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

Table 2. Differentially expressed genes identified by SAGE

a(CHEBI:"angiotensin II") -| r(MGI:Sdhd)

a(CHEBI:"angiotensin II") -| r(MGI:Slc25a4)

a(CHEBI:"angiotensin II") -| r(MGI:Uqcrfs1)

a(CHEBI:"angiotensin II") -> r(MGI:Col3a1)

a(CHEBI:"angiotensin II") -> r(MGI:Rpl39)

a(CHEBI:"angiotensin II") -> r(MGI:Reep5)

a(CHEBI:"angiotensin II") -> r(MGI:Rpl4)

We found that intrinsic ageing of skin in vivo is accompanied by significant increases of RAR alpha mRNA and protein

a(SCHEM:"cyclic AMP") -| kin(p(HGNC:MAPK14))

Our data demonstrate that increased intracellular cAMP concentration in endothelial cells prevents thrombin-induced ICAM-1 expression by inhibiting p38 MAPK activation, which in turn prevents phosphorylation of RelA/p65 and transcriptional activity of the bound NF-kappaB.

p(PFH:"VEGF Family") -> p(HGNC:PTK2,pmod(P,Y,407))

Exposure of endothelial cells to vascular endothelial growth factor (VEGF) induced tyrosine phosphorylation of focal adhesion kinase (FAK) on site Tyr(407), an effect that required the association of VEGF receptor 2 (VEGFR2) with HSP90.

kin(p(HGNC:SRC)) -> complex(p(HGNC:VCL),p(HGNC:PTK2))

We also found that the recruitment of paxillin to FAK was inhibited by geldanamycin but not by PP2, whereas both geldanamycin and PP2 inhibited the recruitment of vinculin to FAK.

Thus in different cell types, isoform-specific patterns of PHD induction by hypoxia and estrogen alter both the relative abundance of the PHDs and their relative contribution to the regulation of HIF.

bp(GO:"response to hypoxia") -> r(HGNC:EGLN3)

Insulin stimulates glucose transport in muscle and adipose tissues by recruiting intracellular membrane vesicles containing the glucose transporter GLUT4 to the plasma membrane.

kin(p(MGI:Src)) => p(MGI:Dapp1,pmod(P,Y,139))

The positive and negative effects of Bam32 variants on F-actin levels were closely mirrored by their effects on the activation of the GTPase Rac1, which is known to regulate actin remodeling in lymphocytes.

Thus, the Ncb5or -/- animals have a rather pure diabetic/fat phenotype.

kin(p(MGI:Rps6kb1)) -| bp(GO:"cell growth")

The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation.

cat(p(HGNC:AKR1B1)) -> tscript(complex(NCH:"AP-1 Complex"))

Inhibition of AR by sorbinil or tolrestat prevented TNF-alpha-induced increase in Bax and Bak and the downregulation of Bcl-2. Inhibition of AR abrogated AP-1 DNA binding activity and prevented the activation of caspase-3, JNK, and p38 MAPK in cells stimulated by TNF-alpha. Exposure to TNF-alpha also induced apoptotic cell death, which was attenuated by AR inhibition or antisense ablation

bp(GO:"response to hypoxia") -> r(HGNC:ID2)

ID (inhibitor of differentiation/DNA binding) proteins, frequently deregulated in advanced human malignancies, can participate in multiple fundamental traits of cancer, such as block of differentiation, increased proliferation, tissue invasiveness, and angiogenesis. We have previously demonstrated that hypoxia decreases expression of neuronal marker genes in neuroblastoma, but induces genes expressed in the neural crest, such as ID2.

Table 1. Increased transcripts in the trigeminal ganglion of Brn3a mutant mouse embryos

Table 2. Decreased transcripts in the trigeminal ganglion of Brn3a mutant mouse embryos

p(HGNC:SPRY2) -| kin(p(PFH:"MAPK p38 Family"))

FGF signaling is both necessary and sufficient for their expression By contrast, Mkp3, Sef and Spry act within cells as negative feedback inhibitors, modulating and restricting the levels and extent of FGF signaling.

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

FROM FULL TEXT: Both Epo and SCF (Kitl) recruit and activate PI3k

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

Resistin causes defective AMPK activation in response to insulin. Since AMPK signaling affects insulin-sensitive glucose metabolism (19 22) and since AMPK can act upstream of Akt signaling (23, 24), we assessed whether resistin overexpression alters AMPK activity. As demonstrated in Figure 7, AMPK phosphorylation (Thr172) was reduced by 60%, 35%, and 64% (P 0.01) in the skeletal muscle, adipose tissue, and liver of rats injected with Adv-resistin, respectively, while AMPK protein content remained unchanged.

kin(p(HGNC:IGF1R)) -> path(SDIS:"tumor growth")
p(HGNC:INTS6) -| (kin(p(HGNC:IGF1R)) -> path(SDIS:"tumor growth"))

These results demonstrate that DICE1 has a growth-suppressing activity and interferes with anchorage-independent growth of IGF-IR transformed tumor cells dependent upon IGF-I signaling.

cat(p(HGNC:P2RY6)) -> bp(GO:"cell proliferation")

We found that P2Y6 activation controlled cell proliferation but not the activity of the Na+/K+ATPase.

