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

from full text - survivin is one of the most tumour-specific molecules (19), which antagonizes apoptosis (7), promotes tumour-associated angiogenesis (20) (BIRC5 = survivin)

from full text - the aryl hydrocarbon receptor-interacting protein (AIP)56, and HSP90 (Ref . 57), which participate in survivin stability

bp(GO:"response to hypoxia") -> p(HGNC:RPLP2)

Of note, 60S acidic ribosomal protein P2 is increased when the UPR is induced by hypoxia, a condition associated with a global inhibition of protein synthesis (31, 49).

p(HGNC:S100A9) -> kin(p(PFH:"MAPK Erk1/3 Family"))

S100-A9 binds the transcription factors NF-kB and P53, and activates the P38 and ERK MAPK kinases and the receptor for advanced glycated end products (RAGE) (50).

a(SCHEM:Calcium) -> bp(GO:"response to unfolded protein")

The UPR is activated in response to cellular stressors such as RONS, increases in cytosolic calcium, and hypoxia, which impair protein folding in the lumen of the endoplasmic reticulum (ER) (18, 19, 22)

These findings suggest that CLU regulates TGF-beta signaling pathway by modulating the stability of Smad2/3 proteins.

At the nuclear level, phospho-CREB and TORC2 were demonstrated to bind to CRE-I of the Bcl-2 promoter, and GIP treatment resulted in increases in their interaction.

p(HGNC:HES6) -| bp(GO:"cell proliferation")

Hes6 inhibits cell proliferation through induction of p21 cyclin-dependent kinase inhibitor.

p(HGNC:PRKCA) -> bp(GO:"cell cycle arrest")

Analysis of cell cycle distribution revealed that PKCalpha-depletion impaired PMA-induced G2/M arrest in H358 cells (Fig. 6A).

a(CHEBI:"arachidonic acid") => p(HGNC:ALOX5)

See Figure 1: Alternatively, arachidonic acid is also a substrate for lipoxygenases (ALOX-5, 12, and 15), which catalyze the synthesis of proinflammatory leukotrienes and lipoxins.

a(CHEBI:rosiglitazone) -> sec(p(EGID:3630))

In the present study, we examined the effects of rosiglitazone (RGZ) (rosaglitazone is a Pparg agonist) on insulin release and synthesis in pancreatic beta-cell (INS-1). Insulin release and synthesis were stimulated by treatment with RGZ for 24h. RGZ upregulated the expressions of GLUT-2 and glucokinase (GCK). Moreover, it was found that RGZ increased the expression of BETA2/NeuroD gene which could regulate insulin gene expression.

cat(p(HGNC:TLR3)) -> tscript(p(HGNC:IRF3))

Double-stranded RNA is a marker for viral infection that is recognized by TLR3. TLR3 triggering activates specific signaling pathways that culminate in the activation of NF-kappaB and IRF3 transcription factors, as well as apoptosis

kin(p(HGNC:MAPK1)) => p(HGNC:FOXO3,pmod(P,S,344))

Here, we show that Erk downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which consequently promotes cell proliferation and tumorigenesis

kin(p(HGNC:ATM)) -| complex(p(HGNC:MDM2),p(HGNC:TP53))

ATM-mediated phosphorylation of p53 stabilizes this tumor suppressor protein by reducing constitutive interactions with MDM2, which usually promotes the degradation of p53 (Figure 1) (Giaccia and Kastan, 1998; Chin et al., 1999).

a(CHEBI:"reactive oxygen species") -> kin(p(HGNC:MAPK8))

TPA stimulates increased generation of ROS and initiates the stress-activated protein kinase (SAPK) pathway via protein kinase C (PKC) bII activation (Datta et al., 2000), representing typical characteristics of STASIS...Activation of stress kinases (JNK, MAPK, p38) (Day 2008; Gao et al., 2008; Kirkham and Rahman, 2006; Kliment et al., 2008; Koli et al., 2008)

a(SCHEM:"Tetradecanoylphorbol acetate") -> kin(p(HGNC:MAPK8))

tscript(p(HGNC:"NKX2-1")) -| bp(MESHPP:Apoptosis)

Small interfering RNA (siRNA)-mediated knockdown of TITF1 in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis.

a(CHEBI:lipopolysaccharide) -> p(MGI:Pak2,pmod(P,S,141))
p(MGI:Cdkn1a) -> (a(CHEBI:lipopolysaccharide) -> p(MGI:Pak2,pmod(P,S,141)))

MPO Activity and Phosphorylation of p21-Activated Kinase on ser141 Residue Were Decreased in Lungs of p212/2 Mice in Response to CS Exposure or LPS Aerosolization

a(CHEBI:lipopolysaccharide) -> tscript(complex(NCM:"Nfkb Complex"))
p(MGI:Cdkn1a) -> (a(CHEBI:lipopolysaccharide) -> tscript(complex(NCM:"Nfkb Complex")))

Moreover, genetic knockout of p21 attenuated angiotensin II?induced NF-kB activation by decreasing the production of reactive oxygen species (ROS) in vitro and in vivo (25). Targeted disruption of p21 was associated with decreased NF-kB activation in glial cells in response to lipopolysaccharide (LPS) (27).

a(CHEBI:lipopolysaccharide) -> p(MGI:Il1b)
p(MGI:Cdkn1a) -> (a(CHEBI:lipopolysaccharide) -> p(MGI:Il1b))

Our data showed that CS exposure increased the levels of KC, MCP-1, IL-6, and TNF-a in the lungs and that these levels were significantly decreased in p21-/- mice (Figure 6A). The levels of KC, MCP-1, IL-6 and IL-1b were also significantly reduced in the lungs of p21-/- mice compared with WT mice exposed to aerosolized LPS (Figure 6B).

a(CHEBI:lipopolysaccharide) -> p(MGI:Il6)

a(CHEBI:lipopolysaccharide) -> p(MGI:Tnf)

kin(p(PFM:"Mapk p38 Family")) -> r(MGI:Ptgs2)

Kumagai et al. [40] examined the relation between COX-2 mRNA stability and HNE-activated p38 MAPK pathway and found that the p38 MAPK–specific inhibitor accelerated COX-2 mRNA degradation [15••,43].

cat(p(HGNC:EP300)) => tscript(p(HGNC:TP53))

We demonstrate that Skp2 forms a complex with p300 through the CH1 and the CH3 domains of p300 to which p53 is thought to bind and antagonizes the interaction between p300 and p53 in cells and in vitro. As Skp2 antagonizes the interaction between p300 and p53, Skp2 suppresses p300-mediated acetylation of p53 and the transactivation ability of p53.

kin(p(HGNC:PRKCZ)) -> p(HGNC:SP1,pmod(P,S,670))

Here we have used a variety of approaches to identify 3 amino acids (Thr668, Ser670, and Thr681) in the zinc finger domain of Sp1 that are modified by PKC-zeta

kin(p(HGNC:PRKCZ)) -> p(HGNC:SP1,pmod(P,T,681))

p(MGI:Dsg3) -| bp(GO:"cell proliferation")

Anti-Dsg3 adhesion-disrupting antibodies are produced in the majority of Pemphigus vulgaris patients (Amagai et al., 1991; Payne et al., 2004) or experimentally in the mouse (monoclonal anti-Dsg3 (AK23)) (Tsunoda et al., 2003). When added to cultured mouse keratinocytes at the beginning of the transitional phase, they induce, besides other events (for review see Amagai et al., 2006), sustained proliferation, in correlation with a dramatic upregulation of c-Myc (Williamson et al., 2006).

path(SDIS:"integrin mediated cell adhesion") -> bp(GO:"cell proliferation")

Blocking phosphatidylinositol trisphosphate kinase (PI3K) or alternatively, EGF-R of suspension cells, induces apoptosis. Inversely, if integrins are cross-linked, proliferation is maintained (Adams and Watt, 1989; Watt et al., 1993; Rodeck et al., 1997; Nikolopoulos et al., 2005).

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

See Table 2: Inflammatory Gene Expression in 12-16 Week Mdr1a(-/-) Colon Compared to Age-matched Controls. p< 0.05

See Table 3: Significant differences in colonic mucosal gene expression in 4-5 week mdr1a (-/-) mice versus age-matched FVB controls. Note: p<0.05 and all fold changes are greater than or less than 2.

After initial cholesterol loading, mouse SMCs upregulate ABCA1 and ABCG1 while downregulating the typical smooth muscle markers including smooth muscle ?-actin, ?-tropomyosin and myosin heavy chain 32.

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

PPAR-{gamma} inhibits the activities of NF-{kappa}B and AP-1 to suppress the promoter activity of these molecules

ATR activation by DSBs requires ATM and MRN–CtIP, it occurs only during S and G2 phases, and it is abolished by CDK inhibition13,44

complex(p(HGNC:RNF8),p(HGNC:MDC1)) -> p(HGNC:BRCA1)

Recent evidence suggests that RNF8 binds to MDC1 and ubiquitylates phosphorylated H2AX. These events facilitate the recruitment of factors (such as BRCA1 and 53BP1) that are required for DNA repair and checkpoint signalling, probably through a ubiquitin-ligase cascade98?100,102 (FIG. 2). (primary sources used as in statements)

p(MGI:Trim24) -| path(SDIS:calcification)

Calcifications in lungs and vibrissae affected 100% and 88% of the 8- to 10-month-old TIF1/ mutants, respectively.

tscript(p(MGI:Nr1h3)) -> bp(GO:"cholesterol transport")

Liver X receptor (LXR) alpha and beta are members of the nuclear receptor superfamily of ligand-activated transcription factors. Best known for triggering \"reverse cholesterol transport\" gene programs upon their activation by endogenous oxysterols, LXRs have recently also been implicated in regulation of innate immunity.

Figure 6 A. Repression of specific target genes involved in myeloid hyperplasia and/or hematopoiesis by miR-155.

p(HGNC:CXCL1) -> bp(GO:"neutrophil chemotaxis")

Here we demonstrate that cholesterol was absolutely required for polarized redistribution of key chemotactic mediators in human neutrophils in response to all chemoattractants tested (fMet-Leu-Phe, and the chemokines CXCL1, CXCL8 and CXCL12).

p(MGI:Cav1) -> (path(MESHD:Hyperoxia) -> bp(GO:"cell death"))
path(MESHD:Hyperoxia) -> bp(GO:"cell death")

After 72 hours of hyperoxia exposure, we found that cav-1-/- fibroblasts were resistant to hyperoxia-induced cell death, with 60% survival observed in cav-1-/- fibroblasts compared with less than 20% survival in the wild-type fibroblasts (Figure 1A)....Similar results were observed in MLEC cells (Figure 1B). Approximately 50% survival after hyperoxia in cav-1-/- MLEC was found, compared with 20% survival in wild-type MLEC - mouse lung endothelial cells

By utilizing short interfering RNAs against ETS-1, we have also determined that ETS-1 is required to induce the production of fibronectin in response to ANG II.

Here, we examined mechanisms through which the family of PITX proteins control murine FSH beta-subunit (Fshb) transcription. We observed that endogenous PITX1 and PITX2 isoforms from murine LbetaT2 gonadotrope cells could bind a highly conserved proximal cis-element. Transfection of PITX1 or PITX2C in heterologous cells stimulated both murine and human Fshb/FSHB promoter-reporter activities, and in both cases, mutation of the critical cis-element abrogated these effects.In homologous LbetaT2 cells, the same mutation decreased basal reporter activity and greatly reduced activin A-stimulated transcription from murine and human promoter-reporters. Transfecting dominant-negative forms of PITX1 or PITX2C or knocking down PITX1 or -2 expression by RNA interference in LbetaT2 cells inhibited murine Fshb transcription, confirming roles for endogenous PITX proteins.

See Table 2. HOXC6 direct targets affected by loss of HOXC6 expression in normal mouse prostates. All fold changes are greater than or equal to 1.5

tscript(p(HGNC:HOXC6)) => r(HGNC:FAM101A)

tscript(p(HGNC:HOXC6)) => r(HGNC:ZNF536)

MI-43 induced the accumulation of p53 and its downstream target genes, Mdm2, p21, Noxa and Puma only in wt p53-containing cells, indicating that disruption of Mdm2-p53 binding increases p53

Consistently, cotransfection assays demonstrate that STRA13 and DEC2 both antagonize CLOCK:BMAL1 dependent transactivation of the Rev-erbalpha {NR1D1} and Dbp promoters.

tscript(p(HGNC:BHLHE41)) -| r(HGNC:NR1D1)

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

Although AKT can phosphorylate several proteins4, we focused on BAD, FOXO, IKKa, TSC2 and eNOS, as the consequence of AKT phosphorylation of these proteins is not redundant with the functions of the oncoproteins expressed in cells used in the cellmixing assay of tumour maintenance5 (Supplementary Fig. 1).

kin(p(PFH:"AKT Family")) => p(HGNC:NOS3,pmod(P,S))

p(HGNC:CTNNB1) -> (p(HGNC:TGFB1) -> p(HGNC:ACTA2))

Accordingly, silencing of ?-catenin (Fig. 4A and D) by siRNA (100 nM), did not affect basal levels of ?-SMA, but reduced TGF-?1-induced ?-SMA expression (Fig. 4C and E).

TGF-beta1 treatment activated the MAPK pathway, as shown by an increased phosphorylation of extracellular-regulated kinases (ERK)1/2 after 30 min of exposure.

a(CHEBI:"reactive oxygen species") -| kin(p(HGNC:IKBKB))

In addition, IKK? and IKK? contain a redox sensitive cysteine residue that is sensitive to oxidative modification. Oxidative modification of this residue by ROS results in inactivation of IKK (Rossi et al., 2000; Kapahi et al., 2000)

tscript(complex(NCH:"Nfkb Complex")) => r(HGNC:MYLK)

TNF-alpha-induced increase in MLCK promoter activity was mediated by NF-kappaB activation. There were eight kappaB binding sites on MLCK promoter. The NF-kappaB1 site at +48 to +57 mediated TNF-alpha-induced increase in MLCK promoter activity. The NF-kappaB2 site at -325 to -316 had a repressive role on promoter activity. The opposite effects on promoter activity were due to differences in the NF-kappaB dimer type binding to the kappaB sites. p50/p65 dimer preferentially binds to the NF-kappaB1 site and up-regulates promoter activity; while p50/p50 dimer preferentially binds to the NF-kappaB2 site and down-regulates promoter activity.

Genes were considered to be differentially expressed if they had a difference in expression level between the two conditions that was at least twofold and the extent of difference in expression was statistically significant (p ! 0.05) in a parametric Welsh-analysis of variance t-test. Only genes that showed concordant results in all three replicates were selected for further evaluation. Genes that differed significantly between wild-type Meis1 and the nonleukemogenic Meis1DHD mutant (lacking its DNAbinding domain) were then identified. With this approach 134 genes (70 increased and 64 decreased, Table 1) could be identified as significantly differentially expressed and linked to the oncogenicity of Meis1.

tscript(p(MGI:Meis1)) -| r(MGI:"H2-DMb2")

tscript(p(MGI:Meis1)) -> r(MGI:Slc16a12)

tscript(p(MGI:Meis1)) -> r(MGI:"Xlr4e-ps")

p(HGNC:AKT1,pmod(P,S,473)) => kin(p(HGNC:AKT1))

Furthermore, we show that inhibition of mTOR by rapamycin induces the activation of Akt as shown by increased Akt phosphorylation at Ser(473) and the inhibition of 6-TG-induced apoptosis and cell death. Activated Akt is a well-known inhibitor of autophagy.

bp(GO:"response to hypoxia") -> p(EGID:5243)

hypoxia caused HIF-1alpha activation, Pgp overexpression and increased resistance to doxorubicin accumulation and toxicity.

bp(GO:"response to hypoxia") -> r(HGNC:ABCB1)

complex(p(HGNC:IL12A),p(HGNC:IL12B)) -> p(HGNC:STAT3,pmod(P,Y))

IL-12 and IL-23 tyrosine phosphorylated STAT3 and STAT1, respectively; IL-12, IL-23, and IL-27 tyrosine phosphorylated JAK2 and tyrosine kinase-2; and IL-27 tyrosine phosphorylated JAK1.

complex(p(HGNC:IL12A),p(HGNC:IL12B)) -> p(HGNC:TYK2,pmod(P,Y))

See supplemental Table 4: GAPDH normalized mir-29c candidate target gene expression in HeLa and HepG2 cells. Note: all fold changes are greater than 1.5.

p(HGNC:EZH2) -> bp(GO:"DNA methylation")

The knockdown of EZH2 in cultured CC cells decreased p16 INK4a methylation and decreased binding of EZH2 to the p16 INK4a gene promoter. The latter suggested that direct binding of EZH2 is involved in the regulation of the p16 INK4a gene. Our data suggest that over-expression of EZH2 may induce hypermethylation of p16 INK4a promoter followed by decreased expression of p16 INK4a in the multi-step cholangiocarcinogenesis through intraepithelial neoplasm in hepatolithiasis.

p(HGNC:TLR9) -| path(SDIS:"viral infection")

The importance of TLR9 was highlighted by the fact that mice lacking TLR9 showed drastically increased susceptibility to infection with ECTV.

bp(GO:"hypotonic response") -> tloc(p(HGNC:NFAT5),GOCCACC:"GO:0005634",GOCCACC:"GO:0005737")

Knockdown of CK11L, a novel isoform of CK1, inhibits hypotonicity-induced OREBP/TonEBP nuclear export.

p(HGNC:NOV) -| bp(GO:"cell proliferation")

As CCN3 was shown to inhibit cell growth,

It was shown that the frequency of CD29+CD24+ stem cells in the mammary gland increases by a factor of 6.4 following activation of WNT1 (Ref . 201).

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

The Rel/NF-kappaB transcription factors are key regulators of programmed cell death (PCD)... NF-kappaB most commonly antagonizes PCD by activating the expression of antiapoptotic proteins and antioxidant molecules, but it can also promote PCD under certain conditions and in certain cell types

p(RGD:Tgif1) -| (p(RGD:Tgfb1) -> p(RGD:Eln))

As shown in Fig. 4E, the TGF-1-mediated upregulation of tropoelastin expression was inhibited by overexpression of hTGIF.

In the absence of TGF--neutralizing antibody, tropoelastin protein levels were upregulated by TGF-1 but downregulated by EGF.

a(SCHEM:U0126) -| (p(RGD:Egf) -> p(RGD:Tgif1,pmod(P)))

Indeed, AG1478 or U0126 treatment prevented the EGF-mediated increase in phosphorylated and total TGIF levels (Fig. 3B),

p(RGD:Egf) -| (p(RGD:Tgfb1) -> p(RGD:Eln))

but EGF was still able to downregulate tropoelastin protein levels when the TGF- signaling and tropoelastin expression were rescued by the addition of TGF-1.

cells that overexpress human TGIF (hTGIF) wild-type (hTGIF WT) or hTGIF mutant (hTGIF 1-148:177- 262), which is devoid of the Smad interaction domain and is not able to interact with Smad2/3 (35). As shown in Fig. 4D, tropoelastin expression was inhibited by overexpression of hTGIF WT in a dose-dependent manner

tscript(p(HGNC:CBFA2T3)) =| r(HGNC:TCF12)

Our results show that the E-box gene HEB is a direct target of CBFA2T3-ZNF652-mediated transcriptional repression. The CBFA2T3-ZNF652 complex regulates HEB expression by binding to a single ZNF652 response element located within the promoter sequence of HEB. This study also shows that the NHR3 and NHR4 domains of CBFA2T3 interact with a conserved proline-rich region located within the C terminus of ZNF652.

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> p(HGNC:SGK1,pmod(P,S,422))

Here we report that PI3-K-dependent phosphorylation of SGK-1 requires formation of a complex between SGK-1 and heat-shock protein 90 (Hsp90).

a(CHEBI:erlotinib) -| path(SDIS:"tumor growth")

Epidermal growth factor receptor (EGFR)–specific tyrosine kinase inhibitors (TKI) gefitinib and erlotinib have been developed as therapeutic agents for non–small cell lung cancer (NSCLC) treatment (1, 2, 3).

Studies to date suggest that, in these cancers, several (if not all) of the critical downstream signaling pathways, including the phosphoinositide 3-kinase (PI3K)/Akt, signal transducers and activators of transcription, and extracellular signal-regulated kinase 1 and 2 pathways, are solely controlled by EGFR. Thus, when the tumors are exposed to EGFR inhibitors, these intracellular pathways are turned off and the cancer cells undergo apoptosis (21, 22, 24, 25).

kin(p(HGNC:EGFR)) -> tscript(p(PFH:"STAT Family"))

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

Primer extension, using RNA from cells transiently transfected with MEP-CAT fusion plasmids, demonstrates that phorbol ester treatment increases the amount of transcript

p(PFH:"TGFB Family") -| bp(GO:"cell proliferation")

AEC actively inhibit the proliferation of both normal and fibrotic fibroblasts via TGF-beta, which induces the prostaglandin E(2) synthesis in fibroblasts

The regulation of Net1 activity is poorly understood. PAK1-dependent phosphorylation of Net1 on Ser152 and Ser153 inhibits its GEF activity and abolishes Net1-dependent RhoA activation and stress fiber induction [15].

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

Recent studies have also demonstrated that PPAR? activation induces proline oxidase, which will result in increased production of cytotoxic reactive oxygen species (ROS) [36].

Here we found that IL-6 stimulation induced lysosome-dependent degradation of gp130, which correlated with an increase in the K63-linked polyubiquitination of gp130. The stimulation-dependent ubiquitination of gp130 was mediated by c-Cbl, an E3 ligase, which was recruited to gp130 in a tyrosine-phosphorylated SHP2-dependent manner.

Our cellular and molecular dissection showed that the PDGF-BB/PDGFRbeta kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8)

tscript(p(HGNC:NR3C1)) =| tscript(complex(NCH:"AP-1 Complex"))

Moreover, nTrip6 is an essential component of glucocorticoid receptor (GR)-mediated trans-repression of AP-1, in that it mediates the tethering of GR to the promoter-bound AP-1.

gAd induced the phosphorylation of MEK1/2 and ERK1/2 in RAW264 cells. In addition, the gAd-induced phosphorylation of MEK1/2 and ERK1/2 was dramatically reduced by PD98059 and U0126, respectively.

kin(p(HGNC:MAP2K1)) -> tscript(complex(NCH:"Nfkb Complex"))

Besides NF-kB, the activation of C/EBPb also increased in response to MEK induction and the C/EBPb messenger RNA itself was also upregulated during OIS (Figure S9).

cat(p(EGID:3579)) -> a(CHEBI:"reactive oxygen species")

The location of CXCR2 in endosomes can be considered as a surrogate marker for CXCR2 activation (Sai et al., 2006 and Figure S12) and correlates with other effects caused by CXCR2 activation such as production of reactive oxygen species (ROS) (Figure S13).

Transactivated genes in HBMEC exposed to aldosterone (107 M) for 6 h by gene array

tscript(p(HGNC:E2F6)) -| tscript(p(HGNC:E2F1))

During hypoxia (CoCl(2), 800 microM)-induced human embryonic kidney 293 cell apoptosis, E2F6 expression was down-regulated with concurrent increases in E2F1 expression and transactivation. E2F6 overexpression abrogated hypoxia-induced apoptosis and alteration of E2F1. Conversely, specific knockdown of E2F6 by small interfering RNA had opposite effects. Chromatin immunoprecipitation assay confirmed that E2F6 regulated E2F1 expression through the transrepression of E2F1 promoter. Interestingly, E2F1 transactivation and apoptosis induced by hypoxia in cells stably expressing E2F1 were inhibited by E2F6 overexpression, suggesting that the inhibitory effects of E2F6 are not only mediated by the repression of E2F1 promoter.

Expression of CYP7A1, the rate-limiting enzyme of the neutral pathway, is decreased in livers of Rev-erbalpha-deficient mice, whereas adenovirus-mediated hepatic Rev-erbalpha overexpression induces its expression. Moreover, bile acid feeding resulted in a more pronounced suppression of hepatic CYP7A1 expression in Rev-erbalpha-deficient mice.

a(CHEBI:acrolein) -| (a(CHEBI:lipopolysaccharide) -> tscript(complex(NCM:"Nfkb Complex")))

Acrolein decreases NF-kB activation in vivo - NF-kBp65 activity in nuclear extracts was markedly enhanced after LPS challenge, as expected. Moreover, both basal and LPS-induced NF-kBp65 activity was significantly reduced following exposure to acrolein compared with exposure to room air.

p(HGNC:F2) -> bp(GO:"platelet activation")

Fig. 2 Activation of platelets by convulxin (open triangles, n = 5), thrombin (closed circles, n = 6), PAF (open circles, n = 6) and ADP (closed triangles, n = 3).

tscript(p(MGI:Foxo1)) -> sec(a(CHEBI:cholesterol))

Disinhibition of the forkhead transcription factor FoxO1, increases expression of the biliary cholesterol transporters Abcg5 and Abcg8, resulting in an increase in biliary cholesterol secretion.

Phosphorylation of TIF1beta/Ser473 coincides with the induction of cell cycle gene cyclin A2 at the S-phase. Interestingly, chromatin immunoprecipitation demonstrated that the promoter of cyclin A2 gene is occupied by TIF1beta and that such occupancy is inversely correlated with Ser473 phosphorylation. Additionally, when HP1beta was co-expressed with TIF1beta/S473A, but not TIF1beta/S473E, the colocalization of TIF1beta/S473A and HP1beta to the promoters of Cdc2 and Cdc25A was enhanced. Non-phosphorylated TIF1beta/Ser473 allowed greater TIF1beta association with the regulatory regions and the consequent repression of these genes.

tscript(p(HGNC:TRIM28)) =| r(HGNC:CDC25A)

Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice.

a(SCHEM:"Oxidized Low Density Lipoprotein") -| r(HGNC:SLA)

Table 4 -Genes uniquely regulated by oxLDL.

p(PFM:"Raf Family") -| bp(MESHPP:Apoptosis)

Acute DSS exposure induced colon epithelial cell death in both wild-type and Raf KOIE mice; however, apoptosis was significantly higher in the absence of Raf expression following 1- and 4-day DSS treatment.

