\"Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7.\" Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183)
kin(p(HGNC:MAP2K7)) => p(HGNC:MAPK10,pmod(P,T,183))
Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1)
p(HGNC:MAPK8,pmod(P,Y,185)) => kin(p(HGNC:MAPK8))
Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7.
kin(p(HGNC:MAP2K1)) -> tscript(complex(NCH:"Nfkb Complex"))
Expression of dominant active Ras or dominant active MEKK1 alone can also stimulate NF-kappaB activation.
kin(complex(NCM:"p85/p110 PI3Kinase Complex")) -> kin(p(MGI:Prkcz))
Because PKC-zeta is located downstream from IRS-1 and phosphatidylinositol 3-kinase in established insulin signaling pathways, PKC-zeta may participate in negative feedback pathways to IRS-1 similar to those described previously for Akt and GSK-3.
a(CHEBI:cisplatin) -> kin(p(HGNC:MAPK14))
Treatment of cells with cisplatin induces a sustained activation of the stress activated protein kinase SAPK/JNK and the mitogen-activated protein kinase p38.
Western blot analysis confirmed the induction of MMP-2, MMP-12, MMP-13, and MMP-14 (Figure 7a, and data not shown) and immunohistochemistry demonstrated that MMP-12 was seen predominantly in macrophages, and MMP-9 was seen in parenchymal locations in epithelial cells and interstitial fibroblast-like cells (Figure 7, b–f, and data not shown).
After beta-adrenergic stimulation (iso 3 h) but not after control perfusion (control 3 h) a roughly threefold increase in B-CK mRNA levels and a decrease in M-CK mRNA levels by 18% was found.
kin(p(HGNC:RAF1)) -| surf(p(HGNC:LGALS3))
Activation of BMK1/ERK5 by epidermal growth factor and H2O2 in Cos7 and HEK293 cells was completely blocked by a kinase-inactive MEKK3 (MEKK3kin(-)),
a(SCHEM:"cyclic AMP") -> tscript(p(HGNC:NR3C1))
Incubation of COS-1 cells with 8-bromo-cAMP resulted in activation of the MAPK pathway, as determined by Western blotting with antibodies to the phosphorylated (active) form of Erk-1/2, suggesting an indirect pathway to SRC-1 phosphorylation. Elevation of intracellular cyclic AMP (cAMP), a common second messenger for a number of hormones and a direct activator of protein kinase A (PKA), can induce a ligand-independent activation of chicken PR (cPR) (22), AR (44), and the ER (8), as well as enhance steroid-dependent activation of a broader range of receptors, including PR (13, 35), ER (8), GR (45), AR (19, 30), and the mineralocorticoid receptor (41).
complex(p(HGNC:EGF),p(HGNC:EGFR)) => kin(p(HGNC:EGFR))
This is consistent with our finding that EGF, an upstream activator of MAPK, enhances the effect of SRC-1 on PR-dependent gene transcription (50).
Estrogens have been shown to upregulate ecNOS expression in different human cell culture systems.
a(SCHEM:"serum glucose") -> cat(complex(NCH:"NADPH Oxidase Complex"))
High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells [vascular SMCs and ECs]
a(CHEBI:"hydrogen peroxide") -> r(HGNC:GADD45A)
Similarly H2O2 and IL-1 also induced GADD45alpha expression in cultured human keratinocytes.
bp(GO:"response to UV") -> r(HGNC:GADD45A)
The expression of GADD45 was examined in cultured skin keratinocytes and in human skin in vivo following UV irradiation. Northern blot analysis revealed that UV-induced the expression of GADD45 (alpha, beta, gamma) in a time- and dose-dependent manner. Messenger RNA of GADD45 (alpha, beta, gamma) increased within 30 min, peaked at 4 h and remained elevated for at least 8 h following UV irradiation
tloc(p(MGI:Alox5),GOCCACC:"GO:0005737",GOCCACC:"GO:0005634") -> cat(p(MGI:Alox5))
(WHI-P97) is a rationally designed potent inhibitor of Janus kinase (JAK)-3. Treatment of mast cells with WHI-P97 inhibited the translocation of 5-lipoxygenase (5-LO) from the nucleoplasm to the nuclear membrane and consequently 5-LO-dependent leukotriene (LT) synthesis
kin(p(RGD:Fgfr3)) -> p(PFR:"Akt Family",pmod(P))
table 1 - genes induced by E2 in breast cancer cells
STAT6 transcription factor inhibits the IFN-gamma induced CD40 expression in the presence of IL4.