LKB1-deficient tumors are shown here to exhibit elevated levels of S6K1 activity and phospho-4EBP1, indicative of hyperactivation of mTOR signaling

phos(complex(NCH:"Calcineurin Complex")) -> r(HGNC:RCAN1)

VEGF-stimulated induction of DSCR1 was blocked by anti-VEGF receptor-2 monoclonal antibody (mAb), or the specific calcineurin inhibitors cyclosporin A and FK506.

a(CHEBI:"gamma-aminobutyric acid") -> p(RGD:Fgf1)

Histamine, glutamate, carbachol, serotonin or gamma-aminobutyric acid (GABA) caused an increase of FGF-1 content

cat(p(PFR:"Adrb Family")) -| r(RGD:Fgf1)

This mechanism was proved to function in vivo by stimulation of FGF-1 expression in neurons of the cerebral cortex after intracerebral administration of propranolol, an antagonist of adrenergic beta receptors

The IL-3-induced generation of IL-4, IL-13 and histamine was inhibited to a statistically significant (P<0.05) extent, only by compounds that act as inhibitors of PDE4.

a(SCHEM:"Org 30029") -| (p(HGNC:IGHE) -> p(HGNC:IL4))

The effects of the isoform-selective inhibitors, 8-methoxymethyl-IBMX (PDE 1 inhibitor), siguazodan (PDE3 inhibitor), rolipram (PDE4 inhibitor), denbufylline (PDE4 inhibitor), Org 30029 (mixed PDE3 and 4 inhibitor) and zaprinast (PDE5 inhibitor), were studied. Of these selective compounds, only rolipram, denbufylline and Org 30029 inhibited the IgE-dependent generation of IL-4, IL-13 and histamine from basophils

a(CHEBI:rolipram) -| (p(HGNC:IGHE) -> p(HGNC:IL4))

cat(p(PFH:"PDE4 Family")) -> (p(HGNC:IGHE) -> p(HGNC:IL13))

a(SCHEM:"1-Methyl-3-isobutylxanthine") -| (p(HGNC:IGHE) -> p(HGNC:IL13))

The nonselective PDE inhibitors, isobutyl-methylxanthine (IBMX) and theophylline, attenuated the IgE-mediated generation of IL-4 and IL-13 and, also, the release of histamine from basophils.

a(CHEBI:theophylline) -| (p(HGNC:IGHE) -> p(HGNC:IL13))

cat(p(HGNC:NOS3)) => a(CHEBI:"nitric oxide")

OS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone.

a(SCHEM:Isoproterenol) -> sec(p(PFR:"Ldh Family"))

Isoproterenol (150 mg kg(-1) intraperitonially twice at an interval of 24 h) caused increase in the levels of serum marker enzymes via creatinekinase (CK), creatinekinase-MB (CK-MB) isoenzyme, lactatedehydrogenase (LDH) and lactatedehydrogenase isoenzyme (LDH1).

a(SCHEM:"cyclic AMP") -> sec(p(RGD:Ckm))

We show here that Nucling was up-regulated by proapoptotic stimuli and important for the induction of apoptosis after cytotoxic stress. We further demonstrated that overexpressed Nucling was able to induce apoptosis.

Supplemental information 1 Increased gene expression in the skeletal muscle of FOXO1 mice.

TABLE II - Gene with decreased expression in the skeletal muscle of FOXO1 mice

RIZ1 is an estrogen receptor (ER) coactivator but is also a histone lysine methyltransferase that methylates lysine 9 of histone H3, an activity known to repress transcription

a(CHEBI:"okadaic acid") -> kin(p(PFH:"AKT Family"))

We upregulated Akt activity using two experimental models: treatment with a protein phosphatase inhibitor, okadaic acid

a(SCHEM:"SC 58125") -| cat(p(MGI:Ptgs2))

To confirm that COX-2 was the source of peroxides in the K-rasV12 transfected cells, we treated the cells with COX-2- specific inhibitor, SC58125.

kin(p(PFH:"PRKA Family")) -> (a(SCHEM:"cyclic AMP") -> r(HGNC:AREG))

Furthermore, the induction of AR mRNA by cAMP was strongly suppressed by a protein kinase A type I-selective inhibitor, whereas treatment with an exchange protein directly activated by cAMP-specific agonist did not increase AR levels.