Functional studies revealed that the wild-type and mutant OTX2 proteins localized to the nucleus and bound to the target sequences within the IRBP (interstitial retinoid-binding protein), HESX1 (HESX homeobox 1), and POU1F1 promoters. Furthermore, the wild-type OTX2 protein markedly transactivated the promoters of IRBP ( approximately 27-fold), HESX1 ( approximately 4.5-fold), and POU1F1 ( approximately 19-fold),

Nicotine activates survivin gene transcription in A549 NSCLC cells by increasing the recruitment of E2F1 and the concomitant dissociation of Rb from the survivin promoter (7).

kin(p(HGNC:EIF2AK3)) => p(HGNC:EIF2S1,pmod(P,S,52))

Activated PERK then phosphorylates the translation-initiation factor eIF2a, reducing the overall frequency of messenger RNA translation initiation. However, selected mRNAs, such as ATF4 mRNA, are preferentially translated in the presence of phosphorylated eIF2a. ATF4 activates the transcription of UPR target genes encoding factors involved in amino-acid biosynthesis, the antioxidative-stress response and apoptosis.

p(PFM:"Akt Family",pmod(P,T,308)) => kin(p(PFM:"Akt Family"))

from full text Results - Collectively, these results indicate that PKCz is an upstream regulator of Akt activation by phosphorylating Ser124. To demonstrate that PKCz is actually required in vivo for the phosphorylation of Akt’s Ser473 and Thr308, we analysed these parameters in EFs WT and KO for PKCz

Table 1: Genes responsive to PI3K, mTOR and p70S6K inhibitions in breast cancer cell lines.;MCF-7 breast cancer cell line, RPS6KB1-suppressed

In keratinocytes and mammary epithelial cells, c-MYC downregulation is mediated by a TGF?-induced protein complex containing Smad3/4, p107, E2F4/5, and C/EBP? (Chen et al., 2002; Gomis et al., 2006b).

p(HGNC:EGF) -> p(PFH:"CREB Family",pmod(P,S))

TABLE V Survey of cell signaling proteins that show a reaction to EGF ligand stimulation over a 180-min time course - 500ng/mL EGF results

p(HGNC:EGF) -> p(HGNC:EGFR,pmod(P,Y,992))

p(HGNC:EGF) -> p(HGNC:KIT,pmod(P,Y,703))

p(HGNC:EGF) -> p(HGNC:RPS6KA2,pmod(P,S,380))

p(HGNC:EGF) -> p(HGNC:SHC1,pmod(P,Y,416))

We conclude that metformin treatment leads to the overexpression of UCP2 in adipocytes to minimize the oxidative stress that is probably due to the inhibition of respiration caused by the drug.

In vitro, treatment with siRNA for EMMPRIN hindered the induction of MMP-9 and MT1- MMP as well as of various cytokines such as interleukin-6 or TNF-alpha indicating a role for EMMPRIN far beyond simple MMP induction [31,32].

a(SCHEM:"Benzo(a)perylene") -> p(HGNC:PTGS2)

benzo[a]pyrene (B[a]P), induce COX-2 expression in lymphocytes, epithelial cells, and fibroblasts (9–11).

HMGB1 is also found extracellularly after passive release by necrotic cells or through active secretion from stimulated inflammatory cells (19). In the extracellular environment, this alarmin initiates proinflammatory responses to coordinate repair of damaged tissue through recruitment of leukocytes and stimulation of angiogenesis (19–22).

bp(GO:"inflammatory response") -> sec(p(HGNC:CAMP))

Like other alarmins, hCAP-18/LL-37 is constitutively secreted by a variety of immune and epithelial cells and is elevated in response to inflammation and tissue injury (13).

The differential expressed genes from the functional effects of ATF5 were examined by array profiling. Over a hundred genes were identified, among which ID1 contains the ATF/CREB target binding sequences within its promoter region. An inverse relationship between ATF5 expressions with ID1 transcriptions was verified in HCC (P = 0.019), and a direct interaction of ATF5 on the promoter of ID1 was further demonstrated from electromobility shift assay.

a(CHEBI:glutathione) -> cat(p(PFH:"GPX Family"))

However, this detoxification process can be overwhelmed in some circumstances. One such circumstance is the depletion of mitochondrial, reduced glutathione. Normally, glutathione peroxidase plays a key role in H2O2 detoxification, as liver mitochondria do not have catalase. However, glutathione peroxidase needs adequate amounts of reduced glutathione in the mitochondrial matrix to detoxify H2O2. The depletion of mitochondrial glutathione below a critical threshold can impair mitochondrial H2O2 detoxification, which can trigger mitochondrial dysfunction, mitochondrial permeability transition (MPT) and cell death [22].

a(CHEBI:glutathione) -| path(SDIS:"mitochondrial damage")

cat(complex(NCH:"proton-transporting ATP synthase complex")) -> a(SCHEM:"Adenosine triphosphate")

The ??m serves as a reservoir of potential energy. When cells need energy, the rise in ADP levels within the mitochondria induces the re-entry of protons into the mitochondrial matrix through the membrane-spanning F0 portion of the ATP synthase complex (also referred to as the 'complex V of the MRC'). This re-entry of protons partially dissipates the ??m, thus liberating energy, which is used by the F1 portion of ATP synthase to phosphorylate ADP into ATP (Figure 1).

Meis2 and Islet1 proteins can bind and activate reporter gene transcription via the I56ii enhancer sequence......I56i and I56ii in the Dlx5/6 cluster.

path(SDIS:"Inflammatory Bowel Disease") -> p(HGNC:NFATC2)

Figure 1. Enhanced expression of NFATc2 transcription factors in patients with IBDs compared with control patients. (A) Immunohistochemistry for NFATc2 expression. Colon cross sections were incubated with NFATc2-specific antibodies and analyzed by microscopy. An increased expression of NFATc2 was observed in sections from UC and CD patients compared with control patients.

PRDM16 binds and activates the transcriptional function of PPARalpha

p(MGI:Cpt1c) -> path(SDIS:"food intake")

CPT1c knockout (KO) mice have lower food intake, weigh less and have less body fat, consistent with the role as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c protects against the effects of a high-fat diet. CPT1cKO mice exhibit decreased rates of fatty acid oxidation, consistent with their increased susceptibility to diet-induced obesity. Cpt1c is the neuronal CPT1 enzyme, the rate limiting enzyme of fatty acid beta oxidation.

cat(p(HGNC:FASN)) -| a(SCHEM:"Malonyl coenzyme A")

The cellular malonyl-CoA level is determined by its rate of synthesis, catalyzed by acetyl-CoA carboxylase (ACC) {Official Gene Symbols: ACACA, ACACB}, and rate of removal, by fatty acid synthase (FAS).

kin(p(PFH:"RAF Family")) -> kin(p(PFH:"MEK1/2 Family"))

Growth factor and other survival signals are transduced through receptor tyrosine kinases via adaptor proteins (such as GRB2 and the guanine-nucleotide exchange factor SOS) and activate Ras and its downstream targets, Raf and MEK1/2, which results in the activation of ERK1/2.

bp(GO:"response to hypoxia") -> p(HGNC:NOS3)

hypoxia-induced AMPK activation of endothelial NOS (eNOS) drives angiogenesis

gtp(p(HGNC:RAC1)) -> tscript(p(PFH:"SMAD Family"))

We also show that the Smad site in the CTGF/CCN2 promoter is responsive to both Rac1 inhibition and cytochalasin D treatment, suggesting a role of TGFbeta/Smad signaling in mediating the effects of actin dynamics and Rac1.

path(SDIS:"food intake") -> r(HGNC:CEBPA)

During caloric restriction, adipose tissue C/EBPalpha mRNA levels were reduced in subjects with the metabolic syndrome (P = 0.024) and correlated to metabolic parameters.

p(MGI:Scarb1) -| path(SDIS:"Atherosclerotic lesion")

However, bone marrow transplantation experiments have demonstrated that macrophage-specific SR-BI deficiency leads to increased atherosclerotic lesions in Apoe/ mice [29].

tscript(p(HGNC:NR0B2)) -| m(HGNC:MIR433)

Estrogen related receptor (ERRgamma, NR3B3) robustly activated miR-433 and miR-127 promoter reporters through ERRE, which was transrepressed by SHP.

a(SCHEM:"Mycobacterium tuberculosis, ext.") -> r(MGI:Ccr5)

Bacterial load in the lungs, the lesions associated with infection and gene expression profiling was performed by comparing normal lungs tissue to lungs from mice collected at 20, 40 and 100 days after aerosol infection with the H37Rv strain of M. tuberculosis.

a(SCHEM:"Mycobacterium tuberculosis, ext.") -> r(MGI:Ctss)

a(SCHEM:"Mycobacterium tuberculosis, ext.") -> r(MGI:Ms4a6d)

a(SCHEM:"Mycobacterium tuberculosis, ext.") -> r(MGI:Ncf1)

a(SCHEM:"Mycobacterium tuberculosis, ext.") -> r(MGI:Slc26a4)

We demonstrate that multiple transcriptional co-activators are involved in MMP-9 promoter activation, including CBP/p300, PCAF, CARM1 and GRIP1. Furthermore, enhancement of MMP-9 promoter activity requires the histone acetyltransferase activity of PCAF but not that of CBP/p300, and the methyltransferase activity of CARM1. More importantly, these co-activators are able to activate MMP-9 promoter activity independently, and function in a synergistic manner. Chromatin immunoprecipitation assays demonstrate that these co-activators associate with the endogenous MMP-9 promoter, and that siRNA knockdown of expression of these co-activators reduces endogenous MMP-9 expression.

bp(GO:"response to UV-B") -| r(HGNC:ABCD3)

Microarray analysis identified 21 genes as UVB-responsive genes with a peak at 24 h in 6 subjects, and real-time PCR validated the significant down-regulation of 9 (ABCB10, ATF1, ABCD3, TANK, FAS, SLC30A9, CHUK, CASP1, and ABCE1) out of the 21 genes in 11 subjects.

bp(GO:"response to UV-B") -| r(HGNC:ABCE1)

bp(GO:"response to UV-B") -| r(HGNC:CASP1)

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

Supplementary Table 1. Genes with altered expression, as defined by FDR-adjusted p < 0.05 and >=1/5 or <=-1 log2-fold change, in subpallium from Arx-/Y; Pou3f4-Cre+ mice when compared to genes expressed in the subpallium of Arxwt/Y; Pou3f4-Cre+ mice. {4 WT and 4 KO mice used in analysis}

Specific mis-sense mutations in the human Ant1 cause autosomal dominant Progressive External Ophthalmoplegia (adPEO), mitochondrial myopathy and cardiomyopathy, which are commonly manifested by fractional mitochondrial DNA (mtDNA) deletions.

a(CHEBI:lipopolysaccharide) -> sec(p(HGNC:SAA3P))

We also found that both S100A8 and lipopolysaccharide (LPS) stimulated SAA3 protein secretion into LCM. (By WB, in lung endothelial cells)

p(HGNC:TLR4) -| p(HGNC:NFKBIA,pmod(P,S))

We found that SAA3–GST induced phosphorylation of I?B-? in macrophages derived from wild-type mice but not in those derived from TLR4 knockout (TLR4–/–) mice (Fig. 3f).

a(CHEBI:fulvestrant) -| tscript(p(HGNC:ESR1))

Similarly, treatment with ICI 182780 (Fulvestrant ) resulted in a dose-dependent decrease in ESR1/ERE transactivation in both cell lines (Fig. 1D).

Figure 5a shows that treatment of A549 cells with nicotine causes an increase in the levels of mesenchymal proteins like fibronectin and vimentin with a concomitant downregulation of epithelial markers E-cadherin and b-catenin. Interestingly, nicotine induced EMT in breast cancer cell lines like MCF-7 and MDA-MB-468; this is significant as smoking has been correlated with increased metastasis of breast cancers.

It was found that the maximal effect of nicotine was observed at 1 lM concentration, whereas 0.1 lM nicotine also induced EMT like changes (Fig. 5b)... levels of fibronectin, vimentin and N-cadherin were elevated

a(CHEBI:nicotine) -> tloc(p(HGNC:TJP1),GOCCACC:"GO:0016020",GOCCACC:"GO:0005737")

when the cells were treated with 1 lM nicotine for 48 or 72 hr, diffuse ZO-1 staining was observed, characteristic of a migratory mesenchymal phenotype (Fig. 7, middle and bottom panel).26,27 Furthermore, the overall intensity of the ZO-1 staining was reduced.

we identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins. Both these factors are shown to bind to the same single consensus-binding element in the ABCC6 proximal promoter in cell lines of hepatic and renal origin by reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation.

tscript(p(HGNC:PLAGL1)) => r(HGNC:ABCC6)

a(CHEBI:"leukotriene B4") -> r(HGNC:TNF)

In cultured monocytes, LTB4 upregulated IL-6, MCP-1, and TNF-a expression at 3 h (Real Time-PCR). U-75302, Ly-2552837, and PTX significantly diminished LTB4-mediated gene overexpression (Figure 5A).

tscript(complex(NCH:"Nfkb Complex")) -> (a(CHEBI:"leukotriene B4") -> r(HGNC:TNF))

Pretreatment with NF-kB inhibitors MG-132, Bay-117032, and parthenolide significantly decreased IL-6, MCP-1, and TNF-a mRNA induction caused by LTB4 in monocytes (Figure 5B).

Abcg1/ macrophages accumulate sterols, notably 7-ketocholesterol and desmosterol after feeding of a high-cholesterol diet (Table) as well as 27-OH cholesterol (0.260.04 versus 0.440.04 ng/mg protein in macrophages from WT and Abcg1/ mice fed a chow diet, respectively; P0.05).

Senescent fibroblasts exhibited enhanced expression of phosphorylated and acetylated p53, and cyclin-dependent kinase inhibitor, p21. Together, these results demonstrated that knockdown of endogenous MBP-1 is involved in cellular senescence of HFF through p53-p21 pathway.

Table 1. Genes differentially expressed in MBP-1 depleted HFF.

This protein, designated HBp17, was found to bind the heparin-binding peptide growth factors HBGF-1 and HBGF-2 in a noncovalent, reversible manner. In addition HBp17 was found to inhibit the biological activities of both HBGF-1 and HBGF-2. Both the binding and inactivation of HBGF-1 and HBGF-2 by HBp17 were abolished by heparin

path(SDIS:Diabetes) negativeCorrelation r(RGD:Ckb)

Quantitation of CK-M and CK-B mRNA levels on Northern blots with specific cDNA probes showed that, in diabetic hearts, CK-B mRNA levels represent only 19.8% of control levels and are more markedly depressed than CK-M mRNA levels

bp(GO:"response to hypoxia") -> p(HGNC:HIF1A)

Accumulation of both HIF-1a and HIF-2a in response to hypoxia was demonstrated in vitro in human and mouse macrophages and macrophage cell lines and in vivo in TAMs, as well as in macrophages from healing wounds, inflamed rheumatoid synovium, and atherosclerotic lesions (Talks et al., 2000; Burke et al., 2002b; Mi et al., 2007; Griffiths et al., 2000; Crowther et al., 2001; Hollander et al., 2001; Distler et al., 2004; Vink et al., 2007; Onita et al., 2002; Koga et al., 2004; Bosco et al., 2008).

bp(GO:"response to hypoxia") -> r(HGNC:CCL20)

CCL20 chemokine, a selective chemoattractant for iDCs, effector/memory T lymphocytes, and naive B cells (Schutyser et al., 2003) is an exception to this pattern, because it is induced by hypoxia in primary human monocytes (Bosco et al., 2006) and, to a lower extent, in macrophages (Battaglia et al., 2008).

bp(GO:"response to hypoxia") -| r(HGNC:CEBPA)

Down-regulation of several HIF-1 transcriptional cofactors, including CCAAT enhancer binding protein alpha (C/EBPa), CREB-binding protein (CBP), microphthalmia-associated transcription factor (MITF), and nuclear receptor co-activator 1 (NCOA1/ SRC-1), was also observed in hypoxic monocytes (Bosco et al., 2006).

bp(GO:"response to hypoxia") -> r(HGNC:TFPI2)

Furthermore, we reported that the tissue inhibitor of metalloproteinase 1 (TIMP1) and tissue factor pathway inhibitors 1 and 2 (TFPI1, 2), which reduce ECM degradation inhibiting cell migratory activity (Nagase et al., 2006) are up-regulated in hypoxic monocytes (Bosco et al., 2006).

bp(GO:"response to hypoxia") -> r(HGNC:DUSP1)

Human monocytic cells exposed to in vitro hypoxia express higher levels of the MAPK phosphatase 1 (MKP-1), with consequent reversal of MAPK phosphorylation required for cell migration (Grimshaw and Balkwill, 2001), and of the regulator of G-protein signaling 1 (RGS1) (Bosco et al., 2006), a member of a new class of G-protein signaling deactivators which inactivates several chemotactic receptors consequently inhibiting chemoattractant-induced migration (Denecke et al., 1999).

bp(GO:"response to hypoxia") -| r(HGNC:CCL2)

Monocyte exposure to hypoxia in vitro profoundly and differentially modulates the expression of a cluster of chemokine genes, with a characteristic dichotomy resulting in upregulation of those active on neutrophils, such as CXCL2, CXCL3, CXCL5, CXCL6, and CXCL8 (Metinko et al., 1992; Bosco et al., 2006), and in the inhibition of chemokines predominantly active on monocytes, macrophages, T lymphocytes, NK cells, basophils and/or DCs, such as CCL2, CCL8, CCL15, CCL18, CCL19, CCL23, and CXCL11 (Bosco et al., 2006).

bp(GO:"response to hypoxia") -| r(HGNC:CCL23)

bp(GO:"response to hypoxia") -| r(HGNC:CCL8)

bp(GO:"response to hypoxia") -| r(HGNC:CXCL11)

bp(GO:"response to hypoxia") -> r(HGNC:CXCL2)

bp(GO:"response to hypoxia") -> r(HGNC:CXCL6)

bp(GO:"response to hypoxia") -> r(HGNC:SPP1)

Most of these genes, including VEGF, adrenomedullin (ADM), coagulation factor III (F3), acid fibroblast growth factor 1 (FGF1), VEGF receptor-1 (FLT1), macrophage migration inhibitory factor (MIF), and osteopontin (SPP1), are similarly upregulated by hypoxia in primary human monocytes (Melillo et al., 1999; Bosco et al., 2006).

bp(GO:"response to hypoxia") -> p(HGNC:TEK)

Recently, the tie-2 receptor for the proangiogenic factor, Ang2, was reported to be induced by hypoxia in monocytes and macrophages. This was shown to lead to a downregulation of IL-12 expression in Ang2-treated hypoxic cells (Murdoch et al., 2007).

bp(GO:"response to hypoxia") -> r(HGNC:MMP16)

The expression of other members of the MMP family is deregulated in hypoxic monocytes, which show reduced levels of MMP25 and increased amounts of MMP1, MMP16, and MMP19, relative to the normoxic counterparts (Bosco et al., 2006).

bp(GO:"inflammatory response") -> p(PFH:"TGFB Family")

Using immunohistochemical staining, we have examined lung sections of patients with advanced idiopathic pulmonary fibrosis (IPF), a disease characterized by chronic inflammation and fibrosis and demonstrated a marked and consistent increase in TGF-beta production in epithelial cells and macrophages when compared to patients with nonspecific inflammation and those with no inflammation or fibrosis.

path(SDIS:"Respiratory Syncytial Virus Infection") -> r(MGI:Hmox1)

Figure 8. Suppression of antioxidant response element (ARE)-responsive antioxidant/detoxifying enzyme induction by RSV in Nrf22/2 mice.

See TABLE 1. mRNAs repressed by miR-140 overexpression and derepressed by silencing of miR-140.

Furthermore, at baseline and in hyperoxia, chromatin immunoprecipitation (ChIP) revealed increased Bach1 binding to the HO-1 distal enhancers (DEs) in the neonates compared with adults. These data suggest that elevated levels of Bach1 may help to limit HO-1 induction in the newborn at baseline and in response to oxidative stress.

Overexpression of S1P1 in HEK293 cells markedly increases the expression level of P- and E-cadherin, but not ?- and ?-catenin, and induces cell–cell aggregation in a Ca2+ dependent manner (Lee et al., 1998).

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:S1PR1)

S1P1 was first cloned from endothelial cells as an immediate early transcript induced by the tumor promoter phorbol 12-myristate 13-acetate (PMA) (Hla and Maciag, 1990).

p(HGNC:S1PR1) -> bp(GO:"cell-cell adhesion")

Transfection of human embryonic kidney 293 cells (HEK293), which express little if any endogenous S1P1, induces a network of cell–cell aggregates. This morphology resembles the network formation of differentiated endothelial cells, and is completely prevented by the chelating agent EGTA and C3 exotoxin, a specific inhibitor of the small GTPase Rho

complex(p(RGD:Fos),p(RGD:Jun)) -> bp(GO:"inflammatory response")

AP1, together with the transcription factor Sp1, also mediates angiotensin II-induced inflammation in rats [24]

a(SCHEM:"Oxidized Low Density Lipoprotein") -> tscript(p(HGNC:NFKB1))

Activation of NF-?B by minimally modified LDL in endothelial cells was reported by Rajavashisth et al. [36], and by Cu2+-or cell-oxidized LDL in fibroblasts, endothelial cells, and smooth muscle cells by our group [37].

a(CHEBI:paclitaxel) -| path(SDIS:"tumor growth")
p(MGI:Adam17) -| (a(CHEBI:paclitaxel) -| path(SDIS:"tumor growth"))

ADAM10 and ADAM17 inhibitor in cell and animal models. This inhibitor also acts synergistically with the chemotherapeutic agent paclitaxel to reduce tumour volume in a mouse model of non-small-cell lung cancer103.

Indeed, all TLRs except TLR3 require IRAK-4 and MyD88 to signal

IL-4 induced the higher proliferation of CM-NK cells, but abolished their NK activity and decreased CD16 and CD56 Ag expression.

p(HGNC:WRN) -| a(CHEBI:"reactive oxygen species")

Compared with normal fibroblasts, both WSF1 cells and CSE-exposed fibroblasts significantly increased intracellular ROS production (Figure 6A).

We examined the effect of blockade of type 1 IGF tyrosine kinase receptor (IGF-IR) in a murine model of bleomycin-induced lung injury and fibrosis. Mice were treated with a monoclonal antibody against the IGF-I receptor (A12) or vehicle after intratracheal bleomycin instillation. MEASUREMENTS AND MAIN RESULTS: Mice treated with A12 antibody had significantly improved survival after bleomycin injury compared with control mice. Both groups of mice had a similar degree of fibrosis on days 7 and 14, but by Day 28 the A12-treated group had significantly less fibrosis. Delayed treatment with A12 also resulted in decreased fibrosis. A12-treated mice had significantly decreased apoptotic cells on Day 28 compared with control mice. We confirmed that A12 treatment induced mouse lung fibroblast apoptosis in vitro. In addition, IGF-I increased lung fibroblast migration. The primary pathway activated by IGF-I in lung fibroblasts was the insulin receptor substrate-2/phosphatidylinositol 3-kinase/Akt axis.

kin(p(PFH:"AKT Family")) => p(HGNC:TBC1D4,pmod(P,T,642))

In contrast, phosphorylation of AKT substrate 160kDa (AS160) at T642, which is essential for 14-3-3 recruitment and GLUT4 translocation, was reduced by 50% in basal and insulin-stimulated cells and this was mirrored by decreased 14-3-3 association.

Supplemental Table 2. Up-regulated genes in miR-133a dKO mutant hearts at P1. (Since single KO of miRNA133a have no phenotype, we assumed that miRNA133a-1 and miRNA133a-2 have redundant function)

IL-1b and PGE2 have the capacity to decrease E-cadherin expression and promote EMT. These inflammatory mediators have the capacity to up-regulate the zinc-finger E-box?binding transcriptional repressors of E-cadherin, including Zeb1, Snail, and Slug, thus leading to EMT progression (15, 52).

kin(p(PFH:"PRKC Family")) -| tscript(p(HGNC:TCF4))

In addition, enzastaurininduced b-catenin coimmunoprecipitated with its cofactor T-cell factor 4 (Figure S1B), subsequently activating the T-cell factor 4 promoter in MM.1S, HEK293, and HeLa cell lines, as shown by the TOP-FLASH reporter assay (Figure S1C). Taken together, these results demonstrate that enzastaurin triggers accumulation of transcriptionally active b- catenin because of inhibition of its degradation, rather than induced overexpression.

kin(p(PFH:"PRKC Family")) -| tscript(complex(p(HGNC:CTNNB1),p(HGNC:TCF4)))

MPO activity was measured in the supernatant of PMA-activated neutrophils of six healthy nonsmoking human donors (two females, four males, ages 25-50 years). Vit A and RA effectively inhibited MPO activity by 31 and 21%, respectively (Fig. 3).

Western blot analysis of lung proteins showed that Srx1 proteinwas present constitutively, and its level increased significantly on exposure to CS in Nrf2+/+ mice. By contrast, expression of Srx1 protein was low in Nrf2?/? mice and did not change significantly with CS exposure (Figs. 1B and C).

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> kin(p(PFH:"AKT Family"))

The PI3K/Akt pathway is involved in prototypical endothelial functions such as the regulation of vascular tone, angiogenesis, control of adhesion, and recruitment of leucocytes to the vessel wall (Figure 1).

a(CHEBI:"hyaluronic acid") -> tscript(p(HGNC:RELA))

Further analyses indicate that activation of SIRT1 (deacetylase) by resveratrol (a natural antioxidant) induces SIRT1-p300 association and acetyltransferase inactivation, leading to deacetylation of HA/CD44-induced beta-catenin and NFkappaB-p65, inhibition of beta-catenin-T-cell factor/lymphocyte enhancer factor and NFkappaB-specific transcriptional activation, and the impairment of MDR1 and Bcl-x(L) gene expression.

tscript(p(MGI:Nfatc3)) -> bp(MESHPP:"Liver Regeneration")

Hepatocyte proliferation and thus liver regeneration following hepatectomy was suppressed in NFAT4 knockout (KO) mice.

p(MGI:Kras,sub(G,12,V)) -> a(CHEBI:glutathione)

Indeed, significantly elevated GSH levels of 85 +/- 10 and 122 +/- 34 nmoles/mg protein were found in the K-Ras mutants G12V and G13D, whereas in the parental NIH3T3 cells and in the mock transfectants the GSH levels did not exceed 25 +/- 6 and 29 +/- 6 nmoles/mg protein, respectively. It is noteworthy that the Wt K-ras transfectants also exhibited a considerable increase of the intracellular GSH concentration to 62 +/- 5 nmoles/mg protein (Fig. 4).