Synovial IL-18, TNFalpha and IL-1beta levels were strongly reduced at 90 min after blockage of endogenous IL-18 and were still reduced at 4 hrs.
The TNF-alpha induced activation of NF-kB is completely inhibited by the presence of dominant negative forms of IkB-alpha, IKK-alpha, IKK-beta, IKK-gamma and RIP, where in control cells it is almost 100%.
Furthermore, IL-8, MCP-1, and GRO-1 are known to promote expression of CD11b/CD18 (CR3) on the surface of neutrophils and monocytes ( 32 , 33 ).
p(HGNC:MIF) -| (p(HGNC:COPS5) -> tscript(p(HGNC:JUN)))
Jab1 activates c-Jun amino-terminal kinase (JNK) activity and enhances endogenous phospho-c-Jun levels, and MIF inhibits these effects. MIF also antagonizes Jab1-dependent cell-cycle regulation by increasing p27Kip1 expression through stabilization of p27Kip1 protein
MIF colocalizes with Jab1 in the cytosol, and both endogenous and exogenously added MIF following endocytosis bind Jab1. MIF inhibits Jab1- and stimulus-enhanced AP-1 activity
p(HGNC:MAPK10,pmod(P)) => kin(p(HGNC:MAPK10))
Cellular transfection of beta-arrestin 2 caused cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor activated JNK3
stimulation of AGTR1 activated JNK3 and triggered the colocalization of ARBB2 and active JNK3 to intracellular vesicles
Addition of interleukin-1 alpha (IL-1 alpha) and prostaglandin E(2) (PGE(2)) and F(2 alpha) (PGF(2 alpha)) induced TN-C expression in the stromal cells at both protein and mRNA levels
p(HGNC:VEGFA) -> complex(p(HGNC:ITGAV),p(HGNC:ITGB3),p(HGNC:IBSP))
(Gerber et al., 1998). VEGF and aVb3 have been impli- cated in bone formation and metabolism (Gerber et al., 1999; McHugh et al., 2000), and the effects of VEGF165 stimulation on HUVEC adhesion to the bone matrix pro- tein, bone sialoprotein (BSP) VEGF165, even with incubation times up to 6 hr. The marked influence of VEGF165 on cell migration was demonstrable with a second aVb3 ligand. When HUVECs were provided with a BSP substrate, a substantial in- crease in HUVEC migration was observed when the cells were stimulated with VEGF165(Figure 2C).
cat(complex(p(HGNC:ITGA1),p(HGNC:ITGB1))) -> bp(GO:angiogenesis)
Certain tumor cells exhibited high spontaneous adhesion and migration, which were attributable to a VEGF-dependent autocrine/paracrine activation of integrins. This activation was mediated by the VEGFR2 receptor and regulated via phosphatidylinositol-3-kinase, Akt, and the PTEN signaling axis Of the 22 integrin heterodimers, at least six, aVb3, aVb5, a5b1, a2b1, aVb1, and a1b1, have been implicated in angiogenesis
cat(complex(p(HGNC:ITGAV),p(HGNC:ITGB5))) -> bp(GO:angiogenesis)
kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> (kin(p(HGNC:KDR)) -> cat(complex(p(HGNC:ITGA2),p(HGNC:ITGB1))))
kin(p(HGNC:KDR)) -> cat(complex(p(HGNC:ITGA2),p(HGNC:ITGB1)))
Eighth, the signaling pathway from VEGFR to integrin activation involves PI3-kinase and Akt and is negatively regulated by PTEN.