Similar effects of AR mRNA induction were seen in T cells treated with cAMP-elevating agents such as prostaglandin E(2) and forskolin as well as with the phosphodiesterase inhibitors rolipram and isobutylmethylxanthine.

cat(p(HGNC:AKR1B1)) -| a(SCHEM:"Adenosine triphosphate")

Furthermore, ATP content was higher in WT mice compared with ARTg mice during ischemia and reperfusion.

path(MESHD:Ischemia) -> path(SDIS:"tissue damage")

Infarct size measured by staining techniques and myocardial damage evaluated histologically were also significantly worse in ARTg

path(MESHD:Ischemia) -> sec(p(HGNC:CKM))

Recently, we demonstrated that aldose reductase is a component of myocardial ischemic injury CK release was significantly greater in ARTg mice

kin(p(MGI:Jak2)) -> tscript(p(MGI:Stat1))

In response to IFNgamma, SRC-family kinases are required to activate STAT3 (but not STAT1) through tyrosine phosphorylation, whereas the receptor-bound kinases JAK1 and JAK2 are required to activate both STATs.

bp(GO:"hyperosmotic response") -| r(RGD:Slc4a1)

Toward this end, the expression and regulation of AE1 and SLC26A7 was examined in water deprivation, a condition known to increase the osmolality of the medulla. Rats were subjected to 3 d of water deprivation while having free access to food. Northern hybridizations demonstrated that in the outer medulla, the mRNA expression of SLC26A7 increased by approximately 300% (P < 0.01 versus control; n = 3), whereas the expression of AE1 decreased by approximately 50% (P < 0.05 versus control, n = 3) in water-deprived rats

bp(GO:"response to osmotic stress") -| r(RGD:Slc4a1)

a(CHEBI:staurosporine) -> bp(GO:"chromosome condensation")

Non-small-cell lung carcinomas (NSCLCs) are resistant to the induction of apoptosis by conventional anticancer treatment. However, NSCLC cell lines are sensitive to the action of the broad protein kinase inhibitor, staurosporine (STS). In the NSCLC cell line U1810, STS induced the mitochondrial release of apoptosis-inducing factor (AIF) and cytochrome c (Cyt c) followed by activation of caspases, nuclear condensation, DNA fragmentation and finally cell death.

AKT promotes the nuclear translocation of MDM2, thereby negatively regulating p53-mediated apoptosis

kin(p(HGNC:ATM)) => p(HGNC:BRCA1,pmod(P))

histone H2AX, 53BP1, BRCA1 and NBS1 are all targets of ATM and ATR

Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation.

RESULTS: SNP upregulated mACON enzymatic activity and gene expression in PC-3 cells.

a(CHEBI:"ascorbic acid") -| r(HGNC:ACO2)

The addition of ascorbic acid to the SNP treatment resulted in a decrease in mACON enzymatic activity and gene expression.

kin(p(HGNC:EGFR)) -> path(SDIS:metastasis)

An interaction between EGFR and AR has been demonstrated by immunoconfocal and co-immunoprecipitation analysis in PC3-AR cells, suggesting a possible interference of AR on EGFR signalling by interaction of the two proteins.

kin(p(HGNC:EGFR)) -> path(SDIS:"tumor cell invasion")

Immunoprecipitation studies demonstrated a reduction of EGF-induced tyrosine phosphorylation of EGFR in PC3-AR cells.

p(HGNC:AR) -| (p(HGNC:EGF) -> path(SDIS:metastasis))

In addition, EGF-stimulated PI3K activity, a key signalling pathway for invasion of these cells, was decreased in PC3-AR cells and further reduced by treatment with R1881, indicating decreased functionality of EGFR.

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> path(SDIS:metastasis)

p(MGI:Igf1) -> path(SDIS:immortalization)

Elevated levels of IGF-I in the circulation are associated with increased risk for the development of prostate cancer in men, and transgenic expression of human IGF-I in mouse epithelial prostate cells results in spontaneous prostate tumorigenesis.

Stat3 controls cell death and tissue remodeling in the mouse mammary gland during involution, which is partially induced by IL6 and LIF.

cat(p(MGI:Il6st)) -| tscript(p(PFM:"Stat5 Family"))

The decline of phosphorylated Stat5 was delayed in gp130-null tissue as compared with wild-type tissue

gp130 can transduce signals upon IL6 stimulation, which result in EGFR phosphorylation.

kin(p(HGNC:MAP2K7)) -| tscript(p(HGNC:NR3C1))

A similar inhibition of activation of the MMTV promoter-driven luciferase construct was seen in HeLa cells transfected with MKK7(D), a constitutively functional activator of JNK.

kin(p(HGNC:MAPK8)) -| tscript(p(HGNC:NR3C1))

The mitogen-activated protein (MAP) kinases, p38 and c-Jun N-terminal kinase (JNK), are important mediators of target gene activation by TNF, and JNK activation was earlier shown to inhibit GR-mediated transcriptional activation by direct phosphorylation of GR at Ser-246.

kin(p(HGNC:MAPK9)) -| tscript(p(HGNC:NR3C1))

kin(p(HGNC:MAP2K6)) -| tscript(p(HGNC:NR3C1))

Transfection of HeLa cells with MKK6b(E), a constitutively active specific upstream activator of p38, led to a potent inhibition of GR activation of the MMTV promoter-driven luciferase construct.