NIH3T3 cells transformed by different mutants of Kras (WT, G12V and G13D) and differentially expressed proteins in the pH range 6 to 11 and identified by mass spec. Fold change >1.3 and p-value < 0.05.

p(MGI:Kras,sub(G,13,D)) -| p(MGI:Serpinh1)

a(CHEBI:"hydrogen peroxide") -> bp(GO:"cell death")

The H2O2-mediated cell death was confirmed by an at least 6-fold increased cytotoxicity in NIH3T3 cells and mock controls compared with the less pronounced toxic effect on the oncogenic K-ras–expressing cell lines G12V and G13D (2- to 3-fold; Fig. 5B).

a(CHEBI:"hydrogen peroxide") -> cat(p(MGI:Casp3))

cells were left untreated or treated with H202 and formaldehyde followed by incubation with the profluorescent Z-DEVD-rhodamine 110 substrate. The catalytic activity of the two effectors, caspase-3 and caspase-7, was determined by measuring the fluorescence of the cleavage product. In the presence of 100 Amol/L H2O2, the caspase-3/7 activity was 8- to 11-fold elevated in parental, mock, and Wt K-ras–transfected cells in comparison with the untreated cells, whereas the enzymatic activity was only 2- to 3-fold enhanced in the two K-ras mutants (Fig. 5D). It is noteworthy that an altered caspase activity in cells treated with formaldehyde was not observed (data not shown).

a(CHEBI:"hydrogen peroxide") -> cat(p(MGI:Casp7))

We show that miRNAs belonging to the miR-20a family (that is, miR-20a, miR-17-5p and miR-106b) could regulate APP expression in vitro and at the endogenous level in neuronal cell lines. ......Of note, APP mRNA expression was not affected by miR-20a overexpression (Fig. 2C), indicating that this miRNA blocks protein translation and does not induce (direct) degradation of the target mRNA.

a(CHEBI:estradiol) -> (a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:TFF1))
a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:TFF1)

Bryostatin alone also inhibited growth The effect of TPA on MCF-7 cells was partially reversed by bryostatin TPA alone increased pNR2 and pNR100 levels in MCF-7 cells and the combined effect of oestradiol and TPA had a marked synergistic effect in increasing the transcript levels of these genes.

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

The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) (10 nM) produce a marked reduction in the growth, measured by thymidine uptake, of MCF-7 cells

Proinflammatory cytokines (IL-1b, IL-6, and TNF-alpha) increased VEGF and MMP-9 in corneal cells and macrophages.

Another member of this family, MTA3, is induced by estrogen and represses the expression of the transcriptional repressor Snail, a master regulator of \"epithelial to mesenchymal transitions\", resulting in the expression of the cell adhesion molecule E-cadherin and maintenance of a differentiated, normal epithelial phenotype in breast cells.

p(HGNC:TP53,pmod(P,S,46)) => tscript(p(HGNC:TP53))

Mutation of p53 Ser(58) (equivalent to human p53 Ser(46)) abrogates transcription of these genes

We also found that BJ cells entering senescence after shMTH1 knockdown up-regulated the levels of the p53, p21Cip1/Waf1 and p16INK4a tumor suppressor proteins

cat(p(HGNC:HDAC3)) -| p(HGNC:STAT3,pmod(P,S,727))

Here, we show that treatment of HeLa cells with a histone deacetylase (HDAC) inhibitor, trichostatin A, or small-interfering RNA (siRNA)-mediated repression of HDAC3, enhances phosphorylation of STAT3 at Ser727.

kin(p(HGNC:GSK3B)) => p(HGNC:SREBF1,pmod(P,T,426))

Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1.

Combining microarray techniques with DNA sequence analysis to identify potential let-7 targets, we discovered 838 genes with a let-7 binding site in their 3'UTR, that were down-regulated upon overexpression of let-7b. (From Suppl Table 1). To identify potential let-7 targets, we looked for genes consistently down-regulated in the presence of let-7 (i.e., genes within cluster 2 or 4) that also contain at least one let-7 recognition site within their 3’ UTR, resulting in 838 genes (Supplementary Table 1).

a(CHEBI:atorvastatin) -> p(MGI:Prkaa1,pmod(P,T,183))

Shear stress, atorvastatin, and adiponectin all increased AMPK Thr172 (activating phosphorylation found at Thr183 on the Uniprot sequence Q5EG47) and eNOS Ser633 phosphorylations (Ser632 from sequence Uniprot P70313), which were abolished if AMPK was pharmacologically inhibited or genetically ablated. The constitutively active form of AMPK or an AMPK agonist caused a sustained Ser633 phosphorylation.

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

Moreover, IL-6 triggered a rapid formation of Fer/gp130 and Fer/STAT3 complexes in a time-dependent manner and consistent with changes in Fer and STAT3 phosphorylation and cytoplasmic/nuclear distribution.

p(HGNC:IL10) -| bp(GO:"platelet aggregation")

NO and interleukin (IL)-10 suppresses adhesion and aggregation of blood platelets [96].

cat(p(HGNC:PTGIR)) -| bp(GO:"platelet aggregation")

PGI2 acts on the PGI2 receptor (IP receptor) to inhibit platelet aggregation and smooth muscle relaxation [137].

cat(p(HGNC:ACE)) -> path(MESHD:"Myocardial Infarction")

The potential link between Ang II and atherosclerosis is strengthened by the Heart Outcomes Prevention Evaluation (HOPE) trial where ACE (angiotensin converting enzyme) inhibition reduced the rates of death, myocardial infarction, and stroke in patients with atherosclerosis [57].

a(SCHEM:"alpha-Cobratoxin") -> bp(MESHPP:Apoptosis)

In conclusion, the results of this study show that a-CbT, a powerful high-affinity a7-nAChR inhibitor, induces antitumor activity against NSCLC by triggering apoptosis.

a(CHEBI:nicotine) -> bp(GO:"cell proliferation")
cat(p(HGNC:CHRNA7)) -> (a(CHEBI:nicotine) -> bp(GO:"cell proliferation"))

Studies have shown that a7 is the main nAChR7 subunit that mediates the proliferative effects of nicotine in lung cancer cells (26–31).

p21 is directly regulated by miR-106b through the 3'-UTR. The reporter containing the 3'-UTR of p21 (FL-p21) was transfected into HeLa cells along with miRNA duplexes

bp(GO:"replicative cell aging") -> r(HGNC:CDKN1A)

from full text - Figure 2. Analysis of the senescence transriptome reveals significant overlap between cells undergoing RS and SIPS. A, microarray analysis of young BJ fibroblasts and BJ fibroblasts undergoing RS or bleomycin-induced SIPS. Hierarchical clustering of consistent transcript alterations across all conditions and replicas is plotted. B, Venn diagram plots genes that significantly overlap in fibroblasts undergoing RS and SIPS versus young. C, GO analysis of up-regulated classes in cells undergoing RS and SIPS compared with their younger counterparts (i.e., immune & inflammation, mitogens & regulation of proliferation, and extracellular matrix & secreted factors).

bp(GO:"replicative cell aging") -> r(HGNC:F3)

bp(GO:"replicative cell aging") -> r(HGNC:FUS)

bp(GO:"replicative cell aging") -> r(HGNC:HIST1H2BD)

bp(GO:"replicative cell aging") -> r(HGNC:IFI6)

bp(GO:"replicative cell aging") -> r(HGNC:ITFG1)

bp(GO:"replicative cell aging") -> r(HGNC:MMP3)

bp(GO:"replicative cell aging") -> r(HGNC:MX1)

bp(GO:"replicative cell aging") -> r(HGNC:MYBL1)

bp(GO:"replicative cell aging") -> r(HGNC:OAS2)

bp(GO:"replicative cell aging") -> r(HGNC:ODC1)

bp(GO:"replicative cell aging") -> r(HGNC:PSG3)

bp(GO:"replicative cell aging") -> r(HGNC:PSG5)

bp(GO:"replicative cell aging") -> r(HGNC:PTP4A1)

bp(GO:"replicative cell aging") -> r(HGNC:STAT1)

bp(GO:"replicative cell aging") -> r(HGNC:TAP2)

path(SDIS:"bacterial infection") -> a(CHEBI:lipopolysaccharide)

The lipid A domain of lipopolysaccharide (LPS) is a unique, glucosamine-based phospholipid that makes up the outer monolayer of the outer membrane of most gram-negative bacteria.

a(CHEBI:lipopolysaccharide) -| p(MGI:Pparg)

As shownin Fig.2Aand B, LPS-inducedup-regulation of AEBP1 expression is accompanied by significant inhibition of PPAR1 and LXR expression where their levels drop by 5 and 3 folds, respectively, 24 h post LPS treatment.

p(PFH:"PRKA Family") -> path(SDIS:"I(Cl,PKA) PKA-dependent chloride current")

At the molecular level, all cardiac Cl? channels described so far may fall into the following Cl? channel gene families: (1) the cystic fibrosis transmembrane conductance regulator (CFTR), which is a member of the adenosine triphosphate-binding cassette (ABC) transporter superfamily and may be responsible for the Cl? currents activated by protein kinase A (PKA) (I Cl,PKA), protein kinase C (PKC) (I Cl,PKC) , and extracellular ATP (I Cl,ATP) in the heart; (2) ClC-2, which is a member of the ClC voltage-gated Cl? channel superfamily and may be responsible for the hyperpolarization- and cell swelling-activated inwardly rectifying Cl? current (I Cl,ir) (Duan et al. 2000; Komukai C et al. 2002a,b); (3) ClC-3, which is also a member of the ClC voltage-gated Cl? channel superfamily and may be responsible for the volume-regulated outwardly rectifying Cl? current (I Cl,vol), including the basally activated (I Cl,b) and swelling activated (I Cl,swell) components; (4) CLCA-1, which was thought to be responsible for the Ca2+-activated Cl? current (I Cl,Ca); (5) Bestrophin, a candidate also for I Cl,Ca; and (6) TMEM16, a novel candidate for I Cl,Ca

p(PFH:"PRKC Family") -> path(SDIS:"I(Cl,PKC) PKC-dependent chloride current")

Similarly, TNF-alpha induced activation of IKKbeta, as seen by reduced IkappaBalpha levels, but pretreatment with LA protected the myotubes from the TNF-alpha -induced IKKbeta activation.

bp(GO:"inflammatory response") -> path(MESHD:Sepsis)

Sepsis is a devastating condition characterized by a systemic inflammatory response. Recently, high mobility group box 1 (HMGB1) was identified as a necessary and sufficient mediator of the lethal systemic inflammation caused by sepsis...In this study, we demonstrate that the IFN-beta-mediated JAK/STAT pathway is essential for LPS or Escherichia coli-induced HMGB1 release, which is dependent on Toll/IL-1R domain-containing adapter-inducing IFN-beta adaptor.

a(CHEBI:lipopolysaccharide) -> r(MGI:Mmp9)

Consistently, BBR inhibited LPS-induced expression of proinflammatory genes including IL-1beta, IL-6, iNOS, MCP-1, COX-2, and matrix metalloprotease-9 in peritoneal macrophages and RAW 264.7 cells.

kin(complex(NCR:"AMP Activated Protein Kinase Complex")) -| cat(p(RGD:Lipe))

n summary, despite different fat depots eliciting distinct rates of lipolysis, acute AICAR-induced AMPK activation suppressed HSL phosphorylation/activation and exerted similar antilipolytic effects on both VC and SC adipocytes.

bp(MESHPP:Obesity) negativeCorrelation r(MGI:Car3)

Quantitative comparisons of CA III protein and mRNA levels indicate that this enzyme is expressed at lower levels in adipose tissue from animals that were either genetically obese or had experimentally induced obesity compared to levels in the corresponding lean controls. This decrease in CA III expression was unique to adipose tissue

A549 cells harbor the K-ras mutation. Active Ras can induce p21Cip1/Waf1 expression and cell cycle arrest via the p14Arf-p53 pathway, which is defective in A549 cells (Supplementary Fig. S1A) and via mitogen-activated protein kinase (MAPK) signaling (43).

p(HGNC:RASSF1) -> kin(p(PFH:"MAPK Erk1/3 Family"))

After stimulation with the mitogen phorbol 12-myristate 13- acetate (PMA) or serum, conditionally expressed RASSF1A specifically enhanced the activating phosphorylation of ERK, but not of p38 kinase or c-Jun NH2 kinase (Fig. 5A).

a(SCHEM:"HPV-16") -| (p(HGNC:RASSF1) -> path(SDIS:"Oncogene induced senescence"))
p(HGNC:RASSF1) -> path(SDIS:"Oncogene induced senescence")

RASSF1A-induced senescence was prevented by coexpression of HPV E7 oncogene (Fig. 4B).

p(PFH:"AKT Family") => p(HGNC:RAF1,pmod(P,S,259))

Raf itself is negatively regulated by phosphorylation at Ser259 through Akt, an important effector of phosphoinositide 3-kinase (PI3K) signaling (30, 44).

p(HGNC:CDKN2A) -> path(SDIS:"Oncogene induced senescence")

The CDK inhibitor p16Ink4a is another p53-independent regulator of oncogene-induced cell cycle arrest and senescence (5, 13).

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> bp(GO:"cell migration")

Stimulation with those CCR6 ligands leads to calcium mobilization and elevated active RhoA, phosphorylated myosin light chain, and F-actin accumulation. HBD2 and CCL20 were unable to stimulate migration in the presence of either Rho-kinase or phosphoinositide 3-kinase inhibitors or an intracellular calcium chelator.

p(HGNC:IL32) -| (p(HGNC:HGF) => kin(p(HGNC:MET)))

NK4, a competitive antagonist for HGF and the c-Met receptor, prevents tumor cell growth and metastasis via its bifunctional properties to act as an HGF antagonist and angiogenesis inhibitor.

Transforming growth factor (TGF)-alpha is a ligand for the epidermal growth factor receptor (EGFR).

By knocking down the expression of endogenous miR-21 in MCF-7 breast cancer cells, we observed an increase in the abundance of 58 proteins, implying that they could be potential targets of miR-21. Validation of 12 of these candidate targets in luciferase assays showed that 6 of them were likely direct targets of miR-21. Importantly, the mRNA of the majority of the candidate targets tested did not show a concomitant increase in abundance.

cat(p(HGNC:F2R)) -> p(HGNC:PDE3A,pmod(P,S,312))

Stimulation of platelets with the PAR-1 agonist SFLLRN resulted in rapid and transient phosphorylation of PDE3A on Ser(312), Ser(428), Ser(438), Ser(465), and Ser(492). Furthermore, phosphorylation and activation of PDE3A required the activation of PKC, but not of PI3K/PKB, mTOR/p70S6K, or ERK/RSK. Activation of PKC by phorbol esters also resulted in phosphorylation of the same PDE3A sites in a PKC-dependent manner.

kin(p(PFH:"PRKC Family")) -> p(HGNC:PDE3A,pmod(P,S,312))

Activation of the inflammasome is responsible for the generation of active caspase-1, which cleaves a number of pro-inflammatory cytokines into their bio-active form, including IL-1B , IL-18, and IL-33.

As depicted in Fig. 1A, Western blot analysis shows a HIF-1a induction upon culture of IGR-Heu under hypoxic conditions.

tscript(complex(NCM:"Nfkb Complex")) => r(MGI:Cebpd)

Pharmacological inhibition of NF-kappaB blocked LPS-induced Cebpd transcription (Fig. 1d), and LPS-induced Cebpd mRNA (Fig. 1d) and protein (Fig. 1e) quantities were substantially increased in Atf3-null macrophages. Taken together, these data demonstrate that LPS-induced transcription of Cebpd is absolutely dependent on NFkappaB, and that NFkappaB-dependent Cebpd mRNA production is attenuated by ATF3. ChIP analysis demonstrated rapid and transient recruitment of Rel to the promoter of the Cebpd gene; maximal binding was seen 1 hr after stimulation with LPS (Fig. 1f). By contrast, LPS-stimulated ATF3 binding to the promoter of the Cebpd gene (over basal amounts) occurred after 3 h and was sustained (Fig. 1f).

a(CHEBI:"hydrogen peroxide") -| a(SCHEM:"Adenosine triphosphate")

Interaction of hydrogen peroxide with endothelial cells rapidly depletes adenosine triphosphate (ATP) and causes the extracellular appearance of xanthine and hypoxanthine.

Indo increased IL-2 production by sup burn PBMCs significantly more (160% +/- 20%, p less than 0.005) than control (57% +/- 5%) and nonsup PBMCs (67% +/- 8%).

bp(GO:"response to hypoxia") -> tscript(p(HGNC:HIF1A))

The results showed a reduction of HIF-1a mRNA (A) by siHIF-1a and of HIF-2a mRNA (B) by siHIF-2a, simultaneously CCR7 mRNA was reduced more significantly in siHIF-1a than siHIF-2a tansfected cells. These effects were also confirmed on protein levels (C).

p(MGI:Maoa) -| bp(GO:"response to stress")

MAO-A knockout mice have elevated brain levels of serotonin, norepinephrine and, to a lesser extent, dopamine [17], whereas only 2-phenylethylamine levels are increased in MAO-B knockout mice [79]. Both MAO-A and -B knockout mice show an increased response to stress, similar to that observed after the administration of non-selective MAO inhibitors.

p(MGI:Maob) -| bp(GO:"response to stress")

cat(p(MGI:Lpl)) rateLimitingStepOf path(SDIS:"VLDL biosynthesis")

LPL is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins, chylomicrons, and very low-density lipoproteins (VLDL). LPL-catalyzed reaction products, fatty acids, and monoacylglycerol are in part taken up by the tissues locally and processed differentially; e.g., they are stored as neutral lipids in adipose tissue, oxidized, or stored in skeletal and cardiac muscle or as cholesteryl ester and TG in macrophages.

To examine this divergent regulation further, transgenic and knockout murine models of tissue-specific LPL expression have been developed. Mice with overexpression of LPL in skeletal muscle accumulate TG in muscle, develop insulin resistance, are protected from excessive weight gain, and increase their metabolic rate in the cold.

a(CHEBI:erlotinib) -| p(PFH:"AKT Family",pmod(P))
p(HGNC:PTEN) -> (a(CHEBI:erlotinib) -| p(PFH:"AKT Family",pmod(P)))

PTEN loss in PC9 cells (PC9PTENkd) induced the uncoupling of EGFR and downstream Akt signaling as shown by continuous Akt phosphorylation under erlotinib treatment (Fig. 3B).

Correlative Western blot experiments showed that EZH2, SirT1, and combined EZH2/SirT1 knockdown modestly increased Dkk-1 protein levels in untreated Calu-6cells

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:MMP9)
a(SCHEM:Splitomicin) -| (a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:MMP9))

Pretreatment with the nonspecific sirtuin inhibitor splitomycin (1?100 M) significantly enhanced PMA-induced MMP9 expression in a concentration- dependent manner (Fig. 1A).

SIRT1 knockdown increased the amount of the lower-molecular- weight active form (85–88 kDa) of MMP9, which was shown by zymography (Fig. 1C, center panel).

kin(p(HGNC:MAPK3)) => p(HGNC:MBP,pmod(P,T,232))

Additionally, expression of PDK4, CPT1-M {Official Gene Symbol: CPT1B}, CPT2, and FACO {Official Gene Symbol: ACOX1} mRNAs was increased.

p(HGNC:NFE2L2) -> bp(GO:"cell proliferation")

Knockdown of Nrf2 with Nrf2-siRNA potently inhibited the proliferation of A549 cells (Fig. 2D, left).

a(CHEBI:cisplatin) -> bp(MESHPP:Apoptosis)
p(HGNC:NFE2L2) -| (a(CHEBI:cisplatin) -> bp(MESHPP:Apoptosis))

Nrf2 knockdown augmented CDDP-induced DNA interstrand crosslink formation and apoptosis in A549 cells... The proportion of both early apoptotic cells that were positive for only Annexin V and late apoptotic cells that were positive for both Annexin V and propidium iodide was significantly increased in Nrf2-siRNAtransfected A549 cells compared with NC-siRNA-transfected A549 cells (Fig. 4B).

tscript(p(MGI:Stat6)) -> bp(GO:"inflammatory response")

IL-4 develops Th2-biased immunity or allergic inflammation through activation of STAT6-dependent signaling.

Acylation stimulating protein (ASP) is a 14 kDa plasma protein which causes in vitro triacylglycerol synthesis in human adipocytes and fibroblasts to increase substantially. ASP was found to stimulate human adipose tissue microsomal glycerophosphate acyltransferase and diacylglycerol acyltransferase activities by 23% and 90%.

Moreover, ceramide directly induced SOCS-3 and inhibited UCP3 mRNA in cultured adipocytes suggesting a direct role for ceramide in regulation of metabolism and energy expenditure.

p(EGID:64798) -| kin(p(PFH:"AKT Family"))

Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities.

bp(GO:"response to hypoxia") -> r(HGNC:ADM)

Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2

bp(GO:"response to hypoxia") -> r(MGI:Adm)

bp(GO:"response to hypoxia") -> r(MGI:Vegfa)

bp(GO:"response to hypoxia") -> tscript(p(HGNC:EPAS1))

These studies showed that both HIF-1 and -2, but not NF-kappaB, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia

bp(GO:"response to hypoxia") -> tscript(p(MGI:Hif1a))

TLR4 and Syk were required for mmLDL activation of guanine nucleotide exchanging factor Vav1, small GTPase Ras, kinases Raf, MEK1 and ERK1/2; in turn, ERK1/2 phosphorylated paxillin at Ser126 and activated small GTPases Cdc42, Rac and Rho (Figure 3 and Online Figure III). These signaling events lead to actin polymerization, a necessary step in membrane ruffling. Our results agree with the reports of Syk-dependent ERK1/2 activation in phagocytosis45, ERK1/2 activation in TLR4-dependent antigen uptake by dendritic cells46, and the role of paxillin and small GTPases in actin reorganization and pinocytic vesicle formation9,26,27,47.

bp(GO:"response to hypoxia") -> a(CHEBI:"thromboxane B2")

Hypoxia induced a very large increase in plasma concentration of most eicosanoids; thromboxane B2 (TxB2) and leukotriene B4 (LTB4) were maximum at H1 and H2 (about 5 times the normoxic value); prostaglandins PGE2, 6-keto-PGF1 alpha and PGF2 alpha were maximum at H3 or H4 (about 2.5-5 times of normoxic value).

p(HGNC:GSK3B,pmod(P,S,9)) =| kin(p(HGNC:GSK3B))

. A major mechanism of cell necrosis is the opening of the mitochondrial permeability transition pore (mPTP), which consists of multiple protein subunits, including adenine nucleotide translocase (ANT). The threshold for mPTP opening is elevated by phosphorylation of GSK-3beta at Ser9, which reduces activity of this kinase. {FROM FULL TEST: The mPTP is a non-selective large conductance channel in the mitochondrial inner membrane, which is physiologically closed. Opening of mPTPs is involved in cell death induced by a variety of causes (for example, ischemia/reperfusion, alcohol, endotoxin, anti-cancer agents), therefore 'opening' is modeled as tportof(mitochondrial permeability transition pore) and increased threshold for opening is modeled as decrease in tportof -SE}

a(CHEBI:"hydrogen peroxide") -> a(CHEBI:"reactive oxygen species")
p(MGI:Keap1) -> (a(CHEBI:"hydrogen peroxide") -> a(CHEBI:"reactive oxygen species"))

However, after exposure to 100 ?M hydrogen peroxide the levels of ROS was significantly decreased in Keap1?2-3/?2-3;CctCre+ mice compared to Keap1flox/flox mice (Figure 4B and D, respectively)

m(HGNC:"MIR16-1") -| bp(GO:"cell cycle")

Consistent with these results, overexpression of these miRNAs induces cell cycle arrest in G(1)-G(0)

from full text Results - All cell lines transfected with miR-15a/miR-16 precursors gave rise to reduced levels of CCND1, CCND3, and CCNE1 mRNAs relative to the control transfected with an unrelated RNA (cell lines from Fig 3)

We further identified and validated LRRFIP1, whose product is an inhibitor of NF-kappaB signaling, as a direct target gene of miR-21

p(HGNC:DNM1) -> (p(HGNC:EGF) -> kin(p(HGNC:MAPK1)))

The expression of dn-dynamin (Fig. 7B) resulted in an 2-fold decrease in ERK1/2 activation in response to EGF stimulation (Fig. 7, A and C);

Thrombin, on the other hand, has been studied extensively in platelets. As one of the major platelet agonists, it activates the protease activated receptor 1 and 4 (PAR1/4) on the platelet surface which leads to activation of PI3K and phospholipase C? (PLC?) pathways.

cat(p(HGNC:F2R)) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

As shown in Fig. 4D, cells exposed to siRNA against MUC1 demonstrated statistically significant reductions in both migration and invasion

p(HGNC:MUC1) -> p(PFH:"AKT Family",pmod(P,S,473))

Exposure of these cell lines to MUC1 siRNA was associated with downregulation of MUC1 protein (Fig. 3A). As shown in Fig. 3A, transfection of cells with MUC1 siRNA resulted in downregulation of phosphorylated tyrosine STAT3, Src, and FAK. The phosphorylated serine Akt, however, was downregulated by MUC1 siRNA only in H358 cells but not in HCC827 and H441 cells

Measurement of the percentage of cells positive for ApopTag showed that MUC1 knockdown resulted in a significant increase in apoptosis compared with the control (Fig. 5A). MUC1 siRNA-transfected cells also expressed less Ki-67 indicative of reduced proliferation of these cells in vivo.

cat(p(MGI:S1pr1)) -> bp(GO:"regulation of vascular permeability")

Increased leak was associated with increased interendothelial cell gaps in venules and was reversed by transfusion with wild-type erythrocytes (which restored plasma S1P levels) and by acute treatment with an agonist for the S1P receptor 1 (S1pr1).

kin(complex(NCH:"AMP Activated Protein Kinase Complex")) =| cat(p(HGNC:HMGCR))

AMP-activated protein kinase (AMPK) was initially identified as the kinase that phosphorylates the 3-hydroxy 3-methylglutaryl coenzyme A reductase {inhibitor phosphorylation-SE}