These defects in cell adhesion and tissue organization are explained by loss of E-cadherin and beta-catenin localization to cell adhesion sites in both cell culture and in the intact embryos.

a(SCHEM:"Tetradecanoylphorbol acetate") -> r(HGNC:NR0B2)

Here, we show that SHP expression increases during monocytic differentiaton with exposure HL-60 leukemia cells to a 12-O-tetradecanoylphorbol-13-acetate (TPA) response element, whose treatment induced the SHP promoter activity dependent on c-Jun expression,

kin(p(HGNC:GSK3B)) -| gtp(complex(NCH:"EIF2B Complex"))

EIF2B is activated through Akt-mediated phosphorylation and inactivation of GSK3B

bp(GO:"satellite cell activation") -> r(HGNC:MYF6)

after proliferation, satellite cells initiate expression of the genes encoding myogenin, mrf4, p21, and, after a permanent exit from the cell cycle, they fuse with damaged myofibers or give rise to new myofibers

by promoting fusion of myoblasts with preformed myotubes, IL4 may actively participate in the regeneration process

p(HGNC:FST) -| complex(p(HGNC:MSTN),p(HGNC:ACVR2B))

follistatin can block the binding of myostatin to the activin IIB receptor by interacting with the C-terminal region of a myostatin dimer

cat(p(PFH:"HDAC Family")) -| r(HGNC:FST)

follistatin gene expression is activated by exposure of skeletal muscle cells to deacetylase inhibitors

bp(MESHPP:Exercise) -> bp(GO:"satellite cell activation")

microtraumas resulting from chronic exercise also lead to satellite cell activation and proliferation

kin(p(HGNC:AKT1)) => p(EGID:2475,pmod(P))

once Akt1 is activated, it initiates a cascade of phosphorylation events targeting mammalian target of rapamycin, mTOR, which in turn phosphorylates the p70S6 kinase and GSK3B

kin(p(HGNC:AKT1)) => p(HGNC:GSK3B,pmod(P,S))

kin(p(EGID:2475)) -> p(HGNC:RPS6KB1,pmod(P))

bp(GO:"satellite cell activation") -> r(HGNC:MYF5)

once satellite cells are activated, they express the genes encoding the 2 myogenic regulatory factors Myf5 and MyoD, which are not detectable in quiescent cells

bp(GO:"satellite cell activation") -> r(HGNC:MYOD1)

phosphorylated IRS1 also stimulates the Ras-Raf-MEK-ERK pathway, a MAPK pathway

phosphorylation of mTOR represses, through an adaptor protein known as Raptor, 4EBP1, an inhibitor of EIF4E

kin(p(HGNC:IGF1R)) => p(HGNC:IRS1,pmod(P,Y))

upon binding of IGF1, the IGFR, which is a receptor tyrosine kinase, becomes phosphorylated and recruits the substrate IRS1, leading to the activation of the lipid kinase PI3K

kin(p(HGNC:RPS6KA2)) -> tscript(p(HGNC:CREB1))

Activated p90rsk phosphorylates several transcription factors including Elk and the cAMP-response element-binding protein (CREB) and the activating protein 1 family of c-Jun, c-fos and activating transcription factor (Pearson et al. 2001).

kin(p(HGNC:RPS6KA2)) -> tscript(p(HGNC:JUN))

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

Activation of JNK in response to skeletal muscle contraction is associated with a rapid induction of the early response genes c-Jun and c-fos, as evidenced by increased mRNA levels (Aronson et al. 1997a).

Examples of genes having MEF2-binding sites include GLUT4, creatine kinase, AMP deaminase, myoglobin, myosin (heavy light chains), dystrophin, MyoD and cJun (Black Olson, 1998).

tscript(p(PFH:"MEF2 Family")) -> r(HGNC:MYH9)

PD98059 (MAPK/ERK1 inhibitor) and SB203580 (p38 MAPK inhibitor) respectively. In isolated rat skeletal muscle specific inhibition of ERK1/2 by PD98059 completely abolishes contraction-mediated p90rsk activity (Ryder et al. 2000).

kin(p(HGNC:MAP3K7)) -> kin(p(HGNC:MAP2K6))

exercise leads to the activation of at least three MAPK signalling pathways, i.e. ERK1/2, p38 MAPK and JNK, in skeletal muscle (Zierath, 2002).