Carrageenin-induced acute lung inflammation was also exacerbated in Nrf2?/? mice compared with Nrf2+/+ mice (Mochizuki et al., 2005). A selective COX-2 inhibitor (NS-398) suppressed the antiinflammatory 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) accumulation and ARE responsiveness, and caused greater lung injury in Nrf2?/? mice than in Nrf2+/+ mice (Mochizuki et al., 2005).

a(CHEBI:"hydrogen peroxide") -> cat(p(RGD:Gss))

Enhanced mRNA expression and enzyme activity of NQO1 and gamma glutamyl cysteine ligase (GCL) were elicited by oxidant exposure (e.g., hyperoxia, hydrogen peroxide) in pulmonary tissues or cells (Whitney and Frank, 1993; Rahman et al., 1996).

a(CHEBI:"hydrogen peroxide") -> r(RGD:Gss)

p(MGI:Nfe2l2) -| bp(GO:"inflammatory response")

In an experimental sepsis model, Nrf2 deficiency increased the inflammation and mortality of mice against bacterial endotoxin (LPS)- and cecal ligation and puncture-induced septic shock (Thimmulappa et al., 2006a).

kin(p(PFM:"Akt Family")) -| r(MGI:Cdkn1b)

The Ras effector Akt is known to regulate p27 mRNA abundance by phosphorylating and inactivating the FOXO transcription factors. Phosphorylated Akt and FOXO proteins were both increased in lung tumors, correlating with a reduction in p27 mRNA transcript.

kin(complex(NCM:"p85/p110 PI3Kinase Complex")) -| tscript(p(PFM:"Foxo Family"))

from full text Results - Treatment of the mouse lung tumor cell line SP10 with LY294002 led to a reduction of phospho-Akt, a reduction in phospho- FOXO, and an increase in both p27 transcript and protein levels - LY294002 not in system

kin(p(PFH:"PRKA Family")) => p(HGNC:RAP1B,pmod(P,S,179))

Rap1b has been implicated in the transduction of the cAMP mitogenic response. Agonists that increase intracellular cAMP rapidly activate (i.e. GTP binding) and phosphorylate Rap1b on Ser(179) at its C terminus.cAMP-dependent protein kinase (PKA)-mediated phosphorylation of Rap1b is required for cAMP-dependent mitogenesis, tumorigenesis, and inhibition of AKT activity

path(MESHD:Hyperoxia) -> kin(p(MGI:Mapk3))

Hyperoxia was associated with a significant increase in pJNKs and pERKs in WT mice as seen by Western blot. NOX1, but not NOX2, deficiency decreased ERK and JNK phosphorylation without modification of JNK and ERK protein levels (Figures 7A?7F).NOX1, but not NOX2, deficiency decreased ERK and JNK phosphorylation without modification of JNK and ERK protein levels (Figures 7A?7F). pERK staining was associated with type II pneumocytes and endothelial cell markers during hyperoxia (Figure 8A), whereas pJNK staining was detected mainly in endothelial cells (Figure 8B).

p(MGI:Nox1) -> a(CHEBI:"reactive oxygen species")

These results indicate that NOX1 but not NOX2 is mainly responsible for ROS formation in lungs and in primary type II AECs and MLECs

p(HGNC:PTEN) -| kin(p(PFH:"AKT Family"))

Jin et al. [78] reported that wild PTEN gene delivery significantly inhibited lung cancer growth by inactivation of Akt signal. PDCD4 gene delivery also significantly inhibited lung tumorigenesis and induced apoptosis in lung cancer mice model [79, 80].

a(SCHEM:Mapatumumab) -> bp(MESHPP:Apoptosis)

Mapatumuma is fully human monoclonal antibodies that bind and activate TRAIL-1 [73], and mapatumuma treatment significantly inhibits lung cancer growth through inducing the apoptosis in in vitro as well as in vivo model [74].

a(CHEBI:erlotinib) -| kin(p(PFH:"MAPK Erk1/3 Family"))

Erlotinib decreased cellular levels of phosphorylated ERK1/2, phosphorylated AKT, Rad51 protein, and mRNA in erlotinib-sensitive H1650, A549, and H1869 cells, leading to cell death via apoptosis (also Erlotinib decreased Rad51 protein levels by enhancing Rad51 mRNA and protein instability, so will add protein as well as exp)

overexpression of Rad51 by transfection with Rad51 vector could protect the cells from cytotoxic effects

The neurohypophyseal peptide [Arg8]-vasopressin (AVP) is involved in diverse functions including regulation of body fluid homeostasis, vasoconstriction, and adrenocorticotropic hormone release. These physiological effects are mediated by three subtypes of AVP receptors, designated V1a, V1b, and V2.1

a(CHEBI:"sorafenib tosylate") =| kin(p(HGNC:PDGFRB))

from full text - Sorafenib is a potent TKI of VEGFR-2, VEGFR-3, B-RAF, and PDGFR-B

kin(p(PFH:"MAPK Erk1/3 Family")) -> r(HGNC:SPP1)

Further, ERK inhibitor inhibited significantly OPN expression, Elk1 phosphorylation, and activator protein-1 (AP-1)-DNA binding activation

p(HGNC:PTK2) -> kin(p(PFH:"MAPK Erk1/3 Family"))

Transfecting hPLFs with FAK (Official Gene Symbol: PTK2) antisense oligonucleotide diminished ERK1/2 activation and force-induced OPN (Official Gene Symbol: SPP1) expression.

Table S1 - Genes that show differential expression in response to rapamycin in WB-F344 (non-tumorigenic rat liver epithelial cell line)

tscript(complex(NCH:"Nfkb Complex")) -> p(HGNC:SOD2)

We have shown previously that NHEK senescence arises in part through hydrogen peroxide (H2O2) accumulation. This accumulation was shown to result from an activation of NF-nB and ensuing up-regulation of MnSOD, responsible for the dismutation of O2 to H2O2. Without any coup- regulation of downstream H2O2-degrading enzymes, this leads to H2O2 accumulation (23).

a(CHEBI:lipopolysaccharide) -> p(HGNC:CXCL1)

AM Gro-alpha can be induced by LPS, and an approximate 50- to 100-fold increase in Gro-alpha expression was seen in LPS-stimulated AM when compared with nontreated cultures [167].

a(CHEBI:lipopolysaccharide) -> p(HGNC:IL1B)

Evaluation of BAL fluid supernatants recovered from human subjects at 90 and 240 minutes after LPS exposure revealed that the concentration of IL-1b was significantly increased in smokers (~12-fold) when compared with those of non-smokers (?6-fold).

bp(GO:"inflammatory response") -> path(MESHD:Fibrosis)

Hepatic fibrosis occurs during most chronic liver diseases and is driven by inflammatory responses to injured tissue.

Our results suggest that activation of HIF-1alpha by hypoxia decreases HDAC2 levels, resulting in amplified inflammation

a(CHEBI:"nitric oxide") -> r(HGNC:HMOX1)
a(CHEBI:genistein) -| (a(CHEBI:"nitric oxide") -> r(HGNC:HMOX1))

As seen in Table 1, SB 203580, a specific inhibitor of p38 MAPK, as well as genistein, a broad-spectrum tyrosine kinase inhibitor, completely suppressed gene induction of a selection of NO-responsive genes in cells exposed to DPTA-NO for 3 h.

Figure 1 - Comparison of mRNA levels of genes sensitive to various NO fluxes. U937 cells were exposed to (A) 500 ?M DPTA-NO for 3 h or (B) 200 uM DETA-NO for 17 h. mRNA levels were measured by TaqMan low-density array analysis.

a(CHEBI:"nitric oxide") -> r(HGNC:BNIP3)

a(CHEBI:"nitric oxide") -> r(HGNC:CDKN1A)

a(CHEBI:lipopolysaccharide) -> r(MGI:Bcl10)

Selventa analysis of microarray data: Inhaled LPS vs Control (16 weeks) - RMA normalization, Fold change > 2, minimum abundance of 150, BH FDR P-value < 0.001. Dataset can be found at GEO (GSE18341)

a(CHEBI:lipopolysaccharide) -> r(MGI:Birc3)

a(CHEBI:lipopolysaccharide) -> r(MGI:Gch1)

a(CHEBI:lipopolysaccharide) -> r(MGI:Hbegf)

a(CHEBI:lipopolysaccharide) -> r(MGI:Slc26a4)

p(HGNC:IFNG) -> p(HGNC:STAT3,pmod(P,Y,705))

We therefore determined phosphorylation of the signaling molecules by IFN-gamma in macrophages. Time-course analysis of the cell extract revealed that STAT1 and STAT3 were phosphorylated as early as 5 min after exposure of the cells to IFN-gamma

path(SDIS:"laminar shear stress") -> kin(p(HGNC:KDR))

We found that FSS-mediated phosphorylation of VEGFR2, Akt, and eNOS were significantly decreased in CSE-treated cells in a concentrationdependent manner when compared with control treatments (p < 0.01; Fig. 2).

p(MGI:Nfe2l2) -> (a(CHEBI:"hydrogen peroxide") -> bp(GO:"cell death"))

Likewise, siNrf2-transfected cells abolished the protective effect of eckol against H2O2-induced death (Fig. 4C), suggesting the involvement of Nrf2 transcription factor in eckol-mediated HO-1 gene induction and cytoprotection.

By contrast, selective MR stimulation with aldosterone promoted the expression of IL-6, PAI-1, chemerin and leptin.

p(HGNC:IL6) -> path(SDIS:"osteoclast activity")

These results indicate that OSCC provides a suitable microenvironment for osteoclast formation not only by producing IL-6 and PTHrP but also by stimulating stromal cells to synthesize IL-6.

kin(p(HGNC:PAK2)) =| tscript(p(HGNC:MYC))

Mutational inactivation of the Myc p21 activated kinase 2 (PAK2) phosphorylation sites increased Myc activity and further enhanced epidermal differentiation.

bp(GO:"response to hypoxia") -> tscript(p(HGNC:CREB1))

The transcription factor CREB (cAMP response element binding protein) was activated with decreasing oxygen tensions in both cell types. This effect was again more marked in A549 cells, demonstrating epithelial cells to be more oxygen sensitive.

bp(GO:"response to hypoxia") -> bp(GO:"cell proliferation")
kin(p(HGNC:EGFR)) -> (bp(GO:"response to hypoxia") -> bp(GO:"cell proliferation"))

Hypoxic hPMVEC had a twofold greater level of proliferation compared with normoxic controls, and this increase in proliferation was prevented by the addition of AG-1478 (a pharmacological inhibitor of EGFR).

cat(p(HGNC:ARG2)) -> (bp(GO:"response to hypoxia") -> bp(GO:"cell proliferation"))

The hypoxic induction of arginase II protein was prevented by treatment with AG-1478. Proliferation assays were performed in the presence of arginase inhibitors, and hypoxia-induced proliferation was also prevented by arginase inhibition.

a(CHEBI:lipopolysaccharide) -> r(MGI:Vcam1)
p(MGI:Ilk) -> (a(CHEBI:lipopolysaccharide) -> r(MGI:Vcam1))

Transfection with ILK-siRNA weakened LPS-induced ICAM-1 and VCAM-1 expression to 60 and 20% of the control values but did not affect LPS-induced expression of E-selectin.

kin(p(MGI:Mapk7)) -> tscript(p(MGI:Pparg))

We demonstrate that Erk5 phosphorylation allows activation of PPARgamma transcription factor by displacement of SMRT co-repressor. PPARgamma, in turn is critical for NFkappaB activation, PEDF-dependent apoptosis, and anti-angiogenesis.

cat(p(HGNC:NOX1)) -> a(CHEBI:"reactive oxygen species")

Downregulation of Nrf2 by si-NOX1 could be prevented by the addition of the proteasome inhibitor MG132, suggesting that NOX1-derived ROS interfere with the redox dependent proteasomal degradation of Nrf2 (Fig. 3C).

p(HGNC:NOX1) -> (bp(GO:"response to hypoxia") -> p(HGNC:HIF1A))

Treatment of cells with si-Nrf2, si-Trx1, and si- NOX1 resulted in themost pronounced downregulation of HIF-1A in IH6 and was less apparent in H2 and H6, as demonstrated by Western blot (Fig. 6A).

p(HGNC:TXN) -> (bp(GO:"response to hypoxia") -> p(HGNC:HIF1A))

we demonstrated that overexpression of Trx1 induced HIF-1A both in continuous (H2, H6) and in intermittent hypoxia (IH6) (Fig. 6C).

p(HGNC:TNF) -> tloc(p(HGNC:RELA),GOCCACC:"GO:0005737",GOCCACC:"GO:0005634")

After GSH with H2O2 pretreatment for 30 min, TNF induced p65 nuclear translocation decreased (Fig. 1C) and there was no detectable induction of this process in H2O2- or GSH-treated ECs (Fig. 1D).

In platelets, glucose uptake can be stimulated by thrombin or insulin and is primarily mediated by the glucose transporter, GLUT3 [40]. Glucose uptake stimulated by thrombin or insulin is reduced in the presence of the Akt inhibitor, ML-9, suggesting that Akt contributes to glucose uptake in platelets, as it does in skeletal muscle or adipocytes [40]. However, the role of Akt in glucose uptake is not responsible for its role in platelet aggregation, since insulin induces Akt phosphorylation in platelets, but not platelet aggregation.

bp(GO:"response to heat") -> r(HGNC:DNAJA4)

To validate these microarray results, we then conducted qRT-PCR analyses for the gene targets that exhibited statistical significance: HSPA1A (Hsp70), HSPA6 (Hsp70), HSPA4L (Hsp70L), DNAJA4 (Hsp40), DNAJB1 (Hsp40), and HSPH1 (Hsp105) (Fig. 1b). For all of the genes tested, we found that the treatment group exhibited statistically significant increases in expression compared to the sham group.

bp(GO:"response to heat") -> r(HGNC:HSPH1)

bp(GO:"response to heat") -> r(HGNC:HSPA1A)

As a result of sphingomyelin catabolism, aSMase produces ceramide (a lipid second messenger) (91).

F ig. 2. Effect of Toll-like receptor signalling on macrophage cholesterol metabolism. Stimulation of TLR3 or TLR4 leads to TRIFdependent activation of IRF3, which inhibits transcription of liver X receptor-dependent genes, many of which (e.g. ATP-binding cassette transporter A1, PLTP, apoE and ABCG-1) are critically involved in the efflux of cholesterol from macrophages.

p(HGNC:TNF) -> kin(p(PFH:"MAPK JNK Family"))
p(HGNC:TNFAIP3) -| (p(HGNC:TNF) -> kin(p(PFH:"MAPK JNK Family")))

First, the ectopic expression of A20 drastically inhibits TNF-induced JNK activation and apoptosis in multiple cell types including those deficient of NF-??B activation.

cat(p(HGNC:PARP1)) -| cat(p(HGNC:SIRT1))

Inhibition of poly(ADP-ribose)-polymerase-1 (PARP-1) attenuated CS-induced autophagy via SIRT1 activation (Fig. 5).

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

cyclo H inhibits EGF-induced EGFR phosphorylation, EGF-induced ROS production and EGF-induced CD11b upregulation (Fig. 1H,J);

a(SCHEM:Calcium) -> bp(MESHPP:"Protein Biosynthesis")

Perfusion of livers with a concentration of tBuHQ previously shown to completely inhibit microsomal calcium sequestration in isolated hepatocytes caused a 50% inhibition of protein biosynthesis.

Here we show that thrombospondin-1 (TSP-1) prevents cAMP/protein kinase A (PKA) signaling through a CD36-dependent mechanism.

Previously, we demonstrated that lipopolysaccharide (LPS, TLR4 ligand)-increased macrophage motility required the participation of Src and FAK, which was inducible nitric oxide synthase (iNOS)-dependent.

Rosiglitazone treatment of db/db mice elicited significant changes in the expression of a comparable number of genes to that observed between db/+ and the diabetic control db/db reference group // 100mg/kg/day

Rosiglitazone treatment of db/db mice elicited significant changes in the expression of a comparable number of genes to that observed between db/+ and the diabetic control db/db reference group // 10mg/kg/day

Rosiglitazone treatment of db/db mice elicited significant changes in the expression of a comparable number of genes to that observed between db/+ and the diabetic control db/db reference group // 30mg/kg/day

bp(GO:"response to starvation") -> bp(GO:autophagy)
p(HGNC:EIF2A,pmod(P,S,51)) -> (bp(GO:"response to starvation") -> bp(GO:autophagy))

Cells that carry a non-phosphorylatable mutant of eIF2alpha (S51A) fail to induce autophagy in response to starvation, suggesting that eIF2alpha phosphorylation on serine 51 (and by extension eIF2alpha kinases) plays a major role in autophagy regulation (Kouroku et al., 2007; Talloczy et al., 2002).

bp(GO:"response to endoplasmic reticulum stress") -> kin(p(HGNC:EIF2AK3))

Yeast GCN2 and mammalian PKR and PERK have been shown to be required for autophagy induced by starvation, viral infection, and ER stress, respectively (He and Klionsky, 2009).

Treatment for 3 days with IFN-gamma alone, dexamethasone alone, and IFN plus dexamethasone increased the content of surfactant protein A (SP-A, 28 to 36 kD) by approximately 3-, 2.5-, and 10-fold, respectively.

The overall secretion of this peptide by populations of freshly isolated or 3-day cultured monocytes was augmented by exposure for 6 hr to bacterial LPS, recombinant human IFN-gamma or recombinant human TNF alpha

a(CHEBI:lipopolysaccharide) -| r(HGNC:C4A)

LPS decreases monocyte C4 expression and completely abrogates the effect of IFN-gamma on the expression of this gene.

p(MGI:Il10) -> kin(complex(NCM:"p85/p110 PI3Kinase Complex"))

IL-10 activates the class I phosphatidylinositol 3-kinase (PI3K) pathway, which results in the phosphorylation of p70S6K through the activation of Akt and a mammalian target of the rapamycin complex 1 (mTORC 1).

cat(p(HGNC:TICAM1)) -> tscript(p(HGNC:IRF3))

while TRAM recruits TRIF to TLR4 for activation of IRF3.

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> p(HGNC:AKT1,pmod(P,S,473))

FIGURE 3. Amino acids induce Akt phosphorylations (Thr-308,Ser-473) via class I PI3K

Here, we show that the mechanism by which PML induces a permanent cell cycle exit and activates p53 and senescence involves a recruitment of E2F transcription factors bound to their promoters and the retinoblastoma (Rb) proteins to PML nuclear bodies enriched in heterochromatin proteins and protein phosphatase 1.

kin(p(HGNC:MAPK3)) -> tscript(complex(NCH:"Nfkb Complex"))

These demonstrate that Ang II is capable of inducing CRP generation in macrophages via AT(1)-ROS-ERK1/2/p38MAPK-NF-kB signal pathway, which contributes to better understanding of the proinflammatory and proatherosclerotic actions of Ang II.

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

Recent evidence has correlated skin fibrosis in SSc with stabilization of proto-oncogene Ha-Ras secondary to auto-antibody stimulation of reactive oxygen species production.

Here, we show that RhoB activity increases in human breast and cervical cancer cell lines after treatment with DNA damaging agents. Furthermore, RhoB activity is necessary for DNA damage-induced cell death, as the stable loss of RhoB protein expression using shRNA partially protects cells and prevents the phosphorylation of c-Jun N-terminal kinases (JNKs) and the induction of the pro-apoptotic protein Bim after IR.

Wild-type and TNF receptor knockout mice were treated with intravenous (iv) TNF, and the surface expression of leukocyte adhesion molecules VCAM-1, E-selectin, and ICAM-1 was quantitatively assessed on PECs by flow cytometry...E-selectin showed peak expression on PECs at 2 h after TNF treatment, while VCAM-1 and ICAM-1 expression was greater at 4 h

a(CHEBI:lipopolysaccharide) -> p(HGNC:CFB)
p(HGNC:IL4) -| (a(CHEBI:lipopolysaccharide) -> p(HGNC:CFB))

IL-4 also abrogated the effects of IL-1 and LPS on factor B synthesis, but did not affect the increase in synthesis of factor B induced by IFN-gamma.

In contrast to the pattern for effect of IL-4 on factor B synthesis, the TNF-induced rate of synthesis of C3 was augmented by IL-4.

p(HGNC:IL4) -| (p(HGNC:TNF) -> p(HGNC:CFB))

TNF increased synthesis of factor B by 18.6-fold; IL-4 reduced the TNF effect on factor B synthesis by 83%.

Thrombospondin 1 (TSP1), an activator of latent transforming growth factor (TGF)-B, is overexpressed by scleroderma fibroblasts.

a(CHEBI:"amino acid") -> (gtp(p(HGNC:RHEB)) -> kin(p(EGID:2475)))

In mammalian cells, in response to AAs, the Rag GTPase complex recruits mTORC1 to lysosomes, where mTOR is activated by Rheb.

The expression of JunD colocalised with pSmad 3 in fibrotic skin and silencing of Smad 3 or Smad 4 by siRNA prevented the induction of JunD by TGFbeta......The expression of JunD was analysed by real-time PCR, immunofluorescence, western blotting and immunohistochemistry.

PC-12 cells treated with 4 nM of NGF for 5 minutes exhibited rapid increase in Microtubule associated protein kinase (MAP kinase) activity, reaching a maximum at 5-10 minutes and declined by 20-25 minutes which was followed by a second phase of ac compared to control cells.

a(SCHEM:"Concanavalin A") -| r(MGI:Tubb2a)

The increase in beta-tubulin mRNA expression which was observed after cell culture and after stimulation by dB-cAMP was suppressed by the addition of Con A.

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

t-PA expression is modulated by PMA on the level of transcription. the PMA-mediated induction

Class I PI3K, a heterodimer consisting of a regulatory and a catalytic subunit, is a negative regulator of autophagy that is activated by the insulin receptor and the insulin receptor substrate proteins. Activated class I PI3K mainly uses PtdIns(4,5)P2 as substrate to yield PtdIns(3,4,5)P3 at the plasma membrane, which increases membrane recruitment of both PKB/Akt and its activator phosphoinositide- dependent protein kinase 1, leading to the activation of PKB/Akt, a downstream negative regulator of autophagy. Activated PKB/Akt further activates mTOR through inhibiting a downstream protein complex, the tuberous sclerosis complex 1/2, that represses the small G protein Rheb, causing inhibition of autophagy.

beta-all transretinoic acid (RA) resulted in an increased level of two lysosomal-associated membrane glycoproteins (LAMP-1 and LAMP-2)

kin(p(HGNC:EGFR)) => p(HGNC:PLCG1,pmod(P,Y))

Phospholipase C gamma 1 (PLC gamma 1) and p21ras guanosine triphosphatase (GTPase) activating protein (GAP) bind to and are phosphorylated by activated growth factor receptors

Rheumatoid arthritic synoviocytes were incubated for 48 hours in the medium containing IL-1Beta (100U/ml). IL-1Beta induced GM-CSF production.

a(CHEBI:"reactive oxygen species") -> cat(p(MGI:Parp1))

cadmium generated reactive oxygen species (ROS) at relatively low levels, and caused poly(ADP-ribose) polymerase-1 (PARP) activation and ATP depletion.

p(HGNC:F2) -> bp(GO:"regulation of vascular permeability")

Exposure to thrombin induced a redistribution of VE-cadherin into a zigzag wide pattern typical for unstable and activated junctions and the generation of intercellular gaps. Ang-1 preincubation attenuated the effect of thrombin on VE-cadherin redistribution and gap formation. However, still some intercellular gaps were visible in accordance with the thrombin-induced permeability in Ang-1 treated cells (Figure 3c). In contrast, the effect of thrombin was enhanced in Ang-2 treated cells, which resulted in even wider VE-cadherin staining and a stronger zigzag pattern together with more intercellular gaps (Figure 3c).

During adipose conversion, insulin promotes an accumulation of G3PDH mRNA which is linked to cell differentiation

p(HGNC:NRAS,sub(Q,61,K)) => gtp(p(HGNC:NRAS))

Maximal expression was found 4 h and 12 h post-TNF-? stimulation for ESELE and VCAM-1, respectively. ICAM-1 expression stayed high between 8 and 48 h (see Figure 1).

a(SCHEM:"serum insulin") -> r(MGI:Zfp36)

By differential hybridization screening of a cDNA library derived from insulin-stimulated cells, we selected a clone which hybridized to an mRNA species that rapidly accumulated in response to insulin.

Stimulation of intact neutrophils with nanomolar concentrations of FMLP, leukotriene B4, 10-100 U/ml of tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor resulted in parallel release of tetranectin and translocation of alkaline phosphatase to the plasma membrane.

p(HGNC:TGFB1) -| bp(GO:"osteoclast differentiation")

Osteoinductive factor (OIF) is a glycoprotein in bone that induces ectopic bone formation. Implantation of OIF plus transforming growth factor beta (TGF-beta) type 1 or 2 into subcutaneous tissues of rats induces formation of bone at the implantation site. Since TGF-beta is also present in bone matrix and inhibits formation of multinucleated cells that express an osteoclast phenotype in long-term human marrow cultures, we tested the effects of OIF on formation of these osteoclast-like cells to determine the effects of OIF on cells in the osteoclast lineage. We found that OIF inhibited total multinucleated cell (MNC) formation in a dose-dependent fashion and preferentially inhibited formation of MNCs that react with monoclonal antibody 23c6 (23c6-positive MNCs), an antibody that identifies osteoclasts. In addition, low concentrations of OIF in combination with low concentrations of TGF-beta acted synergistically to inhibit 23c6-positive MNC formation. The inhibition of 23c6-positive MNC formation by OIF was not mediated by prostaglandin synthesis. These data suggest that regulatory growth factors, such as OIF or TGF-beta, that are stored within the bone matrix and released when bone is resorbed can serve as natural inhibitors of osteoclast activity by inhibiting osteoclast formation.