tscript(p(HGNC:PPARGC1A)) -> tscript(complex(NCH:"AP-1 Complex"))

Activation of NRF-1 by PGC-1 increases the expression of genes that encode mitochondrial respiratory chain proteins (Scarpulla, 2002) and 5-aminolevulinate synthase (Briadotti et al. 1993), as well as mitochondrial transcription factor A, a regulator of mitochondrial DNA transcription and replication

tscript(p(HGNC:PPARGC1A)) -> tscript(p(HGNC:NRF1))

kin(p(PFR:"Prka Family")) => p(RGD:Lipe,pmod(P,S,863))

kin(p(PFR:"Prka Family")) => p(RGD:Lipe,pmod(P,S,959))

kin(p(PFR:"Prka Family")) => p(RGD:Lipe,pmod(P,S,960))

a(SCHEM:"serum insulin") -> (bp(MESHPP:Exercise) -> bp(GO:"skeletal muscle hypertrophy"))
bp(MESHPP:Exercise) -> bp(GO:"skeletal muscle hypertrophy")

Indeed, each of these select proteins is indispensable in mediating skeletal muscle growth and, whereas proposing the up-regulation of distinct proteins as potential markers of hypertrophy is tempting, a coordinated response from multiple signal transduction pathways is essential to the overall process. Integration of signalling by insulin, amino acids and resistance exercise A thorough review of amino acids and insulin and their contribution to regulating skeletal muscle protein synthesis is beyond the scope of the present paper. Thus, the intent of the present brief overview will be to focus exclusively on the impact of amino acids or insulin on protein synthesis in the context of resistance exercise. Without question, investigating the singular role of amino acids or insulin in promoting changes in skeletal muscle protein synthesis with resistance exercise is crucial to elucidating mechanisms regulating muscle hypertrophy. However, in a physiological state the concept is essentially irrelevant, as insulin and amino acids do not function in isolation because both participate to optimize the anabolic response in skeletal muscle. Nonetheless, key findings in both areas will be briefly highlighted to emphasize their contribution with resistance exercise. Although insulin concentrations remain relatively unchanged in the recovery period following resistance exercise (Kraemer et al. 1998; Biolo et al. 1999; Hernandez et al. 2000), a permissive amount of insulin is required to mediate increases in skeletal-muscle protein synthesis.

After 14-day simultaneous denervation of the soleus (Sol), tibialis anterior (TA), extensor digitorum longus (EDL), and gastrocnemius (Gastr) muscles by sciatic nerve section, DHPR mRNA increased preferentially in the Sol and TA (+1.6-fold), whereas it increased in the EDL (+1.6-fold) and TA (+1.8-fold) after selective denervation of these muscles by peroneal nerve section

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

kin(p(HGNC:FLT1)) -> p(HGNC:FLT1,pmod(P,Y))

Flt1 reveals a weak tyrosine autophosphorylation in response to VEGF

kin(p(HGNC:TGFBR1)) -> kin(p(HGNC:MAP2K2))

complex(p(HGNC:TNF),p(HGNC:TNFRSF1A)) => cat(p(HGNC:TNFRSF1A))

Overexpression of NCOA-1, NCOA-2, and NCOA-3 enhanced E2-mediated gene expression by 3.17 +/- 0.51-, 2.33 +/- 0.8-, and 3.65 +/- 0.65-fold, respectively, and enhanced cell survival by suppressing tumor necrosis factor alpha (TNF-alpha)-induced cell death Overexpression of NCOA-1 and NCOA-3 exerted potent survival effects in breast carcinoma cells.

Supplementary Table 1. Gene Regulation by Caloric Restriction and Compounds Including Nuclear Receptor Agonists downregulated by caloric restriction

path(SDIS:"food intake") -> r(MGI:Ethe1)

path(SDIS:"food intake") -> r(EGID:109901)

path(SDIS:"food intake") -> r(MGI:Tmem147)

Yeast two-hybrid analysis using the ligand-binding domain (LBD) of TAK1 as bait identified a novel TAK1-interacting protein, referred to as TIP27, which functions as a repressor of TAK1-mediated transactivation.

p(HGNC:EGR3) -> bp(GO:"spindle assembly")

Egr3 expression is required for the formation of muscle spindle fibers

p(HGNC:NRG1) -> surf(p(PFH:"CHRM Family"))

in addition to increasing the expression of acetylcholine receptors on the myotube surface, NRG treatment results in a transient increase of several members of the early growth response (Egr) family of transcription factors. Three Egrs, Egr1, -2, and -3, are induced within the first hour of NRG treatment, with Egr1 and -3 RNA levels showing the most significant increases of approximately 9- and 16-fold, respectively

a(SCHEM:"serum glucose") -> p(HGNC:ICAM1)

\"Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin and interleukin-6 expression in human umbilical endothelial cells in culture: the role of poly(ADP-ribose) polymerase.\" We found that oscillating glucose was more effective in triggering the generation of nitrotyrosine and inducing the expression of adhesion molecules and IL-6 than stable high glucose.

bp(GO:"response to UV") -> (cat(p(HGNC:CASP3)) -> kin(p(HGNC:PRKCD)))
cat(p(HGNC:CASP3)) -> kin(p(HGNC:PRKCD))

The constitutively active catalytic domain of protein kinase C (PKC)delta is an apoptotic effector generated by caspase-3 cleavage of full-length PKCdelta in response to a wide variety of apoptotic stimuli, including UV radiation.

a(CHEBI:etoposide) -> p(HGNC:H2AFX,pmod(P,S,140))

In KD clones, but not in RD-clones, formation of etoposide-induced gamma-H2AX was increased, indicating that PrxV inhibits conversion of topoisomerase II cleavage complexes into double-strand DNA breaks but this inhibition is not caused by its antioxidant activity.

phos(p(HGNC:PTEN)) -| tscript(p(HGNC:RUNX2))

Although transfection resulted in the inhibition of RUNX2 activity, PTEN wild type was more effective at inhibiting RUNX2 DNA binding (70% inhibition) than the mutant vector (30% inhibition) (Fig. 3D).

IGF-1 increased active ERK1/2 within 5 min, a response that was ablated by pretreatment with LY294002.

IGF-1 treatment increased RUNX2 DNA binding activity in HBME cells up to 10-fold relative to untreated cells (Fig. 2A).

loss of function of HELLS/SMARCA6 by allelic loss and aberrant proteins by tumor-specific exon creation may result in epigenetic deregulation, leading lung cells to malignancy or its progression.

Most robustly expressed were gene sequences NFI-B, ATP1B1, RHOGAP, PLA2G4A, BAX, CASP3, P53, MAO-A, FRA1, HSP70.2, and NR4A1 (NUR77) These data indicate that ischemia elicits expression of an array of functional gene clusters

tscript(complex(NCH:"AP-1 Complex")) -> r(HGNC:GSTP1)

Both the stimulated expression of GST-P gene by TPA and that by over-expressed c-Jun were suppressed to the basal level by dexamethasone, an inhibitor of AP-1.

bp(MESHPP:Obesity) positiveCorrelation kin(p(MGI:Rps6kb1))

Moreover, wild-type mice on a high fat diet as well as K/K A(y) and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity-have markedly elevated S6K1 activity

identified by MALDI-TOF Up-regulation of TrpRS, RS, prohibitin and down-regulation of BTF3 were involved in inhibition of transcription and protein synthesis in the apoptotic K562 cells

p(HGNC:FOXO3) -| bp(GO:"cell proliferation")

Foxo3a deficiency leads to spontaneous lymphoproliferation, associated with inflammation of several organs, in the absence of overt apoptotic defects.

kin(p(HGNC:ACVR1)) -> tscript(p(HGNC:SMAD9))

BMP signaling leading to Smad1/5/8 activation via ALK2/3/6

kin(p(HGNC:BMPR1A)) -> tscript(p(HGNC:SMAD9))

kin(p(HGNC:BMPR1B)) -> tscript(p(HGNC:SMAD5))

a(SCHEM:"Oxidized Low Density Lipoprotein") -> bp(GO:"endothelial cell activation")

Oxidized low density lipoprotein (ox-LDL), a marker of oxidative stress, is present in the plasma as well as in the atherosclerotic arteries of patients with atherosclerosis. Ox-LDL leads to endothelial activation, dysfunction and injury

bp(GO:"response to hypoxia") -> r(HGNC:NPM1)

Here we report that this proliferation-promoting protein is strongly induced in response to hypoxia in human normal and cancer cells

bp(GO:"response to hypoxia") -> bp(MESHPP:Apoptosis)
p(HGNC:NPM1) -| (bp(GO:"response to hypoxia") -> bp(MESHPP:Apoptosis))

Suppression of NPM expression by small interfering RNA targeting NPM increases hypoxia-induced apoptosis

Exposure of HEL, K562, and Hep-G2 cells to hypoxia for 18 hours resulted in a significant increase in FECH mRNA expression (p Hypoxia also transactivated the minimal promoter for the FECH gene in the cells. Transient co-expression of wild-type HIF-1alpha or a dominant negative HIF-1alpha with the FECH minimal promoter luciferase construct stimulated or blocked FECH promoter activity, respectively. Expression of the von Hippel-Lindau (VHL) tumor suppressor factor blocked the expression of both FECH mRNA and HIF-1alpha protein