Human serum albumin, but not bovine serum albumin was able to prevent the inhibition

kin(p(RGD:Uck2)) -> bp(GO:"cell growth")

The controversial issue of the effects of prednisolone and 17 beta-estradiol on replication of fetal rat pancreatic islets in culture was studied Further support for a lack of inhibition of growth of islet cells treated with steroid hormones was provided by the observation that prednisolone increased uridine kinase activity and RNA biosynthesis, both of which may participate in the growth of cells preceding mitosis and (the latter) in protein hormone biosynthesis.

a(SCHEM:"Tetradecanoylphorbol acetate") -| p(HGNC:FGF1)

At 170 pg/ml, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) caused a 50% inhibition of heparin-binding growth factor type one (HBGF-1)

p(RGD:Il1b) -> path(SDIS:"systemic acute phase reaction")

the 2 cytokines most intensively involved in eliciting the acute phase response are IL6 and IL1

a(CHEBI:glucocorticoid) -| r(HGNC:GAPDH)

Both dexamethasone and 13-cis-RA also reduced the mRNA level of glyceraldehyde-3-phosphate dehydrogenase, indicating that glucocorticoids and retinoids have both similar and different effects on gene expression in HSF

bp(GO:"response to virus") -> r(HGNC:MX1)

In human fibroblasts, expression of MxA and MxB is strongly induced by alpha interferon (IFN-alpha), IFN-beta, Newcastle disease virus, and, to a much lesser extent, IFN-gamma

alpha 2-macroglobulin, alpha 1-antichymotrypsin ( = contrapsin), cysteine protease inhibitor ( = thiostatin), alpha 1-antitrypsin, ceruloplasmin and fibrinogens are predominantly regulated by the keratinocyte-derived HSF-III/-II or IL-6

a(CHEBI:histamine) -> sec(a(SCHEM:Epoprostenol))

The present studies demonstrate that rat aortic endothelial cells, when stimulated with either bradykinin or histamine, caused the release of both PGI2 and PGE2.

cat(p(MGI:Ank)) -| bp(GO:"inflammatory response")

By light microscopy, the earliest synovial lesion was inflammatory followed by synovial proliferation and cartilage erosions.

kin(p(PFR:"Prka Family")) -> cat(p(RGD:Lipa))

rat liver cholesterol ester hydrolase is activated by cyclic AMP dependent protein kinase and protein kinase C. Deactivation is accomplished by dephosphorylation catalyzed by a phosphoprotein phosphatase, dependent on Mg2+.

Norepinephrine (NE), isoproterenol, or phenylephrine also induced TIS mRNA accumulation

Enzyme activity was present at the earliest age tested, 2 days, and tended to increase in older animals

Estradiol produced selective inhibitions of glucose synthesis from various substrates and diminished malate dehydrogenase activity by 22%

kin(p(PFH:"PRKC Family")) -> r(HGNC:TFF1)

pS2 mRNA, but not cathepsin-D mRNA, was also induced up to 8-fold by protein kinase-C activation with 12-O-tetradecanoylphorbol-13-acetate

kin(p(PFM:"Prkc Family")) -> r(MGI:Zfp36)

When GM-CSF-deprived 32D clone 3 cells were exposed to GM-CSF or to TPA, four TIS mRNAs (TIS7, TIS8, TIS10, and TIS11) were rapidly and transiently induced.

The RP2 gene was found to contain at least two promoters, only one of which was highly sensitive to testosterone.

cat(p(HGNC:F2)) -> bp(GO:"platelet activation")

Activation of and degranulation of platelets by thrombin treatment caused release of lysosomal enzymes (beta-glucuronidase and N-acetyl-D-glucosaminidase), alpha-granule proteins (beta-thromboglobulin and fibrinogen) as well as mitogenic activity for MCF-7 cells and IGF-I as measured by radioimmunoassay (RIA) and radioreceptor assay.

bp(GO:"response to starvation") -| p(RGD:Pfkfb1)

Both enzymatic activities fell to 20% of control values with fasting or streptozotocin-induced diabetes and were coordinately restored to normal within 48 h of refeeding or 24 h of insulin administration. These alterations in enzymatic activities were always mirrored by corresponding changes in amount of enzyme

bp(GO:"response to starvation") -| kin(p(RGD:Pfkfb1))

p(HGNC:ANXA2) -| cat(p(PFH:"PLA2 Family"))

phosphorylation of lipocortin has been shown to block its inhibitory activity

Effects comparable to that induced by testosterone were elicited by other androgens (androstenedione and 5 alpha-dihydrotestosterone)

In contrast, adult monocytes increased C3 synthesis by 11.5-fold and factor B synthesis by 3.1-fold in response to LPS.

The 5-lipoxygenase activity is stimulated by Ca++ and ATP

We have purified two 35 kd phospholipase A2 inhibitors from human placenta, which we refer to as lipocortin I and II.

kin(p(HGNC:EGFR)) => p(HGNC:ENO1,pmod(P,Y))

Here we show that purified EGF (epidermal growth factor)-receptor kinase phosphorylates the enzymes PGM and enolase and also the key regulatory enzymes of the glycolytic pathway, phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in an EGF-dependent manner. (From Results: Tyrosine is the only amino acid in these enzyme substrates that was phosphorylated by purified EGFreceptor kinase (Fig. 2).)

p(HGNC:KRAS,sub(G,12,V)) => gtp(p(HGNC:KRAS))

p(HGNC:IL1A) -> sec(a(SCHEM:"1-Alkyl-2-acetyl-sn-glycero-3-phosphocholine"))
p(HGNC:SERPINA3) -| (p(HGNC:IL1A) -> sec(a(SCHEM:"1-Alkyl-2-acetyl-sn-glycero-3-phosphocholine")))

Both antiproteinases also inhibited PAF production stimulated by phagocytosis in macrophages and induced with IL-1 in neutrophils or with TNF in vascular endothelial cells.

TNF and IL-1 stimulate the synthesis and release of platelet-activating factor (PAF) by neutrophils and vascular endothelial cells.

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

Androgen controls the expression of beta-glucuronidase and several other proteins in the kidney of the standard laboratory mouse, Mus musculus.

a(CHEBI:glucocorticoid) -> cat(p(RGD:Got1))

Glucocorticoid hormones increased the activity of cytosolic but not mitochondrial aspartate aminotransferase in both liver and kidney. The increase in the enzyme activity was accompanied by an increase in the amount of the three corresponding mRNAs, while the mitochondrial enzyme mRNA was not significantly modified.

p(HGNC:KRAS,sub(G,13,D)) => gtp(p(HGNC:KRAS))

Expression of T alpha 1 mRNA is also increased in PC12 cells induced to differentiate and extend neurite processes by nerve growth factor.

bp(GO:"neuron differentiation") -> r(RGD:Tuba1a)

bp(GO:"cell proliferation") negativeCorrelation r(HGNC:COL1A1)

Analyses of populations of dividing and nondividing human lung fibroblasts revealed that, on a per cell basis, the nondividing population contained twice as much alpha 1(III) mRNA than did the dividing population. The same was true for the type I collagen alpha 1(I) and alpha 2(I) mRNA

Conversely, epinephrine suppressed stimulation of expression of the albumin gene by dexamethasone.

bp(GO:"response to hypoxia") -> r(HGNC:UGDH)

Entrez Gene summary: Human: The protein encoded by this gene converts UDP-glucose to UDP-glucuronate and thereby participates in the biosynthesis of glycosaminoglycans such as hyaluronan, chondroitin sulfate, and heparan sulfate. These glycosylated compounds are common components of the extracellular matrix and likely play roles in signal transduction, cell migration, and cancer growth and metastasis. The expression of this gene is up-regulated by transforming growth factor beta and down-regulated by hypoxia.

We have isolated cloned cDNAs corresponding to five mRNAs whose level is increased following stimulation of quiescent rat fibroblasts by either epidermal growth factor or serum lactate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, enolase, triose phosphate isomerase, and actin.

kin(p(HGNC:INSR)) => p(HGNC:TUBA4A,pmod(P,Y))

The purified insulin receptor kinase catalyzed the phosphorylation of native tubulin and microtubule-associated proteins (MAPs; MAP2, tau) on tyrosine residues. Insulin (10(-7) M) stimulated the reaction by 4-10-fold by increasing Vmax with little change in Km. alpha-Tubulin was preferred as a substrate for the kinase compared to beta-tubulin.

Tunicamycin (a specific inhibitor of N-linked glycosylation) inhibited aldosterone-stimulated Na+ transport and AIP synthesis without affecting overall protein synthesis.

a(SCHEM:Dinoprostone) -> kin(p(RGD:Ckb))

We have previously shown that both parathyroid hormone (PTH) and prostaglandin E2 (PGE2) stimulate the activity of creatine kinase BB (CKBB) in rat bone cells in culture.

The major excreted protein of transformed mouse fibroblasts, a secreted, mannose 6-phosphate-containing glycoprotein, is induced in nontransformed cells by a variety of transforming agents, by phorbol esters, and by platelet-derived growth factor.

a(SCHEM:"Tetradecanoylphorbol acetate") -> p(EGID:641050)

cDNA libraries from EL-4 cells treated with 12-O-tetradecanoyl phorbol-13-acetate (TPA) were screened for TPA-inducible sequences by differential hybridization. The most abundant inducible species was a sequence similar to that of mouse mammary tumor virus (MMTV). Induction of the mRNA corresponding to the MMTV-related sequences was already evident 30 min after TPA treatment, whereas the maximum accumulation occurred after 20 h of exposure to TPA. TPA also increased levels of MMTV-related RNA in the normal spleen cells of BALB/c and C57BL/6 mice.

p(HGNC:SERPINA1) -> bp(GO:"cell migration")

In contrast, alpha 2-macroglobulin and alpha 1-antitrypsin enhance leukocyte migration at doses close to physiological serum levels and affect cells irreversibly.

The synthesis of PGI2-LS was inhibited by Indo in both experiments in a time dependent manner.

Hydrocortisone increased the angiotensinogen synthesis in a dose-dependent manner.

Tissue kallikrein and factor Xa were found to activate tissue plasminogen activator (t-PA) at a rate comparable with that of plasmin. During the activation reaction, the single-chain molecule was converted into a two-chain form. A slight t-PA activating activity was also found in plasma kallikrein. Other activated coagulation factors, factor XIIa, factor XIa, factor IXa, factor VIIa, thrombin and activated protein C had no effect on t-PA activation. t-PA was also activated by a tissue kallikrein-like enzyme that was isolated from the culture medium of melanoma cells. These results indicate that tissue kallikrein and factor Xa may participate in the extrinsic pathway of human fibrinolysis.

a(SCHEM:Dinoprostone) -> bp(GO:"erythrocyte differentiation")

Prostaglandins E2 (PGE2) and D2 (PGD2), both of which have been demonstrated to be produced in the bone marrow, were found in the present studies to increase the number of CFU-E colonies in normal mouse bone marrow cultures.

a(CHEBI:"prostaglandin D2") -> bp(GO:"erythrocyte differentiation")

The Dbl-homology domains of Bcr and Abr were active in stimulating GTP binding to CDC42Hs, RhoA, Rac1, and Rac2

tscript(p(HGNC:NR3C1)) -> cat(p(HGNC:SOAT1))

Dexamethasone produced a 60% increase in activity of the enzyme acyl-CoA: cholesterol O-acyltransferase (ACAT), active in synthesis of cholesteryl esters, and a 40% decrease in that of neutral cholesteryl esterase, active in cholesteryl ester breakdown.

p(MGI:Sod2) -> cat(complex(NCM:"Respiratory Chain Complex II"))

Cytochemical analysis revealed a severe reduction in succinate dehydrogenase (complex II; 600857) and aconitase (a tricarboxylic acid cycle enzyme; 100850) activities in the heart and to a lesser extent in other organs.

Homozygous SOD2 -/- mice die within the first 10 days of life with a dilated cardiomyopathy, accumulation of lipid in liver and skeletal muscle, and metabolic acidosis.

p(HGNC:IGF1R,pmod(P,Y,1136)) -> bp(GO:"cell growth")

In addition, they were unable to respond to IGF-I-stimulated cell growth in culture, and tumor formation in nude mice was abrogated.

tscript(p(HGNC:RFX5)) -> r(HGNC:"HLA-DMA")

We report here that CIITA and RFX5, although operating at different levels of transcriptional control, are also both essential regulators of HLA-DMA and -DMB genes.

Both 5HT-alpha 2M and MA-alpha 2M also dose dependently block NGF-promoted autophosphorylation of trk in vivo, whereas normal alpha 2M and plasmin-reacted alpha 2M are inactive or much less active. MA-alpha 2M also blocks NGF-promoted incorporation of 32P from [32P]ATP into trk receptors in vitro.

p(HGNC:FGF2) -> kin(p(PFH:"PRKC Family"))

Activation of the activity of FGF receptor tyrosine kinase in smooth muscle cells by ligand binding resulted in tyrosine phosphorylation of one of the FGF receptors and a 90-kDa-protein as well as increased tyrosine phosphorylation of phospholipase C-gamma. Parallel observations were made in that increased PKC and protein kinase A activities occurred with bFGF as compared with control cells.

a(CHEBI:ranitidine) -| cat(p(HGNC:HRH2))

Histamine alone did not induce protein synthesis or mRNA accumulation for IL-6. Histamine (1-100 microM) enhanced IL-1 alpha-induced synthesis of IL-6 (p < 0.001). Cimetidine and ranitidine, H2 receptor antagonists structurally unrelated to each other, completely reversed the histamine-mediated increase in IL-1 alpha-induced IL-6 synthesis

Functional studies with the human D4 protein demonstrate that D4 has GDI activity against the CDC42Hs and rac I proteins,

We found that the temporal pattern of trk expression in DRG neurons correlates with the observed age-dependent ability of nerve growth factor to induce the biosynthesis of the neuropeptide substance P.

In this report, we show that binding of IFN-gamma to HeLa cells initiated a series of events that resulted in the extremely rapid (15 s) tyrosine phosphorylation of not only Jak1, Jak2, and p91 but also the IFN-gamma R.

cat(p(HGNC:IFNGR2)) -> kin(p(HGNC:JAK2))

Our results indicate that NGF induces NPY gene expression via activation of PKC system.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced by immune cells, which has multiple effects on bone cells and is therefore thought to mediate changes in bone metabolism occurring during inflammation. In the present study we have investigated the effect of TNF-alpha on the secretion of insulin-like growth factor I (IGF-I) and IGF binding protein 4 (IGFBP-4) by clonal mouse osteoblasts (MC3T3-E1 cells) using subconfluent in vitro cultures and serum-free conditions. The IGF-I was determined by radioimmunoassay under conditions eliminating the interference of IGFBPs. Treatment of MC3T3-E1 cultures with TNF-alpha for 24 h resulted in a dose-dependent decrease in IGF-I secretion (maximally to 34 +/- 9.7% of control with 60 pmol/l TNF-alpha; mean +/- SD). The TNF-alpha treatment also resulted in decreased messenger ribonucleic acid (mRNA) levels of IGF-I at 4 and 24 h, as detected by Northern analysis. Because basal secretion of IGFBPs is very low in MC3T3-E1 cells, effects of TNF-alpha on IGFBP secretion were studied in cultures in which IGFBP-4 expression was increased by calcitriol (1,25(OH)2D3) treatment. The presence of TNF-alpha (600 pmol/l) inhibited this calcitriol-induced stimulation of IGFBP-4 mRNA levels from 4 h onwards, with complete inhibition of the calcitriol effect occurring at 24 h. We also observed a dose-dependent inhibition of calcitriol-stimulated IGFBP-4 secretion into the culture medium (as detected by Western ligand blot), with the maximal inhibition occurring with 600 pmol/l TFN-alpha to 25 +/- 7% of control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

kin(p(HGNC:PDGFRA)) => p(HGNC:PDGFRA,pmod(P,Y,754))

As in cultured primary keratinocytes from normal internal stratified epithelia, the in vitro expression of K13 in transformed epidermal cell lines can be induced either by Ca2+ or by retinoic acid (RA).

kin(p(PFH:"PRKC Family")) => p(HGNC:DDX5,pmod(P,S,557))

In H4A7C2 cells, IGF II reduced CK19 and OC.3 protein levels and GGT, transferrin, and HNF-3 beta mRNA

p(HGNC:FGF7) -| (a(SCHEM:Calcium) -> r(HGNC:KRT1))

TGF alpha, keratinocyte growth factor (KGF), and acidic fibroblast growth factor (aFGF), but not basic fibroblast growth factor (bFGF) or insulin-like growth factor type I, block Ca(2+)-mediated expression of K1 while inducing K8

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

Recombinant HVH2 phosphatase exhibited a high substrate specificity toward activated ERK and dephosphorylated both threonine and tyrosine residues of activated ERK1 and ERK2

p(HGNC:MAPK3,pmod(P,T)) => kin(p(HGNC:MAPK3))

phos(p(HGNC:DUSP4)) =| p(HGNC:MAPK3,pmod(P,T,202))

phos(p(HGNC:DUSP4)) =| p(HGNC:MAPK3,pmod(P,Y,204))

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

Cross-linked CD40L was found to induce nuclear expression of NF-kappa B, AP-1 and NF-AT with a time course and intensity similar to that produced by anti-Ig. Examination of NF-kappa B in more detail demonstrated that the CD40 mediated expression of DNA binding complexes correlated with induction of trans-activating activity which again attained similar levels following cross-linking of CD40 and slg. Despite the marked similarity in transcription factor induction triggered through CD40 and slg, differences in the intracellular signaling pathways utilized were apparent in that protein kinase C (PKC) depletion did not affect CD40 mediated induction of NF-kappa B even as induction by anti-Ig was abolished.

We found that mac25 accumulates in senescent cells and is up-regulated in normal, growing mammary epithelial cells by all-trans-retinoic acid or the synthetic retinoid fenretinide.

kin(p(HGNC:PRKCA)) => p(HGNC:KIT,pmod(P,S,821))

Observations in patients receiving infliximab (remicade) for treatment of rheumatoid arthritis or Crohn disease (Keane et al., 2001) have shown that antibody-mediated neutralization of TNF increases susceptibility to tuberculosis

Tyrosine phosphorylation of Fak was induced by cell adhesion to Fibronectin.

We report that exposure of lipopolysaccharide-stimulated murine macrophages to therapeutic concentrations of aspirin (IC50 = 3 mM) and hydrocortisone (IC50 = 5 microM) inhibited the expression of iNOS and production of nitrite.

bp(GO:"response to stress") -> r(HGNC:PDIA5)

Northern blots showed that PDIR is preferentially expressed in cells actively secreting proteins and that the expression of PDIR is stress-inducible. These results suggested that PDIR has oxidoreductase activity of disulfide bonds against polypeptides and that it acts as a catalyst of protein folding in the lumen of the ER.

bp(GO:"response to endoplasmic reticulum stress") -> r(HGNC:PDIA5)

tscript(p(MGI:Nr3c1)) -> tscript(p(MGI:Cebpb))

Induction of C/EBP beta DNA-binding activity in NIH-3T3 beta 2 cells exposed to dexamethasone in the presence of insulin and fetal bovine serum activates the expression of an adipocyte-specific nuclear hormone receptor, PPAR gamma, that stimulates the conversion of these fibroblasts into committed preadipocytes

These data indicate that cAMP-elevating agents decrease sGC activity, possibly by decreasing mRNA or protein levels or both.

cat(p(HGNC:F2R)) -> p(HGNC:PLEK,pmod(P))

Pleckstrin phosphorylation in response to thrombin receptor stimulation is progressively susceptible to inhibition by wortmannin, a potent and specific inhibitor of platelet PI 3-kinases

kin(p(PFH:"PRKC Family")) -> p(HGNC:PLEK,pmod(P,S))

In human platelets activated with thrombin or phorbol esters, and in COS-1 cells expressing pleckstrin, a combination of phosphopeptide analysis and site-directed mutagenesis shows that three residues in the intervening sequence between the two pleckstrin PH domains become phosphorylated: Ser113, Thr114, and Ser117

kin(p(PFH:"PRKC Family")) -> p(HGNC:PLEK,pmod(P,T))

tscript(complex(NCH:"AP-1 Complex")) -> tscript(p(HGNC:ETV5))

The synergy between c-Jun and ERM may be attributed to the enhancing effect of c-Jun on the transcription activity of ERM, because c-Jun increased ERM transcription activity by more than 20-fold

tscript(p(HGNC:JUN)) -> tscript(p(HGNC:ETV5))

bp(GO:"macrophage activation") -> r(HGNC:LGALS3)

We now report that galectin-3 is expressed in normal human peripheral blood monocytes and its level increases dramatically as human monocytes differentiate into macrophages upon culturing in vitro.

The defect in PDGF-induced PGE2 release occurs prior to action of prostaglandin H synthase/cyclooxygenase as release of arachadonic acid (in response to PDGF) does not occur in the superoxide dismutase-overexpressing clones.

The presence of putative Cdx1-binding sites in Hox gene control regions as well as in vitro transactivation of Hoxa-7 indicates a direct regulation.

a(SCHEM:"Tetradecanoylphorbol acetate") -| r(MGI:Gjb5)

Skin hyperplasia induced by one topical application of TPA was accompanied by hyperexpression of both Cx26 and Cx43. In addition, TPA significantly inhibited the expression of Cx31.1.

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(MGI:Gja1)

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

The ERF protein is also hyperphosphorylated in cells transformed by the activated Ha-ras and v-src genes and the transcription repressor activity of ERF is decreased after co-transfection with activated Ha-ras or the kinase domain of the c-Raf-1 gene, indicating that ERF activity is probably regulated by the ras/MAPK pathway.......These data suggest that the repression ability of ERF may be regulated, at least partially, by phosphorylation of Thr526 (Substitution of Thr526 for glutamic acid also decreases the repression ability of ERF).

complex(NCM:"activin A complex") -| r(MGI:Kit)

We examined the effects of erythroid differentiation factor (EDF)/activin A on the expression of c-kit mRNA and protein in murine erythroleukemia (MEL) cells. EDF/activin A induced MEL cells to benzidine positive cells. Northern blot analysis showed that the c-kit mRNA expression was reduced synchronously with increase of beta-globin and uroporphyrinogen decarboxylase gene expression during EDF/activin A induced erythroid differentiation.

in addition to the antioxidant enzyme manganese superoxide dismutase, expression of a variety of stress-responsive genes including heme oxygenase-1, c-fos, c-jun, CAAT-enhancer binding protein (C/EBP)-beta, and C/EBP-delta were increased after hyperoxia.

Through AT1 receptors, endogenous ANG II stimulates EGF and inhibits clusterin expression.

Addition of IL-13 to fibroblast cultures treated with TNF-alpha resulted in a dose-dependent increase in C3 protein biosynthesis and a concomitant down-regulation of factor B protein biosynthesis.

a(SCHEM:"Tetradecanoylphorbol acetate") -| r(HGNC:FDX1)

In steroidogenic cell line Y1, the expression of ferredoxin was stimulated by cAMP and repressed slightly by angiotensin II and phorbol ester PMA

The CAH domain of RPTP beta induced cell adhesion and neurite growth of primary tectal neurons, and differentiation of neuroblastoma cells.

p(HGNC:ADRB1,pmod(P)) =| cat(p(HGNC:ADRB1))

Overexpression of rhodopsin kinase, beta ARK1, beta ARK2, or GRK5 significantly increases agonist-induced beta 1AR phosphorylation

p(PFH:"ADRB Family",pmod(P)) =| cat(p(PFH:"ADRB Family"))

Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase is required for the activation of CDK enzymes. Members of two families of CDK inhibitors, p16/p18 and p21/p27, become physically associated with and inhibit the activity of CDKs in response to a variety of growth-modulating signals. Here, we show that the representative members of both families of CDK inhibitors, p21waf1,cip1, p27kip1, and p18, can prevent the phosphorylation of their CDK partners, CDK2 and CDK6, by CDK-activating kinase.

S115 + A cells possessed mRNA for both acidic FGF (aFGF) and TGF beta 1, both of which were increased by testosterone

kin(p(HGNC:MAPK1)) => p(HGNC:TOP2A,pmod(P,S,1361))

These results suggest that necdin is a nuclear factor that governs the permanent arrest of cell growth of postmitotic neurons during development of the nervous systems of vertebrates.

complex(p(MGI:Egf),p(MGI:Egfr)) -> tloc(p(MGI:Shc1),GOCCACC:"GO:0005737",GOCCACC:"GO:0005886")

In the absence of EGF stimulation, SHC exists in the liver as a cytoplasmic monomer. Intraperitoneal injection of EGF results, within minutes, in the translocation of 50-80% of SHC to the liver plasma membrane. The membrane-associated SHC was found to be tyrosine-phosphorylated; the subsequent release of SHC from the membrane correlated with a tyrosine dephosphorylation

Upon 32P labeling of these cells in culture, annexin I was immunoprecipitated using a specific polyclonal antibody and was found to incorporate radioactivity in a constitutive manner. However, as with epidermal growth factor (200 ng/ml), addition of angiotensin II (10(-7) M), arginine-vasopressin (10(-7) M), or endothelin I (10(-7) M) resulted in a 2-3-fold stimulation of annexin I phosphorylation. The basal phosphorylation as well as the stimulating effect of angiotensin II were also detected by immunoblotting annexin extracts using an antiphosphotyrosine antibody.

The presence of HNF-1 recognition elements in functionally significant regulatory sites of the lysozyme gene and high levels of HNF-1 alpha in the oviduct is a strong indication for the involvement of HNF-1 alpha in the control of the lysozyme gene and possibly other egg white protein genes in the chicken oviduct.

IGF-I, IGF-II, and high concentrations of insulin increased IGFBP-2 and IGFBP-3 levels.