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

a(SCHEM:"Cyclic GMP") -| bp(GO:"platelet aggregation")

Activation of the NO/cGMP pathway results in a strong reduction of platelet aggregation elicited by agonists such as thrombin (Azuma et al., 1986; Radomski et al., 1987; Benjamin et al., 1991; Moro et al., 1996; Rao et al., 1990).

a(CHEBI:"nitric oxide") -| r(RGD:Gucy1a3)

NO has been described to inhibit sGC expression and sGC activity in a cGMP-dependent manner (Filippov et al., 1997).

bp(GO:"response to hypoxia") -> r(HGNC:ATF3)

TABLE 2. Hypoxia-induced translationally regulated genes

bp(GO:"response to hypoxia") -> r(HGNC:BUD31)

bp(GO:"response to hypoxia") -> r(HGNC:CRABP2)

bp(GO:"response to hypoxia") -> r(HGNC:IGFBP4)

bp(GO:"response to hypoxia") -> r(HGNC:MAP2K1)

bp(GO:"response to hypoxia") -> r(HGNC:MEF2A)

bp(GO:"response to hypoxia") -> r(HGNC:PDK3)

bp(GO:"response to hypoxia") -> r(HGNC:PRRX1)

bp(GO:"response to hypoxia") -> r(HGNC:TAX1BP1)

tscript(p(HGNC:TP53)) -| bp(GO:"cell cycle")

together to form a ternary complex. We show that, when overexpressed, L23 inhibits HDM2-induced p53 polyubiquitination and degradation and causes a p53-dependent cell cycle arrest.

Downregulation of Ets2 in prostate cancer cells was associated with reduced levels of the anti-apoptotic protein bcl-x(L) and growth regulatory factors cyclin D1 and c-myc.

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

A cultured myocardial cell model was used to examine the role of protein kinase C-dependent pathways in the transcriptional activation of two cardiac muscle genes [myosin light chain 2 (MLC-2) and atrial natriuretic factor (ANF)] during alpha-adrenergic receptor-mediated hypertrophy. Phorbol ester (phorbol 12-myristate 13-acetate) and the alpha-adrenergic agonist phenylephrine both activate protein kinase C (PKC) and induce 4- to 5-fold increases in the expression of MLC-2 and ANF promoter/luciferase reporter genes with little effect on Rous sarcoma virus/luciferase or minimal prolactin promoter/luciferase genes.

kin(p(PFH:"PRKC Family")) -> p(EGID:29895)

bp(MESHPP:Obesity) positiveCorrelation r(RGD:Adm)

The present study demonstrates for the first time that AM and its receptor component (CRLR/RAMP2) mRNAs were concomitantly expressed in various adipose tissues, whose tissue-specific upregulation was induced during the development of obesity;whereas steady-state AM mRNA levels conversely decreased in other organs, such as kidney and liver

Hook1, Tuba1, Tubd1, Dncic2, Kif3b, Rnf19/Dorfin, Pcnt2, Nin and Smc4l1, all decreased with maternal aging

tscript(p(PFH:"RAR Family")) -> r(HGNC:NEDD9)

We report here the identification of 14 genes that are % rapidly induced by atRA (retinoic acid induced in neuroblastoma or RAINB), % eight of which were previously not known to be atRA responsive (BTBD11, % calmin, cyclin M2, ephrin B2, HOXD10, NEDD9, RAINB6 and tenascin R).

a(SCHEM:"1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid") -| (cat(p(HGNC:ADRB2)) -> kin(p(HGNC:MAPK3)))
cat(p(HGNC:ADRB2)) -> kin(p(HGNC:MAPK3))

In contrast, chelation of intracellular Ca2+ with BAPTA/AM (20 uM) almost fully blunted ERK1/2 phosphorylation (n = 4; p < 0.002) as well as H-Ras activation (n = 5; p < 0.001) induced by the beta2-AR.

In contrast, expression of lipase-inactive H1144L PLC-epsilon (27), which inhibited PLC and Ca2+ signaling in HEK-293 cells (35), strongly reduced (n = 4; p < 0.001) the adrenaline-induced ERK1/2 phosphorylation and H-Ras activation.

complex(p(HGNC:INHBA),p(HGNC:INHBA)) -> p(HGNC:GNRH1)

Second, activin up-regulates gonadotropin-releasing hormone receptor (GnRHR) gene expression, leading to alterations in the synthesis and release of both gonadotropins in response to GnRH. Third, activin can stimulate GnRH release from GnRH neurons in the hypothalamus and thereby affect FSH and LH secretion.

p(HGNC:CREBBP) => p(PFH:"Histone H4 Family",pmod(A))

4. CBP/p300 family H3, H4, H2A, H2B; Nonhistone proteins Worm to human Global coactivator

p(HGNC:ATF2) => p(PFH:"Histone H2B Family",pmod(A))