Combinations of IBMX plus nicotine, VIP, or histamine also synergistically enhanced proenkephalin synthesis, with no further elevation when the cells were also pretreated with pertussis toxin.

complex(p(HGNC:RXRA),p(HGNC:NR4A2)) -> tscript(p(HGNC:RXRA))

NGFI-B and NURR1, which have been shown previously to interact with DNA as monomers, also can heterodimerize with RXR.

bp(GO:"response to heat") -> p(HGNC:HSP90AA1)

Upon heat shock, the level of Hsp90 is increased even more

a(SCHEM:Norepinephrine) -> cat(p(RGD:Lipe))
cat(p(RGD:Pde3a)) -| (a(SCHEM:Norepinephrine) -> cat(p(RGD:Lipe)))

OPC3911 completely blocked (IC50 = 0.3 microM) the maximal inhibitory effect of insulin on noradrenaline-induced lipolysis and the net dephosphorylation of hormone-sensitive lipase and other intracellular target proteins for insulin action, whereas insulin-induced lipogenesis was not changed.

kin(p(PFM:"Prkc Family")) -> r(MGI:Plk3)

FGF-1 induction of Fnk mRNA expression is first detected at 30 min after mitogen addition, reflects transcriptional activation, and does not require de novo protein synthesis. FGF-2, platelet-derived growth factor-BB, calf serum, or phorbol myristate acetate treatment of quiescent cells also induces fnk gene expression

kin(p(HGNC:MET)) -> p(HGNC:SHC1,pmod(P,Y,317))

After stimulation of the HGF receptor, Shc is phosphorylated on Y317VNV, generating an high affinity binding site for Grb2 (Kd = 15 nM). This duplicates the high affinity binding site for Grb2 present on the HGF receptor (Y1356VNV).

complex(p(HGNC:SHC1),p(HGNC:GRB2)) -> gtp(p(PFH:"RAS Family"))

Thus HGF stimulation can trigger the Ras pathway by recruiting Grb2 both directly through the receptor, and indirectly, through Shc.

p(HGNC:ATF2,pmod(P,T,69)) => tscript(p(HGNC:ATF2))

Mutation of either Thr69 or Thr71, or both, led to an almost complete loss of inducibility.

kin(p(HGNC:MAPK8)) => p(HGNC:JUN,pmod(P,S,73))

p54/46 ATF-2 kinases were bound to the GST-ATF-2 column and after elution of the kinases from the column with 2 M urea, fractions were tested for kinase activity (Figure 7A)....we used a mutant of ATF-2 containing point mutations at positions Thr69, Thr71 and Ser9O. As shown in Figure 7B (right panel), both the kinases purified with GST-ATF-2 and with GST-Jun (JNK) hardly phosphorylated GST-ATF-2 protein lacking the putative phosphoacceptor sites (M).....The GST-c-Jun protein containing point mutations at positions Ser63 and Ser73 (M) was phosphorylated less efficiently than wild-type c-Jun (W) by ATF-2 kinases (Figure 7B, left panel), similar to that found for p54/46 JNK (Hibi et al., 1993).

kin(p(HGNC:MAPK9)) => p(HGNC:JUN,pmod(P,S,63))

a(SCHEM:"Tetradecanoylphorbol acetate") -> tscript(p(HGNC:JUN))

transactivation by the Gal4-c-Jun hybrid protein containing the transactivation domain of c-Jun was enhanced by both TPA and UV. In HeLa and GM637 cells, Gal4-c-Jun was already an efficient transactivator in unstimulated cells.

p(HGNC:RB1) -| complex(p(HGNC:E2F2),p(HGNC:TFDP1))

DP-1 and DP-2 associate with Rb protein when complexed with E2F-1, E2F-2 and E2F-3. Rb is able to block transcriptional activation of all of these E2F/DP dimers.

tscript(p(HGNC:RB1)) -| tscript(complex(p(HGNC:E2F1),p(HGNC:TFDP2)))

kin(p(HGNC:PRKCZ)) => p(HGNC:PRKCZ,pmod(P,T,560))

[14C]ceramide specifically binds to and regulates kinase activity of PKC zeta in a biphasic manner. Binding studies indicate high and low affinity binding with bmax values of 60 and 600 nM and Kd values of 7.5 and 320 nM respectively. At ceramide concentrations as low as 0.5 nM an up to 4-fold increase in autophosphorylation is obtained

Interestingly, its gene expression was enhanced by various differentiation-inducing agents, such as phorbol ester, dihydroxy vitamin D3, retinoic acid, and dimethyl sulfoxide.

Thapsigargin, an agent that mobilizes Ca2+ from internal stores, suppressed basal and progesterone-induced fibronectin production in the absence and presence of cyanoketone.

a(CHEBI:"arachidonic acid") -> p(MGI:Tnni3,pmod(P))
a(SCHEM:"Calphostin C") -| (a(CHEBI:"arachidonic acid") -> p(MGI:Tnni3,pmod(P)))

Incubation with either PMA, AA, or ET resulted in similar increases in 32Pi incorporation into troponin I (TnI) and myosin light chain 2 (MLC2), which was inhibited by preincubation with the protein kinase C antagonist calphostin C

a(SCHEM:"Calphostin C") -| (a(SCHEM:"Tetradecanoylphorbol acetate") -> p(MGI:Myl9,pmod(P)))
a(SCHEM:"Tetradecanoylphorbol acetate") -> p(MGI:Myl9,pmod(P))

NGF protects PC12 cells from H2O2 injury by stimulating the synthesis of antioxidant enzymes including catalase, GSH Px, glucose-6-phosphate dehydrogenase, and gamma-glutamylcysteine synthetase

kin(p(HGNC:MAPK3)) => p(HGNC:LIFR,pmod(P,S,1044))

Two other antiprogestins, Mifepristone and Onapristone, likewise stimulated MDGI expression.

Radioligand binding studies revealed that the isolated component, as well as C7 after its incorporation into the terminal complement complex C5b-9, can bind plasminogen. Binding was inhibited by the lysine analogues 6-aminohexanoic acid and tranexamic acid, implicating the lysine binding sites of plasminogen into the binding interaction. tPA-mediated plasminogen activation was enhanced in the presence of C7.

Gel shift analysis revealed that 6 h of insulin treatment decreased the binding of nuclear C/EBP alpha while increasing binding of nuclear C/EBP beta and C/EBP delta.

Treatment of adipocytes with insulin stimulated rapid dephosphorylation of C/EBP alpha, and repressed the expression of C/EBP alpha within 2-4 h, with > 90% suppression occurring at 24 h.

kin(p(HGNC:MAPK10)) => p(HGNC:MAPK10,pmod(P))

JNK3 autophosphorylates both threonine and tyrosine residues

H7 (50 microM), genistein (2 microM) and okadaic acid (20 nM), all block the induction of c-jun and c-fos mRNA accumulation in the H2O2-treated rat lenses.

is now shown to undergo a calcium-dependent translocation process from the cytosol to cellular membranes in both systems.

kin(p(HGNC:MAP2K3)) => p(HGNC:MAP2K3,pmod(P,S,218))

complex(p(MGI:Nck1),p(MGI:Sos1)) => gtp(p(PFM:"Ras Family"))

We also found that NCK binds directly to the guanine nucleotide exchange factor SOS. This interaction is mediated by the SH3 domains of NCK. These findings suggest that NCK can regulate p21ras-dependent gene transcription through interaction with SOS protein.

bp(GO:"response to hypoxia") -| r(RGD:Npr3)

ANPCR-mRNA levels were selectively and significantly downregulated by 48-h and 4-wk hypoxia in lung but were unchanged or upregulated in other tissues.

Short-term Se(-) cells were more sensitive to H2O2-induced killing than Se(+) cells,

a(SCHEM:Selenium) -| (a(CHEBI:"hydrogen peroxide") -> bp(GO:"cell death"))

kin(p(PFH:"MEK1/2 Family")) => p(HGNC:MAP2K1,pmod(P,S,25))

bp(GO:"macrophage differentiation") -> r(MGI:Mpeg1)

The expression of Mpg-1 was found to increase when murine fetal liver hematopoietic progenitor cells were induced to differentiate into macrophages

In 43.5% of slices tested, dopamine preferentially and irreversibly facilitated SDAP production at low bath concentrations (1-100 microM), but at concentrations > 100 microM suppressed all components of the epileptiform responses.

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:IMPDH2)

Recent studies by our group have shown that activation of peripheral blood T lymphocytes with the mitogens PMA and ionomycin results in a 10- and 15-fold induction of IMPDH type II mRNA expression and total cellular enzymatic activity, respectively

Growth factors like NGF are known to increase the expression of PrP gene, a housekeeping gene which is responsible for susceptibility to transmissible spongiform encephalopathies.

p(HGNC:EGF) -> p(HGNC:CALM1,pmod(P,Y,99))

An epidermal-growth-factor(EGF)-receptor preparation isolated by calmodulin-affinity chromatography from rat liver plasma membranes is able to phosphorylate calmodulin. Calmodulin phosphorylation was enhanced 3-8-fold by EGF, was dependent on the presence of a polycation or basic protein and was inhibited by micromolar concentrations of Ca2+. Phosphate incorporation into calmodulin occurs predominantly on tyrosine residues. Partial proteolysis of phosphocalmodulin by thrombin identifies Tyr99, located in the third calcium-binding domain of calmodulin, as the phosphorylated residue.

TGF-beta has been implicated as a cause of fibrosis in most forms of experimental and human kidney disease

In mammals, histamine is inactivated principally by two enzymes: histamine N-methyltransferase (HMT; EC 2.1.1.8) and diamine oxidase (DAO; EC 1.4.3.6.)

Strikingly, Ras, Src, and Mos expression switch Net activity to positive.

The second domain (R-020) of human urinary trypsin inhibitor (UTI) exerts similar inhibitory activities on trypsin, alpha-chymotrypsin, leukocyte elastase, and plasmin to those of UTI itself, and additionally inhibits coagulation factor Xa (FXa) and plasma kallikrein

complex(p(HGNC:EPHA2),p(HGNC:PIK3R2)) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

Additionally, Eck coimmunoprecipitated with p85 in ligand activated cells confirming their interaction in vivo. In keeping with the above observations, activation of Eck by its ligand, B61, increased phosphatidylinositol 3-kinase activity.

p(HGNC:RB1) -> (p(HGNC:IFNG) -> p(HGNC:CD74))

IFN-gamma induction of CD74 surface expression in a series of breast carcinoma lines is enhanced by RB, while RB has no effect on CD74 mRNA induction.

kin(p(HGNC:MAPK9)) => tscript(p(HGNC:JUN))

transcriptional activity of the c-Jun protooncoprotein is augmented through phosphorylation at 2 sites by c-Jun amino-terminal kinases, JNKs

bp(GO:"response to radiation") -> r(HGNC:CDKN1A)

DNA damage elicited by gamma-irradiation induces WAF1/CIP1 in normal human and mouse fibroblasts but does not affect WAF1/CIP1 expression in p53-deficient cells

Constitutive secretion of Macrophage Colony Stimulating Factor (M-CSF) was observed in RA (Rheumatoid arthritis) synovial fibroblasts. Stimulation with IL-1beta led to a marked, time-dependent increase in the production of M-CSF mRNA and protein.

Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.

Northern blot analysis revealed that dexamethasone and 5 alpha-dihydrotestosterone strongly induced the accumulation of Zn-alpha 2-gp mRNA in T-47D human breast cancer cells.

We recently identified a protein, designated receptor accessory factor (RAF), that interacts directly with and enhances the DNA binding of androgen (AR) and glucocorticoid (GR) receptor peptide fragments

kin(p(PFH:"PRKA Family")) => p(HGNC:CCND1,pmod(P,S,197))

a(CHEBI:clofibrate) -| (a(SCHEM:Tretinoin) -| sec(p(MGI:Cga)))

All-trans-retinoic acid and 9-cis-retinoic acid increased CG secretion and CG alpha and CG beta mRNAs, but clofibric acid blunted these stimulatory effects. WY 14,643, another peroxisome proliferator, also reduced CG gene expression

The expression of c-Myc mRNA is rapidly induced by nerve growth factor (NGF) and epidermal growth factor (EGF) in PC-12 pheochromocytoma cells.

p(HGNC:E2F1,pmod(P,S,337)) => tscript(p(HGNC:E2F1))

We have studied the interaction of E2F-1 with the Rb and adenovirus E4 proteins and show that phosphorylation of E2F-1 on serine residues 332 and 337 prevented its interaction with Rb but was a prerequisite for interaction with E4. (PhosphoElm data from PMID 15212693)

There was a 50% decrease in the protein level after incubation with TNF-alpha for 36 hours.

kin(p(HGNC:NTRK2)) => p(HGNC:PLCG1,pmod(P,Y,1254))

Following activation of TrkB, phospholipase C-gamma 1 is phosphorylated on Tyr-783, Tyr-771, and Tyr-1254. Phospholipase C-gamma 1 also forms a complex with TrkB in response to neurotrophin-3 treatment, consistent with the possibility that one of the TrkB autophosphorylation sites provides a binding site for the phospholipase C-gamma 1 SH2 domains, as is the case for other receptor protein-tyrosine kinases. We conclude that phospholipase C-gamma 1 is directly phosphorylated by TrkB.

kin(p(HGNC:NTRK2)) => p(HGNC:NTRK2,pmod(P,Y,674))

In response to brain-derived neurotrophic factor and neurotrophin-3 treatment, TrkB expressed exogenously in Rat-2 cells is rapidly phosphorylated on tyrosine residues. At least 2 regions of TrkB contain phosphorylated tyrosines. The major sites of autophosphorylation are in the region containing Tyr-670, Tyr-674, and Tyr-675, which lies in the kinase domain and corresponds by sequence homology to the Tyr-416 autophosphorylation site in p60c-Src. Tyr-785, which lies just to the COOH-terminal side of the kinase domain in a relatively short tail characteristic of the Trk family of protein-tyrosine kinase receptors, is also phosphorylated in response to neurotrophin-3 treatment.

complex(p(MGI:Nfe2),p(MGI:Mafk)) => tscript(p(MGI:Nfe2))

We show here that products of the maf proto-oncogene family, MafF, MafG and MafK (the small Maf proteins) which possess a b-zip DNA-binding domain but lack a canonical transactivation domain, directly control the DNA-binding properties of p45 by heterodimeric association with p45. Whereas homodimers of the small Maf proteins act as negative regulators, heterodimers composed of Maf and p45 support active transcription in vivo.

gtp(p(PFH:"RAS Family")) -> r(HGNC:MSR1)

These observations suggest that SR gene expression is regulated via a signal transduction pathway involving ras, AP-1, and ets domain proteins

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

1,25-dihydroxyvitamin D3 [1,25-(OH)2D3; 10 nM] and phorbol myristate acetate (10 ng/ml), doses that cause monocytic differentiation of the HL-60 cell, induced small increases in CA-II mRNA

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:CA2)

p(HGNC:GAS1) -| bp(GO:"cell proliferation")

Overexpression of h-gas1 is able to block cell proliferation in the A549 lung carcinoma and the T24 bladder carcinoma cell lines.

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:MSR1)

Immunoelectron microscopy demonstrated that the human macrophage scavenger receptor was expressed after 12-o-tetradecanoylphorbol-13-acetate treatment

kin(p(HGNC:INSR)) -> p(HGNC:PTPN11,pmod(P))

A full length SH-PTP2 was phosphorylated by insulin receptor kinase

TSC-22 mRNA transiently increased 4-fold in the presence of FSH, reached maximal levels at 3 h, and returned to prestimulation levels by 12 h. The FSH-stimulated increase was independent of protein synthesis because it occurred in the presence of cycloheximide and FSH. TSC-22 mRNA was detected in all tissues examined in male and female rats, and the highest levels in the 16-day animal were observed in the testis, ovary, uterus, and lung.

bp(GO:"response to heat") -> r(HGNC:DUSP1)
Expression of the human CL100 gene is induced in skin fibroblasts in response to oxidative/heat stress and growth factors.
a(SCHEM:"Tetradecanoylphorbol acetate") -| r(HGNC:MNDA)
Induction of differentiation in the myeloid cell lines with phorbol ester induces monocyte differentiation which was accompanied by a decrease in MNDA mRNA level.
p(HGNC:IFNA1) -| (a(SCHEM:"Tetradecanoylphorbol acetate") -| r(HGNC:MNDA))
The ability of interferon alpha to up-regulate MNDA mRNA in phorbol ester treated myeloid cell lines is consistent with the observations made in primary monocytes.
UCP gene expression, which was virtually undetectable under basic conditions, was stimulated by acute catecholamine or cyclic AMP treatment to levels comparable to primary cultures of brown adipocytes.
bp(GO:"response to heat") -> r(HGNC:SPARC)
Both the mRNA levels and the secretion of osteonectin increased concurrently when Pam and HSC-1 cells cultured in low calcium medium were exposed to various stresses including heat shock and treatment with sodium arsenite
kin(p(PFR:"Prkc Family")) -> r(RGD:Agtr1b)
Treatment of WKY rat brain cultures with a phorbol ester, phorbol 12-myristate 13-acetate (PMA), causes a time- and dose-dependent increase in the levels of an approximately 2.3-kb AT1 receptor mRNA transcript.
On the other hand, phagocytosis of latex beads triggers a high expression of the MnSOD gene in macrophages,
The extracellular domain of IFN-gamma receptor interacts with its ligand. The two regions 134-183 and 183-209 must interact in order to form a receptor capable of binding to ligand. Replacement of residues 134-209 greatly reduced the ability of the receptor to signal and ligand binding activity. IFN-gamma receptor alpha chain bind to the ligand with a single high affinity (Ka) of 1E9-1E10/M.
Among the glycolytic enzymes studied, hexokinase, phosphofructokinase and glucose-6-phosphate dehydrogenase were found to be stimulated by elevated levels of serum ET2 and further stimulated by a simultaneous increase in Prl
kin(p(PFH:"PRKC Family")) -> r(HGNC:CD6)
After PMA stimulation, Northern blot analysis showed that steady state levels of CD6 mRNA increased in response to PMA treatment.
path(MESHD:Ischemia) -> bp(GO:"response to hypoxia")
Inflammation and ischemia--reperfusion tissue injury are important pathophysiologic processes with a wide spectrum of clinical presentations; the enzyme xanthine dehydrogenase/oxidase (XDH/XO) is thought to play a key role in ischemia--reperfusion injury.
Micromolar concentrations of C1-inhibitor failed to inhibit the enzyme, and it was inhibited only slowly by antithrombin III with an association rate constant (kass.) of 0.15 M-1.s-1. The kass. values for the other serpins tested (protease nexin I, protein C inhibitor, and mutants of alpha 1-antichymotrypsin and alpha 1-antitrypsin with P1 arginine residues) were at least 1000-fold higher,
p(MGI:Map2k1,pmod(P)) => kin(p(MGI:Map2k1))
MEK1 and MEK2 can also be activated by autophosphorylation. Autophosphorylation of MEKs correlates with their ability to phosphorylate and activate ERKs.
kin(p(PFR:"Prka Family")) => p(RGD:Nr4a1,pmod(P,S,350))
a(CHEBI:staurosporine) -| p(HGNC:TLN1,pmod(P,S))
The tyrosine kinase inhibitor, genestein, blocks 1,25(OH)2D3/CSF-1 induced phosphorylation of the putative CSF-1 receptor but has no effect on talin phosphorylation which occurs exclusively on serine. In contrast to genestein, staurosporin, an inhibitor of PKC, inhibits phosphorylation of talin. Moreover, exposure of 1,25(OH)2D3 pretreated cells to phorbol 12-myristate 13-acetate (PMA) in place of CSF-1 also prompts talin phosphorylation.
a(SCHEM:"Tetradecanoylphorbol acetate") -> p(HGNC:TLN1,pmod(P,S))
cat(p(HGNC:GPX1)) -| a(CHEBI:glutathione)
GSHPx-P exhibits a smaller GSH rate constant than GSHPx-1.
cat(p(HGNC:GPX3)) -| a(CHEBI:"hydrogen peroxide")
The rate constants describing the reactivity of human GSHPx-P and human GSHPx-1 with LinOOH and H2O2 are in the same range; GSHPx-P is more reactive with LinOOH and GSHPx-1 is more reactive with H2O2. GSHPx-P also has a low level of reducing activity toward cholesterol 7 alpha-OOH and no detectable activity with the 5 alpha-OOH isomer in contrast to phospholipid hydroperoxide glutathione peroxidase (PHGPx) which readily reduced both isomers.
cat(p(MGI:Lipe)) -| a(CHEBI:"cholesterol ester")
Macrophages contain a neutral cholesteryl ester hydrolase that can be activated by cAMP-dependent protein kinase. These findings, together with the results of previous studies demonstrating similarities between HSL and macrophage neutral cholesteryl ester hydrolase, strongly support the conclusion that both are products of a single gene.
a(CHEBI:lipopolysaccharide) -> r(HGNC:FN1)
Production of fetal fibronectin was increased by lipopolysaccharide, interleukin-1 beta, and tumor necrosis factor-alpha.
bp(GO:"response to hypoxia") -| a(SCHEM:"Adenosine triphosphate")
A line of transgenic mice that express high levels of the BB-dimer of CK (CKB) After 15 min of hypoxia of normal livers, there is a significant increase in the release of lactate dehydrogenase (LDH). In transgenic livers, ATP is maintained, and no increase in LDH release is observed for up to 90 min, depending on the level of PCr before hypoxia.
kin(p(MGI:Met)) => p(MGI:Met,pmod(P,Y,1234))
p(HGNC:MET,pmod(P,Y,1234)) => kin(p(HGNC:MET))
Substitution of either Tyr1235 or Tyr1234 with phenylalanine severely reduced the in vitro kinase activity toward exogenous substrates.
p(HGNC:MET,pmod(P,Y,1235)) => kin(p(HGNC:MET))
Overexpression of an activated mutant of hck in BAC1.2F5 cells augments tumor necrosis factor (TNF) production in response to LPS, whereas inhibition of endogenous hck expression, by antisense oligonucleotides, interferes with LPS-mediated TNF synthesis
p(PFM:"Prkc Family") -> (p(MGI:Cntf) -> cat(p(MGI:Chat)))
The intracellular mechanisms through which two trophic factors, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), regulate cholinergic development were examined in sympathetic neuron cultures. Treatment with CNTF or LIF increased levels of choline acetyltransferase (ChAT) activity by 375 and 350%, respectively. However, in neuronal cultures depleted of protein kinase C (PKC) activity by chronic phorbol ester treatment, neither CNTF nor LIF elevated ChAT activity. Further, the stimulation of ChAT due to increased cell density was not observed in PKC-depleted sympathetic neurons. The inhibition of CNTF-stimulated ChAT by phorbol ester occurred in a dose-dependent manner and chronic phorbol ester treatments did not alter the levels of the catecholamine biosynthetic enzyme tyrosine hydroxylase. Moreover, increased levels of diacylglycerol, an endogenous activator of PKC, were observed in sympathetic neurons treated with CNTF. However, neither CNTF nor LIF stimulated the hydrolysis of phosphatidylinositol 4,5-bisphosphate. These observations suggest that a common PKC-dependent pathway, which is independent of phosphatidylinositol 4,5-bisphosphate hydrolysis, mediates the cholinergic stimulating effects of CNTF, LIF, and cell-cell contact in cultured sympathetic neurons.
kin(p(HGNC:INSR)) => p(HGNC:PIK3R1,pmod(P,Y,580))
kin(p(HGNC:MVK)) -> a(CHEBI:cholesterol)
OBJECTIVE. Mevalonic aciduria is a consequence of the deficiency of mevalonate kinase, the first enzyme after 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the biosynthesis of cholesterol and nonsterol isoprenes.
The EGF-induced phosphorylation of eIF-4B is not caused by the EGF receptor tyrosine kinase itself, since no tyrosine-phosphorylated eIF-4B could be detected upon immunoprecipitation using an anti-phosphotyrosine antibody.
kin(p(PFH:"PRKA Family")) => p(HGNC:GJB1,pmod(P,S,233))
kin(p(RGD:Mapk1)) -> p(RGD:Anxa11,pmod(P,S))
Annexin XI was phosphorylated by mitogen-activated protein (MAP) kinase, which was reported to be activated in v-src-transformed fibroblast Annexin
The expressed kinases (beta ARK1 and beta ARK2) were fully active as evidenced by their ability to specifically phosphorylate the agonist-occupied beta 2-adrenergic receptor (beta 2AR) and light-activated rhodopsin
The SRY DNA-binding domain specifically recognizes with nanomolar affinity proximal upstream elements (designated SRYe) in the promoters of the sex-specific genes encoding P450 aromatase and Mullerian inhibiting substance (MIS).
In the present work we show that addition of exogenous NO or IL-1 beta-induced intracellular NO generation cause GAPDH ADP-ribosylation and inhibition of enzyme activity
Xanthine oxidase stimulated production of 6-ketoprostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, and thromboxane B2.
kin(p(HGNC:PRKCB)) => p(HGNC:LMNB1,pmod(P,S,395))
Transgenic mice overexpressing transforming growth factor alpha (TGF-alpha) under control of the metallothionein promoter had, on average, 20% reductions in body and carcass weights compared to nontransgenic littermates
bp(MESHPP:Obesity) negativeCorrelation p(RGD:Car3)
An obesity-related decrease in both the concentration and activity of CA III was observed in two lipogenic tissues, liver and white fat
bp(MESHPP:Obesity) negativeCorrelation cat(p(RGD:Car3))
a(SCHEM:"High Density Lipoprotein") -> r(RGD:Egr1)
To demonstrate whether these intracellular responses are only specific to LDL we examined the effects of high- and very low density lipoprotein (HDL and VLDL) on [Ca2+]i and expression of Egr-1 mRNA. The present results show that all lipoproteins induce expression of Egr-1 mRNA and elevation in [Ca2+]i in VSMCs.
a(SCHEM:Calcium) -> (a(SCHEM:"High Density Lipoprotein") -> r(RGD:Egr1))
a(CHEBI:lipopolysaccharide) -> r(HGNC:GC)
In contrast, message for DBP was identified in monocytes activated with lipopolysaccharide when analyzed between 6 and 10 h following stimulation. These results suggest that the temporal expression of the DBP gene could play a major role in the activation of monocytes by 1-25(OH)2D3.
bp(GO:"monocyte activation") -> r(HGNC:GC)
We show that phospholipase C gamma, phosphatidylinositol 3-kinase/p70 S6 kinase, Shc, Grb2, Raf-1, and mitogen-activated protein kinase are downstream components of the Nyk/Mer signal transduction pathways.
The tyrosine kinase JAK1 and the transcription factors STAT1 and STAT3 are phosphorylated in response to epidermal growth factor (EGF) and other growth factors
kin(p(HGNC:RPS6KA3)) -| kin(p(HGNC:GSK3B))
GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k).
gtp(p(HGNC:RHOA)) => complex(p(HGNC:RHOA),p(HGNC:CIT))
Using the yeast two hybrid system and overlay assays we identified a putative rholrac effector, citron, which interacts with the GTP-bound forms of rho and rac1, but not with cdc42.
a(CHEBI:"hydrogen peroxide") -> tscript(complex(NCH:"Nfkb Complex"))
It was shown that the induction by H2O2 is mediated by trans-acting factor NF-kappa B (nuclear factor kappa B), via a putative NF-kappa B site, 'GGGACCCTCC', located from -96 to -86. Co-transfection with an NF-kappa B (p65) expression construct increased the promoter activity, an effect which could be blocked by co-transfection with an I kappa B (MAD-3) expression construct. Deletion of the NF-kappa B site abolished the effect of both H2O2 and co-transfection of NF-kappa B.
a(SCHEM:"Tetradecanoylphorbol acetate") -> r(MGI:Fos)
In resting fibroblasts, c-fos expression is undetectable, but it is induced to maximal levels within 30 minutes of stimulation by growth factors or phorbol esters.....The onset of transcription after treatment of cells with 1.0 or 0.1 ug/ml anisomycin is delayed, as c-fos mRNA levels peak only after 60 minutes.....The transcriptional response observed one hour after anisomycin treatment is comparable to the TPA response that is already apparent after 24 minutes (Fig. la).
IL-1 does enhance release of nonesterified arachidonate from islets, as measured by isotope dilution mass spectrometry, and this effect is suppressed by NMMA and mimicked by the NO-releasing compound 3-morpholinosydnonimine. Although IL-1 increases neither islet phospholipase A2 (PLA2) activities nor mRNA levels for cytosolic or secretory PLA2, a suicide substrate which inhibits an islet Ca(2+)-independent PLA2 prevents enhancement of islet arachidonate release by IL-1.
a(SCHEM:"serum insulin") -> (kin(p(HGNC:INSR)) => p(HGNC:ADRB2,pmod(P,Y,354)))
kin(p(HGNC:INSR)) => p(HGNC:ADRB2,pmod(P,Y,354))
insulin receptor phosphorylates beta2 adrenergic receptor (ADRB2) on tyrosines 350, 354, 360, 132 and 141 causing it to become refractory to agonist insulin is shown to stimulate insulin receptor-catalyzed phosphorylation of the ADRB2
a(SCHEM:"serum insulin") -> (kin(p(HGNC:INSR)) => p(HGNC:ADRB2,pmod(P,Y,360)))
kin(p(HGNC:INSR)) => p(HGNC:ADRB2,pmod(P,Y,360))
a(SCHEM:"cyclic AMP") -> cat(p(HGNC:LIPA))
lipid hydrolysis is stimulated by cyclic AMP and mediated by HSL or cholesteryl esterase(s)
Northern blotting showed that retinoic acid (RA) and T3 regulate in a tissue-specific manner (in the heart and skin but not in the brain) PAFR gene expression at the transcriptional level in intact rats.
Extracellular ATP (ATPo) induces apoptosis and osmotic lysis in several cell lines.
kin(p(MGI:Mapk3)) -> p(MGI:Elk1,pmod(P,S))
title := \"Overlapping and differential expression of BIG-2, BIG-1, TAG-1, and F3: four members of an axon-associated cell adhesion molecule subgroup of the immunoglobulin superfamily.\"
bp(GO:"response to wounding") -| r(HGNC:GJA1)
Cx31.1 and Cx43 were down-regulated in cells both peripheral to and at the wounded edge.
Animals were treated with 12-0-tetradecanoylphorbol-13-acetate (TPA) (8.3 nmol), okadaic acid (OA) (2.5 nmol), chrysarobin (220 nmol), or benzoyl peroxide (BzPo)...All four of the skin-tumor promoters switched on the Cx26 gene, transiently increased expression of Cx43, and significantly inhibited the expression of Cx31.1.
p(HGNC:IGF1R,pmod(P,Y)) => kin(p(HGNC:IGF1R))
Taken together, these data suggest that the vav proto-oncogene is a substrate for the IGF-1 receptor tyrosine++ kinase
kin(p(HGNC:IGF1R)) => p(HGNC:VAV1,pmod(P,Y))
Here, we show that the PML protein, like Sp100 and NDP52, is induced by interferons (IFNs alpha, beta and gamma) in a large variety of human cells.
a(CHEBI:"nitric oxide") -> cat(p(HGNC:FAS))
a(SCHEM:Calcium) -> bp(GO:"keratinocyte differentiation")
Acutely increasing Cao to 0.1 mM or above (calcium switch) leads to rapid changes in genomic and nongenomic events in keratinocytes, eventuating in terminal differentiation.
p(HGNC:APOE) -| path(MESHD:Atherosclerosis)
Human apolipoprotein E is a plasma lipoprotein that appears to play an important protective role in the development of atherosclerosis.
kin(p(HGNC:ERBB4)) => p(HGNC:PIK3R1,pmod(P,Y))
HER4 exhibited in vitro kinase activity and was able to phosphorylate the regulatory subunit of phosphatidylinositol 3-kinase and SHC. Peptide competition studies identified tyrosine 1056 of HER4 as the phosphatidylinositol 3-kinase binding site and tyrosines 1188 and 1242 as two potential SHC binding sites.
p(HGNC:EPO) -> complex(NCH:"Hemoglobin Complex")
EPO-enhanced Pl3K activity was suppressed by WT treatment in a dose-dependent manner and constant inhibition of Pl3K by WT interfered with both hemoglobin synthesis and glycophorin A expression promoted by EPO
a(CHEBI:wortmannin) -| (p(HGNC:EPO) -> complex(NCH:"Hemoglobin Complex"))
a(CHEBI:"25-hydroxycholesterol") -> r(HGNC:CYP51A1)
Pubmed:gene: The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase, a cytochrome P450 whose expression is regulated by oxysterols. In the case of CYP51, cholesterol deprivation led to a 2.6- to 3.8-fold induction of mRNA levels in human adrenocortical H295R cells and this effect was suppressed by the addition of 25-hydroxycholesterol.
When U937 monocytes undergo programmed cell death in response to tumor necrosis factor alpha, the inactive CPP32 precursor is cleaved into its active forms. As a consequence poly(ADP ribose) polymerase, a major substrate of CPP32, is faithfully cleaved into a 85 kD fragment.
tscript(p(HGNC:MAFB)) -| bp(GO:"cell differentiation")
Mafb is specifically expressed in myelomonocytic cells and binds to the DNA-binding domain of Ets-1 via its basic region or leucine-zipper domain. Furthermore, it represses Ets-1 transactivation of synthetic promoters containing Ets binding sites and inhibits Ets-1-mediated transactivation of the transferrin receptor, which is known to be essential for erythroid differentiation. Accordingly, overexpression of MafB in an erythroblast cell line down-regulates the endogenous transferrin receptor gene and inhibits differentiation without affecting cell proliferation
tscript(p(HGNC:MAFB)) -| tscript(p(HGNC:ETS1))
Activation of the mitogen-activated protein kinase cascade is a critical event in mitogenic growth factor signal transduction. Mitogen-activated protein kinase is directly activated by a dual specific kinase. Activation of MEK1 requires the phosphorylation of serine residues 218 and 222. The a-Raf activated by serum stimulation induced activation of MEK1, which is determined by the coupled kinase activity, and immunoprecipitation and yeast-two hybrid analysis showed that MEK1 is direct substrate of a-Raf.
kin(p(HGNC:ARAF)) => kin(p(HGNC:MAP2K1))
When the immunoprecipitated A-Raf was tested in a coupled in vitro kinase assay, A-Raf activated the recombinant GST-MEK1 (Fig. 3A).
kin(p(MGI:Map2k6)) => p(MGI:Mapk14,pmod(P,T,180))
These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182,
We present evidence of an interaction between COUP-TFI/Ear3 and the octamer-binding proteins in vitro and in the cell, suggesting that COUP-TFI and COUP-TFII activate the vHNF1 promoter via an indirect mechanism.
p(MGI:Cdkn1b) -| complex(p(MGI:Cdk2),p(MGI:Ccna2))
Immunodepletion of Kip1 from extracts of both nonstimulated cells and cells treated with PDGF and platelet poor plasma for 24 h eliminated essentially all inhibitory activity toward the cyclin A-Cdk complex.
both mRNA and overall protein levels are maintained at a steady level in actively growing cells
a(SCHEM:"Tetradecanoylphorbol acetate") -| r(HGNC:MPL)
TPA treatment also enhanced the expression of GPIIb mRNA, and induced the expression of interleukin-6 (IL-6) and its receptor mRNAs, while it did not induce transcripts of the genes IL-11 and mpl ligand, and further decreased the transcript of the mpl gene.
a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:IL6)
p(RGD:F2r) -> kin(p(PFR:"MAPK Erk1/3 Family"))
thrombin receptor activates MAPK through PKC-dependent pathways
kin(p(HGNC:GSK3B)) => p(HGNC:APC,pmod(P))
Here it is shown that when beta-catenin is present in excess, APC binds to another component of the WINGLESS pathway, glycogen synthase kinase 3beta (GSK3beta), a mammalian homolog of Drosophila ZESTE WHITE 3.APC was a good substrate for GSK3 beta in vitro, and the phosphorylation sites were mapped to the central region of APC. Binding of beta-catenin to this region was dependent on phosphorylation by GSK3 beta.
Aldosterone at 10(-6)M increased alpha1-mRNA 2.7-fold at 48 h and beta1-mRNA level 10.9-fold at 6 h.
bp(GO:"response to heat") -> r(HGNC:P4HB)
Other stress inducers, tunicamycin, A23187, and heat shock, which caused an accumulation of unfolded proteins, also induced the PDI mRNA, indicating that the unfolded protein accumulation response induces PDI gene expression.
tscript(complex(NCM:"AP-1 Complex")) -> r(EGID:16777)
# Ariadne: RAR alpha, ROR alpha and AP-1 activated the transcription of the murine laminin B1 gene promoter, which consists of three core elements. [Expression]
bp(GO:"cell differentiation") -> r(HGNC:TLE1)
We show that TLE 1 and TLE 3 are expressed during a number of cell-determination events, including embryonic segmentation, central and peripheral neurogenesis, and epithelial differentiation.
Expression of RSP5 in yeast cells potentiated hPR and human glucocorticoid receptor (hGR) transcriptional activity and increased the efficacy of weak agonists of these receptors. Remarkably, expression of this yeast protein in mammalian cells had a similar effect on PR and GR transcriptional activity. Importantly, a human homolog of RSP5, h RPF1, functioned identically in mammalian cells.
a(CHEBI:"okadaic acid") -> bp(MESHPP:Apoptosis)
Incubation with the phosphatase inhibitor okadaic acid maintained pRb in its phosphorylated state, and resulted in significant apoptosis. Overexpression of wild-type Rb inhibited TGF-beta1 induced apoptosis in HuH-7 cells.
kin(p(PFR:"Prkc Family")) -> r(RGD:Ier3)
kin(p(HGNC:PDGFRB)) => kin(p(HGNC:JAK1))
ere, we show that all three of the ubiquitously expressed JAKs--JAK1, JAK2, and Tyk2--become phosphorylated on tyrosine in both mouse BALB/c 3T3 cells and human fibroblasts engineered to express the PDGF-beta receptor. All three proteins are also associated with the activated receptor. Through the use of cell lines each lacking an individual JAK, we find that in contrast to interferon signaling, PDGF-induced JAK phosphorylation and activation of STAT1 and STAT3 is independent of the presence of any other single JAK but does require receptor tyrosine kinase activity.
kin(complex(NCM:"CK II Complex")) -| tscript(p(MGI:Egr1))
CKII phosphorylation of Egr-1 resulted in a decrease
phos(p(HGNC:DUSP1)) -| kin(p(HGNC:RPS6KB1))
a(SCHEM:"serum insulin") -> kin(p(RGD:Mapk1))
Insulin treatment of L6 cells resulted in a rapid increase in MAPK activity (> twofold in 5 min with 10 nM insulin)
phos(p(HGNC:ENPP1)) -| kin(p(HGNC:INSR))
However, we show here that PC-1 is a general protein kinase inhibitor in vitro and that this inhibition results from the hydrolysis of ATP by the intrinsic nucleotide pyrophosphatase activity of PC-1.
gtp(p(PFH:"RAS Family")) -> kin(p(HGNC:MAPK1))
overexpression of either dominant negative Rac2 or the N-terminal regulatory domain of PAK1 inhibits Ras-mediated activation of ERK2
Increasing concentrations of IGF1and IGF2 resulted in an accumulation of IGFBP-3 in the conditioned medium. Incubation with an anti-IGFBP-3 antibody resulted in the binding of 28% to the A549 cells, indicating that the increase of IGFBP3 in conditioned medium is due to the release of cell associated IGFBP-3.
Because thrombin cleavage of OPN results in substantial enhancement of OPN's adhesive properties, and because VPF/VEGF promotes increased microvascular permeability leading to activation of the extrinsic coagulation pathway, we also investigated whether VPF/VEGF facilitates thrombin cleavage of OPN in vivo.
p(HGNC:VEGFA) -> complex(p(HGNC:ITGAV),p(HGNC:ITGB3))
VPF/VEGF induced dermal microvascular EC expression of mRNAs encoding the alphav and beta3 integrin subunits resulting in increased levels of the alphavbeta3 heterodimer at the cell surface,
cat(complex(p(HGNC:ITGAV),p(HGNC:ITGB3))) -> bp(GO:"cell migration")
and VPF/VEGF also induced mRNA encoding osteopontin (OPN), an alphavbeta3 ligand. OPN promoted EC migration in vitro; and VPF/VEGF induction of alphavbeta3 was accompanied by increased EC migration toward OPN.
a(SCHEM:"serum insulin") -> r(HGNC:RRAD)
Insulin infusion induced a significant increase in the mRNA level of Glut 4 (+56 +/- 13%), Rad (+96 +/- 25%), the p85alpha subunit of phosphatidylinositol -3-kinase (+92 +/- 18%) and a decrease in the lipoprotein lipase mRNA level
Clofibrate-induced expression of kidney CYP4A mRNAs was also blocked in the PPAR alpha gene knockout mice.
complex(p(PFM:"Pdgf Family"),p(MGI:Pdgfra)) => kin(p(MGI:Pdgfra))
Ligand stimulation of the platelet-derived growth factor (PDGF) receptor results in its association with phosphoinositide 3-kinase activity and a corresponding synthesis of 3'-phosphorylated lipids.
Two isoforms (B56beta and B56delta) are highly expressed in adult brain; here we show that mRNA for these isoforms increases severalfold when neuroblastoma cell lines are induced to differentiate by retinoic acid treatment.
uPAR interacts and modifies the function of integrin beta1 which promotes both adhesion and migration towards a specific matrix protein, vitronectin and suppresses the normal adhesive function of the integrins.
We have now investigated the activity of the IGF-I promoter, in response to stimulation of cells by either PDGF or EGF. Both growth factors stimulate the activity of the IGF-I promoter, indicating that they regulate the levels of expression of IGF-I.
tscript(p(PFH:"E2F Family")) =| r(HGNC:IGF1)
When the E2F binding sequence in the IGF-I promoter is mutated, the IGF-I promoter is constitutively active
a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:MMP1)
phorbol myristoyl-13 acetate (PMA) induced the expression of transcripts of collagenase, stromelysin-1, gelatinase-B, TIMP-1, and TIMP-3
kin(p(PFH:"PRKC Family")) -> r(HGNC:MMP3)
The cytokines interleukin-1 beta (IL-1 beta) and IL-2 strongly enhanced GM-CSF production, while IL-4, IL-6, GM-CSF, interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) had no effect.
kin(p(HGNC:IGF1R)) -| bp(MESHPP:Apoptosis)
It [IGF1R] is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival.
bp(GO:"response to UV") -> tscript(complex(NCH:"Nfkb Complex"))
NF-kappa B can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli.
p(MGI:Pthlh) -> cat(p(PFM:"Plc Family"))
Although PTH and PTHrP activate both adenyl cyclase and phospholipase C-dependent signal transduction pathways, stimulation of IL-6 and LIF depends on adenyl cyclase since it is not reproduced by PTH(3-34), a partial agonist that only activates phospholipase C.
a(CHEBI:"arachidonic acid") -> bp(GO:"neuron differentiation")
We have shown that neuronal differentiation stimulated by FGF-1 can be inhibited by diacylglycerol lipase inhibitor and mimicked by arachidonic acid, suggesting that the neuronal differentiation is signalled through the phospholipase C gamma pathway
The soluble epoxide hydrolase mRNA level in liver was increased eight-fold upon administration of the hypolipidemic drug and peroxisome proliferator clofibrate for 7 days to mice. The soluble epoxide hydrolase mRNA was back at control levels within 1-2 days after clofibrate withdrawal. The highest expression was in liver, intestine and kidney. Lower levels were found in heart and muscle and very low levels were found in testes, lung, brain and spleen. The mRNA levels were increased in liver, kidney and heart by clofibrate.
kin(p(PFH:"PRKC Family")) -> r(HGNC:THY1)
The up-regulation of Thy-1 by PBu, but not TNF, was inhibited by the protein kinase C inhibitor RO31-8220, suggesting the presence of protein kinase C-dependent and -independent pathways for Thy-1 expression.
kin(p(HGNC:BLK)) => p(HGNC:FCGR2B,pmod(P,Y,292))
In synergism with FSH, IGF-1 stimulates aromatase activity, enhances proteoglycan biosynthesis, increases progesterone action.
FK-506 inhibits the aldosterone-induced synthesis of G alpha i-3 protein but has no effect on glucocorticoid receptor number as quantified by Western blotting
a(SCHEM:Tacrolimus) -| (a(CHEBI:aldosterone) -> p(HGNC:GNAI3))
CRABP II mRNA and protein expression were up-regulated in the proliferative phase of the uterus brought about by PMSG injection or, alternatively, by estrogen treatment of prepubertal rats.
MAPKAP kinase-2 and MAPKAP kinase-3 were both activated in response to cellular stress, interleukin-1 and tumour necrosis factor in KB and HeLa cells
a(SCHEM:Calcium) -> bp(MESHPP:"DNA Fragmentation")
p(HGNC:BCL2) -| (a(SCHEM:Calcium) -> bp(MESHPP:"DNA Fragmentation"))
Overexpression of human BCL-2 in nuclei by stable transfection resulted in an inhibition of Ca2+-stimulated lamin degradation and DNA fragmentation, suggesting that endogenous nuclear BCL-2 regulates activation of the nuclear scaffold protease
cat(p(MGI:Gfpt1)) -> a(CHEBI:"UDP-D-galactose")
The concentrations of all nucleotide-linked sugars were increased 2-3-fold in GLUT1 and were unchanged in GLUT4-overexpressing muscles. [I get the identities of these sugars from the actual article]
cat(p(MGI:Gfpt1)) -> a(SCHEM:"Uridine diphosphate N-acetylglucosamine")
p(HGNC:PRKCA,pmod(P,T,638)) => kin(p(HGNC:PRKCA))
The T638 phosphorylation site is not required for the catalytic function of PKCalpha per se, but serves to control the duration of activation by regulating the rate of dephosphorylation and inactivation of the protein. This is achieved through the cooperative interaction between the T638 and T497 sites; if either of these residues is not phosphorylated, the protein is supersensitive to phosphatase action.
We also show that Lyn phosphorylates Tyr15 of Cdk2 and that incubation of Lyn with Cdk2 results in inhibition of Cdk2 activity.
These data indicate that histamine induces the expression of E-selectin and ICAM-1 synergistically with TNF-alpha through histamine H1 receptors.
p(MGI:Egf) -> a(CHEBI:"reactive oxygen species")
n increase in intracellular ROS is also demonstrated after growth factor [platelet-derived growth factor (PDGF) or epidermal growth factor (EGF)] or cytokine [tumour necrosis factor-alpha (TNF-alpha) or interleukin (IL)-1 beta] stimulation of NIH 3T3 cells.
kin(p(PFH:"PRKA Family")) => p(HGNC:ADD1,pmod(P,S,408))
Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. PKA, in addition, phosphorylated alpha-adducin at Ser-408, -436, and -481 in the neck domain.
Expression of the nuclear domain-associated proteins Sp100, PML, and NDP52, is enhanced by interferons (IFNs) on the mRNA and protein level.
kin(p(HGNC:MAPK1)) => p(HGNC:SOS1,pmod(P,S,1167))
p(HGNC:EGF) -> bp(GO:"cell proliferation")
We show that treatment of A431 cells with 10 nM EGF induced a 15-fold increase in EGF-R autophosphorylation, leading to inhibition of cell proliferation and morphological features of apoptosis. However, at a lower concentration of EGF (0.01 nM), there is a 2-fold increase in EGF-R autophosphorylation and increased cell proliferation when compared to untreated cells.
# Ariadne: Furthermore, SEK WT overexpression enhanced JNK stimulation induced by activated RhoA, RhoB, RhoC, Cdc42, and MEKK (Fig. 4 ). [Regulation]
kin(p(HGNC:EPHA4)) -> (gtp(p(HGNC:RHOB)) -> kin(p(HGNC:MAPK8)))
bp(GO:"response to hypoxia") -> r(HGNC:IFNA1)
IFN-alpha is also produced in normal human islets during short-term cultures, probably as a result of the ischemia present at the center of the islet. This induction of IFN-alpha by hypoxia
kin(p(HGNC:PRKCA)) => p(HGNC:PRKCA,pmod(P,S,657))
The MRP mRNA level in HL-60/R-CP cells increased remarkably after a 24-h incubation with 20 microM cisplatin
a(SCHEM:"serum insulin") -> r(HGNC:TFF1)
Induction by both insulin and estradiol is prevented by the pure antiestrogen. ICI 164384, indicating the requirement for an activatable estrogen receptor.
The sentence from Jubilant Ceramide activated both PKC zeta and NFKB in terminally differentiated 3T3-L1 adipocytes after TNF treatment.
a(SCHEM:"Oxidized Low Density Lipoprotein") -> (bp(GO:"response to hypoxia") -> r(HGNC:HYOU1))
bp(GO:"response to hypoxia") -> r(HGNC:HYOU1)
In support of a role for ORP150 in the mononuclear phagocytes (MPs)' response to the microenvironment of an atheroma, the presence of oxidized LDL enhanced by approximately 10-fold ORP150 expression in hypoxic cultures.
Ariadne: S100A1 inhibited phosphoglucomutase activity in a calcium-dependent manner. In contrast, S100B stimulated phosphoglucomutase activity in a calcium-dependent manner.
a(SCHEM:Calcium) -> (p(HGNC:S100B) -> cat(p(HGNC:PGM1)))
a(CHEBI:"leukotriene B4") -> bp(GO:"inflammatory response")
Leukotriene B4, a potent chemotactic agent that initiates, coordinates, sustains and amplifies the inflammatory response, is shown to be an activating ligand for the transcription factor PPARalpha.
kin(p(PFH:"PRKC Family")) -> r(HGNC:BCL2A1)
The induction of A1 by TNF in this system is mediated via a protein kinase C pathway
NGF markedly increased bcl-2 expression but had little or no effect on the other genes studied.
cat(p(MGI:Tnfrsf1a)) -> kin(p(MGI:Rps6ka1))
he independent signaling competence of Tnfr1 and Tnfr2 was further confirmed in the studies of various kinases of the Erk/Mapk signal transduction cascade; Erk1, Erk2, Raf-1, Raf-B, Mek-1, Mekk, and p90rsk all were found to be activated independently by Tnfr1 as well as Tnfr2.
cat(p(MGI:Tnfrsf1b)) -> kin(p(MGI:Mapk3))
cat(p(MGI:Tnfrsf1b)) -> kin(p(MGI:Raf1))
Osteoclast formation was higher in ovariectomized (OVX) mice than sham operated mice, ovariectomy also increased the mononuclear cell secretion of interleukin IL-1, tumor necrosis factor and M-CSF production. The production of M-CSF protein and mRNA via IL-1 was lowered by the treatment of estrogen or IL-1 receptor antagonist (IL-1ra bound to IL-1 receptors and competed with both IL-1 alpha and IL-1 beta without detectable IL-1 agonistic effects) in ovariectomized bone marrow cells.
tscript(complex(NCH:"Nfy Complex")) -> r(HGNC:HSPA5)
These results provide evidence that CBF is functionally important in transactivating the grp78 C1 transcriptional activity, and suggest a possible mechanism by which grp78 transcription is stimulated by calcium depletion.
tscript(p(HGNC:NR2F1)) -| tscript(p(HGNC:HNF4A))
bp(GO:"response to starvation") -> cat(p(RGD:Ctsb))
The activities of cathepsin B, L, J and H in rat liver were significantly increased by starvation if compared with normal diet rats.
bp(GO:"muscle contraction") -> r(RGD:Gpi)
Muscle disuse resulted in considerable loss of CAIII mRNA in soleus but not in plantaris, whereas, PGI mRNA levels were unaffected in soleus but declined in plantaris.
path(SDIS:"tissue damage") -> r(HGNC:CRIP1)
kin(p(HGNC:RAF1)) -> (p(HGNC:BCL2) -| bp(MESHPP:Apoptosis))
active Raf-1 improved Bcl-2-mediated resistance to apoptosis, whereas a kinase- inactive Raf-1 mutant abrogated apoptosis suppression by Bcl-2
a(SCHEM:"serum insulin") -| cat(p(RGD:Lipa))
Insulin significantly suppressed neutral cholesterol ester hydrolase activities in medial smooth muscle cells
p(HGNC:EGF) -> p(HGNC:SHC1,pmod(P,Y,349))
These residues are present in the central proline-rich (CH1) region and are conserved in all isoforms of Shc. Y239/240 are co-ordinately phosphorylated by the Src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo.
Herbimycin A treatment completely inhibited the tyrosine phosphorylation of FAK and paxillin, indicating that fibronectin activates FAK and paxillin.
kin(complex(NCR:"p85/p110 PI3Kinase Complex")) -> kin(p(RGD:Rps6ka1))
The sentence from Jubilant Treatment with wortmannin, PI3-kinase inhibitor decreased the fibronectin-dependent S6K activation by approximately 70%.
kin(p(HGNC:SRC)) => p(HGNC:IGF1R,pmod(P,Y,1131))
We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain...... We determined that the sites of Src-induced phosphorylation of the IGF-I receptor are the same as the ligand-induced autophosphorylation sites and that the Src kinase can catalyze these phosphorylations directly.
kin(p(HGNC:SRC)) => p(HGNC:IGF1R,pmod(P,Y,1135))
kin(p(HGNC:SRC)) => p(HGNC:IGF1R,pmod(P,Y,950))
p(MGI:Jun,pmod(P)) => tscript(p(MGI:Jun))
PDGF or serum treatment both activate c-Jun N-terminal kinase (JNK), the mitogen-activated protein kinase responsible for phosphorylation and activation of c-Jun.
Site-directed mutagenesis experiments demonstrate that a consensus cyclic AMP response element (CRE) in the murine PGS2 promoter is essential for optimal PGS2 gene expression in response to PDGF or to serum.
p(HGNC:PTK2,pmod(P,Y,577)) => kin(p(HGNC:PTK2))
Previously identified Src sites include catalytic domain tyrosines-576 and -577, important for maximal FAK kinase activity, and tyrosine-925, which permits an SH2-mediated association with Grb2. Here we report that tyrosine-861 is the major Src site in the carboxyl-terminal domain of FAK. Phosphotyrosine-861 may function in additional interactions between FAK and SH2-containing proteins.
kin(p(HGNC:SRC)) => p(HGNC:PTK2,pmod(P,Y,861))
kin(p(HGNC:PDGFRA)) -> gtp(p(PFH:"RAS Family"))
PDGF-AA-induced activation of Ras, initiation of DNA synthesis, or growth of cells alphaPDGFR to activate Ras or initiate a proliferative response
COS 8 augmented the increase of nerve growth factor, brain-derived neurotrophic factor, and NT-3 mRNA expression in the distal stump of the axotomized sciatic nerve.
complex(p(HGNC:GRB2),p(HGNC:SOS1)) => gtp(p(PFH:"RAS Family"))
p(HGNC:BCR,pmod(P,Y,177)) => (complex(p(HGNC:GRB2),p(HGNC:SOS1)) => gtp(p(PFH:"RAS Family")))
Tyrosine phosphorylation led to the association of BCR with the RAS guanine nucleotide exchange complex GRB2-SOS in vivo via the GRB2 SH2 domain, linking BCR to RAS signaling (Maru, Y., Peters, K. L., Afar, D. E. H., Shibuya, M., Witte, O. N., and Smithgall, T. E. (1995) Mol. Cell. Biol. 15, 835-842). In the present study, we demonstrate that BCR Tyr-246 and at least one of the closely spaced tyrosine residues, Tyr-279, Tyr-283, and Tyr-289 (3Y cluster), are phosphorylated by FES both in vitro and in 32Pi-labeled cells. Mutagenesis of BCR Tyr-177 to Phe completely abolished FES-induced BCR binding to the GRB2 SH2 domain, identifying Tyr-177 as an additional phosphorylation site for FES.
p(HGNC:ERG) -> (tscript(complex(NCH:"AP-1 Complex")) => r(HGNC:MMP1))
tscript(complex(NCH:"AP-1 Complex")) => r(HGNC:MMP1)
In gel shift assays however, the Erg protein bound little or not to the collagenase1 promoter, whereas it bound to the stromelysin1 promoter. By site-specific mutagenesis, we identified one major site at -88 that abolished collagenase1 promoter activation by Erg. Surprisingly, mutation of the collagenase1 AP1 site at -73 also abolished the activation by Erg suggesting that Erg cooperates with Fos/Jun in collagenase1 promoter regulation.
kin(p(HGNC:MAPK3)) => p(HGNC:MYB,pmod(P,S,532))
COX-2 expression was also enhanced by dibutyryl cAMP and iloprost, a prostacyclin analogue.
kin(p(HGNC:MAP3K5)) => kin(p(HGNC:MAP2K6))
A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6)
kin(p(HGNC:MAP3K5)) -> bp(MESHPP:Apoptosis)
Overexpression of ASK1 induced apoptotic cell death, and ASK1 was activated in cells treated with tumor necrosis factor-alpha (TNF-alpha). Moreover, TNF-alpha-induced apoptosis was inhibited by a catalytically inactive form of ASK1
Nicotine and cotinine enhanced the production of bFGF, a major mitogen for smooth muscle cells, and up-regulated the expression of several matrix metalloproteinases that are critical in cell migration.
a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:NPY1R)
Phorbol ester caused a rapid, transient 2.6-fold increase in Y1R mRNA levels. However, all trans-retinoic acid caused a rapid, sustained decrease in Y1 receptor mRNA levels (to 25% of control)
p(MGI:Fgf7) -> bp(GO:"cell proliferation")
This report shows that 48 h after intravenous injection of keratinocyte growth factor {FGF7}, hepatocyte proliferation increased approximately 40-fold compared to non-stimulated livers.
a(CHEBI:lipopolysaccharide) -> r(HGNC:FCER2)
Moreover, cytokine treatment resulted in down-modulated expression of the alpha6 integrin subunit and the 67LR.
a(SCHEM:"serum glucose") -> r(HGNC:PFKP)
Glucose (from 5 to 25 mM) induced phosphofructokinase-1 (PFK-1) isoform C, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (4-fold), and L-pyruvate kinase (L-PK) (7-fold) mRNAs
kin(p(PFR:"Prkc Family")) -> cat(p(RGD:Marcks))
Piroxicam also decreased the release of gelatinase and lysozyme induced by TNF alpha, but not by PMA
path(SDIS:"integrin mediated cell adhesion") -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))
Tyrosine-phosphorylated Cbl was found to form complexes with the SH2 domain-containing signaling proteins Src and phosphatidylinositol 3-kinase;in vitro kinase assays demonstrated that these kinases were active in the Cbl complexes following integrin ligand binding.
path(SDIS:"integrin mediated cell adhesion") -> kin(p(HGNC:SRC))
path(MESHD:Ischemia) -> a(CHEBI:creatinine)
At 24 hours after reperfusion subsequent to 30-minute ischemia, serum creatinine increased
a(SCHEM:Tretinoin) -> p(HGNC:STAT1,pmod(P))
The retinoid increases the levels of nuclear complexes that are capable of binding to interferon (IFN)-regulated consensus sequences and contain Stat1 and/or Stat2 proteins, and causes a rapid and long-lasting elevation in Stat1 alpha tyrosine phosphorylation Transient transfection experiments show that ATRA enhances the transactivating properties of Stat1 alpha observed on an appropriate reporter gene
a(CHEBI:lipopolysaccharide) -> kin(p(PFM:"Csnk2 Family"))
Western blot analysis of nuclear extracts prepared from LPS-stimulated macrophages revealed increased phosphorylation of PU.1 at serine residues relative to that in unstimulated controls. LPS-induced phosphorylation of PU.1 at serine 148, located within a casein kinase II (CKII) consensus motif, increases the transactivation function of PU.1
Third, HBP1 can function as a transcriptional repressor of the promoter for N-MYC, which is a critical cell cycle and developmental gene. Fourth, because the activation of the N-MYC promoter in cycling cells required the E2F transcription factor, we show that E2F-1 and HBP1 represent opposite transcriptional signals that can be integrated within the N-MYC promoter.
IGF1 stimulates the phosphorylation of ERK1/2.
gtp(p(PFH:"RAS Family")) -> r(HGNC:KRT18)
Oncogenes which activate ras signal transduction pathways stimulate expression of the K18 gene through transcription factors including members of the AP-1 (jun and fos) and ETS families.
p(HGNC:IFNG) -| tscript(complex(NCH:"AP-1 Complex"))
We report that interferon gamma (IFN-gamma) inhibits transcription of the macrophage scavenger receptor gene by antagonizing the Ras-dependent activities of AP-1 and cooperating ets domain transcription factors
a(CHEBI:"reactive oxygen species") -| tscript(p(RGD:Sp1))
reactive oxygen intermediates dramatically decrease the transcriptional activities of the Sp1-dependent aldolase A and pyruvate kinase M2 promoters leading to reduced reporter gene expression.
We have examined whether N6, 2'-O-dibutyryladenosine 3':5'-cyclic mono-phosphate (DBcAMP) affected GJIC, gap junction protein (connexin43) expression, and the growth of non-transformed and neoplastic mouse lung epithelial cells. DBcAMP (0.01.1 mM) stimulated GJIC (assayed by fluorescent dye microinjection) and connexin43 expression (assessed by Northern and Western blotting) and reduced their proliferation.
a(CHEBI:"prostaglandin A2") -| r(HGNC:IGF1)
In addition to specifically regulating the expression of the IGF-I gene, PGA2 also decreases the abundance of cyclin D1 mRNA and increases the abundance of Waf1 mRNA.
complex(p(HGNC:ERBB3),p(HGNC:ERBB2)) -> complex(p(HGNC:ERBB3),p(HGNC:SHC1))
Binding of heregulin (HRG) to its receptor, ErbB3, results in a dimerization with ErbB2/neu and activation of their intrinsic tyrosine kinases, initiating a cascade of events resulting in the stimulation of acetylcholine receptor (AChR) genes in muscle. We show that phosphatidylinositol 3'-kinase (PI3K) and SHC bind to the HRG-activated ErbB3 in myotubes. Subsequently, p70S6 kinase (p70S6k), and MAP kinase ERK2 and thereby p90rsk are activated.
p(RGD:Il6) -> surf(p(PFR:"Tnfrsf Family"))
These results suggest that the synergistic IL-6 activity on C3 production may occur, at least partially, through its capacity to upregulate the number of TNF-alpha receptors on the surface of the rat liver epithelial cells.
rCD40L induced the release of IL-6 and IL-8 by SMC, EC, and macrophages, as well as TNF-a and macrophages in a time-dependent fashion (Fig.3)
The mRNA levels of rp L23a and growth are diminished in a variety of human tumor cell lines following treatment with human fibroblast interferon, interferon-beta (IFN-beta).
The increase in cGMP, which appeared to be an effect of SNP and A02131-1, stimulated the activity of PKG. When KT5823 (10 micromol/L), an inhibitor of PKG was added, the inhibition of EGF-stimulated [3H] thymidine incorporation by SNP and A02131-1 was reversed.
Wnt-1 was expressed in the caudal mesencephalon and Fgf8 in the most rostral metencephalon. Wnt-1 regulates Fgf8 expression in the adjacent metencephalon, most likely via a secondary mesencephalic signal. Fgf8 expression in Wnt-1 mutant embryos was indistinguishable from that in the wild type up to 6-somites. By 9-somites expression was markedly reduced and by 14-somites metencephalic Fgf8 expression was completely abolished.
B cell Ag receptor (BCR) signaling occurs via tyrosine phosphorylation of CD79a and CD79b ITAMs, leading to recruitment and activation of Lyn and Syk tyrosine kinases and subsequent downstream events.
Interferon-beta (INFB) is known to suppress the synthesis of tumour necrosis factor alpha and interferon-gamma, which have been reported to be elevated in the margin of the areas of demyelination in ALD brains.
bp(GO:"response to heat") -> p(RGD:Cryab)
The levels of hsp27 and alpha B crystallin, which were determined by specific immunoassays, were low in cells in confluent cultures. The levels of the two proteins increased after exposure of cells to heat (42 degrees C for 30 min) or arsenite (50 microM for 1 h).
The levels of hsp70 also increased in cells that had been treated with arsenite in the presence of a prostaglandin, as estimated by Western blot analysis. Northern blot analysis revealed that the expression of messenger RNAs (mRNAs) for hsp27, alpha B crystallin, and hsp70 was enhanced in cells that had been exposed to arsenite in the presence of each prostaglandin.
a(CHEBI:"prostaglandin D2") -> r(RGD:Hspa4)
a(SCHEM:"Sodium arsenite") -> (a(SCHEM:Dinoprostone) -> r(RGD:Hspa4))
When cells were exposed to arsenite in the presence of 10-40 microM prostaglandin, the accumulation of hsp27 and alpha B crystallin in cells was enhanced markedly.
tscript(p(HGNC:USF2)) -| tscript(complex(NCH:"AP-1 Complex"))
In the presence of USF2, the DNA binding activity of c-Maf was markedly reduced
a(CHEBI:"reactive oxygen species") -| cat(p(HGNC:HPGD))
Hyperoxia exposure decreased both lung PGE1 metabolism [Transpulmonary PGE1 clearance] and lung prostaglandin dehydrogenase activity (PGDH).
a(CHEBI:aldosterone) -> phos(complex(NCR:"Calcineurin Complex"))
Its mRNA level is induced by transforming growth factor beta-1 and indomethacin and inhibited by phorbol ester and retinoic acid. WS9-14 is abundantly expressed in all tumor cell lines examined that attach to culture dishes but not in cell lines that grow in suspension and is also up-regulated in senescent fibroblasts
kin(p(PFH:"PRKC Family")) -> surf(p(HGNC:FN1))
title := \"Glucose-induced fibronectin expression in endothelial cells is mediated by protein kinase C.\"
complex(NCR:"Follicle Stimulating Hormone Complex") -> cat(p(RGD:Akr1c1))
The addition of IGF-I also increased basal levels of type I 3 beta-HSD transcripts (3.8-fold). IGF-I enhanced FSH-stimulated 20 alpha-HSD activity and transcripts (2.3-fold and 1.8-fold, respectively) and increased the basal levels of 20 alpha-HSD transcripts (3-fold)
We found that histamine stimulates the expression of both IGF-I and IGF-II mRNAs, as determined by a semiquantitative in situ hybridization analysis.
In embryos Rbp-Jk was activated by notch1. Expression of Hes-5 was severely reduced in Rbp-Jk mutant embryos and expression was also down-regulated in Notch1 mutants. These results are consistent with Rbp-Jk and Notch-1 acting in a common pathway to activate Hes-5 expression in the embryo.
Through the induction of Bcl-2, IL-2 inhibits apoptosis
cat(p(MGI:Casp1)) -> (kin(p(EGID:12537)) -> bp(MESHPP:Apoptosis))
kin(p(EGID:12537)) -> bp(MESHPP:Apoptosis)
Testing of seven murine CASPs for their ability to cleave p110 PITSLRE kinase alpha2-1 in vitro revealed that only CASP-1 (ICE (interleukin-1beta-converting enzyme)) and CASP-3 (CPP32) were able to produce the same 43-kDa cleavage product as observed in cells undergoing TNF-induced apoptosis.
tscript(p(HGNC:ZNF593)) =| tscript(p(HGNC:POU2F2))
One of them, hT86, encoding a putative zinc finger protein was found to derepress beta-galactosidase activity in the Oct-2-harboring tester strain at the transcriptional level. In gel mobility shift assays, hT86 attenuated the intensity of the retarded band composed of the octamer probe and Oct-2, suggesting a dominant negative effect on the DNA-binding activity of Oct-2.
members of the GATA family. GATA-5 binds to the functionally important CEF-1 nuclear protein binding site in the cardiac-specific slowcardiac troponin C (cTnC) transcriptional enhancer and overexpression of GATA-5 transactivates the cTnC enhancer in noncardiac muscle cell lines.
Stimulation of rat VSMC by TGF-beta decreased both their catalase activity and glutathione peroxidase activity in a dose-dependent manner
PD98059, a Mek1 inhibitor, inhibited Creb phosphorylation at serine-133 induced by Abeta (1-40).
cat(p(HGNC:ADRB2)) -> a(SCHEM:"cyclic AMP")
Both procaterol and theophylline elevated cAMP levels
examination of the sites on a three-dimensional model of TGF-alpha suggest the primary mechanism used by IDE for determining cleavage sites is the tertiary structure of the substrate.
the in vitro phosphorylation of GST–Elk and GST–Sap by immunoprecipitated p38 MAPK was abolished in the presence of the inhibitor SB202190, whereas the ability of the MAPK ERK-1 to phosphorylate these two TCFs was unaffected (Figure 1B).
Addition of NRG1 stimulates tyrosine phosphorylation of ERBB3 in MCF-7 cells.
bp(MESHPP:Obesity) positiveCorrelation r(MGI:Tgfb1)
RESULTS: TGF-beta mRNA and protein were increased in the adipose tissue from two different strains of genetically obese mice (i.e., ob/ob and db/db), compared with their lean counterparts. This increase in TGF-beta may result from TNF-alpha since TNF-alpha increased TGF-beta mRNA expression in the adipose tissue of lean mice and stimulated TGF-beta production by cultured adipocytes.
p(HGNC:HBEGF) -> p(HGNC:ERBB4,pmod(P,Y))
Besides binding, HB-EGF activates HER4. For example (i) it induces tyrosine phosphorylation of HER4 in cells overexpressing this receptor and of endogenous HER4 in MDA-MB-453 cells and astrocytes; (ii) it induces association of phosphatidylinositol 3-kinase (PI3-K) activity with HER4; and (iii) it is a potent chemotactic factor for cells overexpressing HER4.
p(EGID:2520) -> tscript(complex(NCH:"AP-1 Complex"))
Gastrin stimulation increased c-fos and c-jun mRNA abundance and AP-1-dependent transcriptional activity
p(HGNC:TGFB1) -> complex(p(HGNC:E2F4),p(HGNC:RB1))
We show here that TGF-beta treatment of HaCaT cells induced the formation of E2F4-RB and E2F4-p107 complexes, which are capable of binding to E2F sites.
In cytokine-stimulated endothelial cells, TGF-beta hinders leukocyte adhesion and transmigration via inhibition of IL-8 and E-selectin expression.
kin(p(HGNC:TGFBR2)) => p(HGNC:TGFBR2,pmod(P,S,213))
p(MGI:Il6) -> path(SDIS:"acute phase reaction")
Accelerated muscle protein degradation and increased hepatic acute phase protein synthesis are hallmarks of an inflammatory response. The cytokines IL-1, IL-6, and TNF-a are able to stimulate hepatic synthesis of acute phase proteins in vivo and in vitro (Richards et al., 1991).
kin(p(HGNC:MERTK)) -> kin(p(HGNC:MAPK1))
We also observed a transient activation of p42 MAP kinase following activation of Mer by Gas6. Thus, Gas6 exerts its biological effects through multiple receptor tyrosine kinases.
complex(p(HGNC:AR),p(HGNC:NR3C1)) -| tscript(p(HGNC:NR3C1))
We now show that coexpressed AR and GR indeed do interact at the transcriptional level and that this interaction is correlated with their ability to form heterodimers at a common DNA site, in vitro and in vivo
tscript(p(HGNC:AR)) -| tscript(p(HGNC:NR3C1))
cat(p(HGNC:CYP24A1)) -| a(CHEBI:calcitriol)
In this study, we examined renal metabolism of a synthetic analog of 1alpha,25(OH)2D3, 24, 24-difluoro-1alpha,25-dihydroxyvitamin D3 (F2-1alpha,25(OH)2D3), C-24 of which was designed to resist metabolic hydroxylation.... Moreover, F2-1alpha,25,26(OH)3D3 was formed in ROS17/2.8 cells transfected with a plasmid expressing 1alpha,25(OH)2D3-24-hydroxylase (CYP24) but not in the cells transfected with that expressing vitamin D3-25-hydroxylase (CYP27) or containing inverted CYP27 cDNA.
kin(p(HGNC:AKT1)) -> kin(p(HGNC:RPS6KB2))
kin(p(HGNC:ATM)) => p(HGNC:ABL1,pmod(P,S,446))
p(HGNC:ABL1,pmod(P,S,465)) => kin(p(HGNC:ABL1))
from full text - Fig 2 and 3 - ATM kinase activates c-Abl kinase. Serine-465 of c-Abl is required for tyrosine kinase activation by ionizing radiation and ATM. 3T3 cells
cat(p(HGNC:F2)) -| p(HGNC:LYN,pmod(P,Y))
In vitro phosphorylation assays showed that Chk suppressed Lyn activity by phosphorylating its C-terminal negative regulatory tyrosine. Upon stimulation of platelets with thrombin, the rapid and complete translocation of Chk away from Lyn caused concomitant activation of Lyn. This activation was accompanied by dephosphorylation of Lyn at its C-terminal negative regulatory tyrosine in cooperation with a protein tyrosine phosphatase
complex(p(HGNC:ITGA6),p(HGNC:ITGB4)) -> p(PFH:"RAS Family")
Alpha6-beta4 mediated cell adhesion causes activation of Ras.
complex(p(HGNC:ITGA6),p(HGNC:ITGB4)) -> gtp(p(PFH:"RAS Family"))
Ligation of alpha6beta4 in primary human keratinocytes caused tyrosine phosphorylation of Shc, recruitment of Grb2, activation of Ras and stimulation of the MAP kinases Erk and Jnk
complex(p(HGNC:ITGA6),p(HGNC:ITGB4)) -> kin(p(PFH:"MAPK JNK Family"))
activation of Jnk was inhibited by dominant-negative Ras and Rac1 and by the phosphoinositide 3-kinase inhibitor
p(HGNC:ITGB4) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))
gtp(p(HGNC:RAC1)) -> kin(p(PFH:"MAPK JNK Family"))
kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> kin(p(PFH:"MAPK JNK Family"))
stimulation of Erk by alpha6beta4 was suppressed by dominant-negative Shc, Ras and RhoA
p(HGNC:CDKN2A,sub(D,84,Y)) -| p(HGNC:CDKN2A)
tscript(complex(NCH:"AP-1 Complex")) => r(HGNC:CCL2)
Site-directed mutagenesis of the AP-1 binding site also decreased the cytokine-induced activity of the promoter.
A decline of the activities in the MSG-treated male mice was restored nearly to the male control levels by subsequent injections of human GH every 12 hr for 7 days. These changes in AO activities in male mice caused by the excitotoxic amino acids were not observed in females.
a(SCHEM:"cyclic AMP") -> tscript(p(HGNC:ESR1))
Cotransfection of the reporter genes with truncated versions of the ER shows that the two non-ligand activators of ER require different regions of the receptor to produce their effects on transcription. EGF acts primarily by means of transactivation domain AF-1, whereas cAMP acts via transactivation domain AF-2 of the ER. A point mutation that removes a major site of inducible phosphorylation within the AF-1 domain of the ER abolishes the response to EGF, but the response to estradiol and cAMP is retained. Specific inhibition of cAMP-activated protein kinase (protein kinase A) prevents the response to elevated cAMP but does not affect EGF or estradiol responses. Overexpression of the protein kinase A catalytic subunit in HeLa cells results in an amplified response to estradiol, similar to that induced by cholera toxin with 3-isobutyl-1-methyl-xanthine. Comparable experiments performed using COS-1 cells produce similar results but also reveal cell type- and promoter-specific aspects of the activation mechanisms. Apparently, the ER may be activated by three different signal molecules, estradiol, EGF, and cAMP, each using a mechanism that is distinguishable from that of the others.
a(SCHEM:"cyclic AMP") -| tport(p(HGNC:ATP2B1))
Addition of forskolin or prostaglandin E1, agents known to elevate platelet cAMP and calcium efflux, to platelets pre-labeled with [32P]PO4 resulted in the direct phosphorylation of platelet PMCA. Similarly, addition of the catalytic subunit of protein kinase A to platelet plasma membranes resulted in a 1.4-fold stimulation of activity. Thus, the previously reported inhibition of platelet activation by elevated intracellular cAMP may be accomplished in part by stimulation of PMCA, likely resulting in a decrease in intracellular calcium.
However, during ATRA-induced differentiation, steady-state STAT1, STAT2, and especially p48 mRNA and corresponding protein levels were elevated both in NB4 and U937 cells
In males, castration dramatically increased FMO3 and FMO1 expression, and testosterone replacement to castrated males resulted in ablation of FMO3 expression. In addition, testosterone administration to females (sexually intact and gonadectomized animals) reduced FMO1 expression and obviated FMO3 expression.
Fyn was tyrosine phosphorylated and comigrated with the sharp pp59 following intergrin ligation in the ARH-77 cells.
Forskolin not only inhibited activation-induced cell death and NF-kappa B activation, but also suppressed expression of Fas and Fas ligand (Fas-L)
tscript(complex(NCH:"Nfkb Complex")) => r(HGNC:IL6)
Mutation of either sequence greatly reduced RSV-mediated induction of IL-11 promoter activity. NF-kappa B sites in IL-1 alpha, IL-6, and IL-8 promoters were also required for RSV-mediated induction of transcription of these promoters. Immunological studies and use of reporter gene constructs provided direct evidence for the activation and nuclear translocation of NF-kappa B by RSV. Sodium salicylate and aspirin, inhibitors of NF-kappa B activation, abolished transcriptional induction of all these cytokines by RSV.
p(HGNC:EPO) -> p(PFH:"STAT5 Family",pmod(P,Y))
EPO induced the tyrosine phosphorylation of Stat1alpha , Stat3, and Stat5 in UT-7/EPO.
a(SCHEM:Colforsin) -> kin(p(PFH:"PRKA Family"))
treatment with forskolin or the cAMP analog 8-Bromo-cAMP resulted in an up to 3.8-fold stimulation of biglycan promoter activity
a(SCHEM:"Tetradecanoylphorbol acetate") -> p(HGNC:DUSP1)
Here we demonstrate that PMA treatment induces MKP-1 protein expression in U937 cells, which is detectable within 30 min with maximal levels attained after 4 h.
a(SCHEM:Epoprostenol) -| bp(GO:"inflammatory response")
These observations suggested that the inverse gene expression of PGIS and TXS in macrophages contributes to immune responses by modulating the relative levels of prostacyclin and thromboxane A2.
a(SCHEM:Epoprostenol) -| bp(GO:"macrophage activation")
cat(p(MGI:Tbxas1)) -> bp(GO:"macrophage activation")
TNF-alpha induced OLG cell death by activating ICE. Z-Asp-CH2-DCB, a specific inhibitor of ICE like protease when added to the cell cultures prevented TNF-alpha induced OLG cell death.
a(SCHEM:Thiazolidinedione) -| r(MGI:Apoc3)
thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased expression of lipoprotein lipase (LPL) and decreased expression of apolipoprotein (apo) C-III
a(SCHEM:Thiazolidinedione) -> r(MGI:Lpl)
a(SCHEM:"D-Glucose, anhydrous") -| surf(p(RGD:Slc2a4))
Neither high glucose nor glucosamine altered basal or insulin-stimulated plasma membrane GLUT1 levels, whereas both treatments decreased basal, but not insulin-stimulated, GLUT4 levels.
complex(GOCCACC:"GO:0043509") -> r(HGNC:CCNE1)
Activin A enhanced expression of cyclin E, which might counteract the inhibitory effect of accumulated p21 CIP1/WAF1 on CDK2 kinase activity.
kin(p(HGNC:MAP2K6)) -> kin(p(HGNC:MAPK13))
SAPK4 was activated in vitro by SKK3 (also called MKK6) MKK6 was found to be the major upstream activator of SAPK4
complex(p(HGNC:HOXB1),p(HGNC:PBX1)) => tscript(p(HGNC:HOXB1))
HOXB1 and Pbx1 cooperatively activate transcription through the Hoxb-1 gene autoregulatory element
coactivators, such as ncoa1 and creb are required for efficient steroid receptor transactivation
ncoa1 is required for progesterone receptor-driven transcription