7. ATF2 H4/H2B Yeast to human Sequence-specific DNA-binding activator

A multitude of synthetic tyrosine kinase inhibitors have been developed and screened for potential preclinical activity, most of which reversibly compete with ATP for binding to the enzyme's intracellular catalytic domain. The quinazoline derivatives ZD1839 (gefitinib, Iressa) and OSI- 774 (erlotinib, Tarceva) appear to be the most promising to date. ZD1839 is a synthetic anilinoquinazoline [4-(3-chloro-4- fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy) quinazoline] that inhibits the EGFR tyrosine kinase, resulting in G1 cell cycle arrest and upregulation of the p27KIP1 cyclin dependent kinase inhibitor [88-91]

AES amino-terminal enhancer of split Groucho/TLE family, represses AR

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

Depsipeptide Depsipeptide was originally isolated from a strain of Chromobacterium violaceum. Initial studies with this bicyclic peptide demonstrated a selective decrease in c-myc expression. However, growth inhibition of the Ha-rastransformed NIH-3T3 clonal cell line Ras-1 was also observed in the absence of altered Ha-ras mRNA expression [67]. Depsipeptide appears to regulate the cell cycle at several points, including cell cycle arrest at G0/G1 and inhibition of signal transduction through mitogen-activated protein kinase (MAPK) with resultant p53-independent G1 arrest. EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS Epidermal Growth Factor Receptor Binding by any member of the EGF family of ligands results in receptor dimerization and activation of the intracytoplasmic tyrosine kinase domain. In addition to homodimers, members of this receptor family can also form heterodimers through a series of complex interactions that result in transphosphorylation and the concerted regulation of the involved receptors. Six EGF-like ligands are known to bind and activate EGFR: EGF, TGF?, amphiregulin (cripto-1; CR-1), heparin-binding EGF (HB-EGF), betacellulin (BTC), and epiregulin (EPR) [78, 79]. Ligand binding to EGFR at the cell membrane triggers a signal transduction cascade that leads to the activation of nuclear transcription factors that promote cell division.

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

a(SCHEM:Flavopiridol) =| kin(p(HGNC:CDK2))

Flavopiridol (L-868275) is one of only two CDKIs to reach human clinical trials. It is a synthetic flavone, derived from the flavonoid rohitukine. It achieves antitumor activity through a variety of mechanisms, including inhibition of cell growth and proliferation, induction of apoptosis, and inhibition of angiogenesis. This agent is a broad spectrum phosphokinase inhibitor with the strongest activity against CDKs (specifically CDK1, CDK2, CDK4, CDK6, and CDK7), although interactions with the EGFR family of receptors, receptor associated protein kinases, and protein kinase C have also been reported

a(SCHEM:Flavopiridol) =| kin(p(HGNC:CDK6))

SMRT TRAC2 Represses unliganded TR, RAR, ER and PR

p(HGNC:NCOA3) => p(PFH:"Histone H3 Family",pmod(A))

SRC-2/TIF-2/Grip1 ND SRC3 3/ACTR/AIB1/PCIP H3/H4

a(SCHEM:Flavopiridol) -| cat(complex(NCH:"RNApo II Complex"))

The inhibition of RNAP II by flavopiridol may contribute to apoptosis in a variety of cell lines and tumors.

However, until now, decreased TF expression, induced by statins, has been demonstrated solely on cultured human macrophages or monocytes [105].

a(SCHEM:Calcium) -| tscript(p(HGNC:HIF1A))

Decreasing the intracellular calcium level by BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) induced HIF-1alpha nuclear accumulation and enhanced HIF-1 DNA binding within 1 h of incubation.

cat(p(HGNC:AIFM1)) -> cat(p(HGNC:PARP1))

Figure 2 | Extrinsic and intrinsic apoptotic signalling pathways in neurons. Black lines represent apoptotic pathways, blue lines represent survival pathways. The extrinsic death pathway is initiated by binding of the extracellular ligands, TNFa (tumour necrosis factor-a) or FAS (apoptosis antigen-1) ligand (FASL), to death receptors TNFR1 (TNF-receptor1) and FAS. TNFR1 activation leads to the formation of a TRADD RIP TRAF2 (TNF receptor death domain receptor interacting protein TNF associated factor 2) complex, which signals through the NFkB (nuclear factorkB) survival pathway (blue lines) or the JNK (cJun N teminal kinase)death pathway (black lines). RIP activates procaspase 2 and cleaves BID (BH3 (BCL2 (B-cell leukaemia/lymphoma-2) homology domain 3) interacting agonist). The TRADD FADD FLICE (TNF receptor death domain FAS associated death domain FADD like interleukin 1b) complex activates procaspase 8, triggering apoptosis through caspase 3 or cleavage of BID to tBID (truncated BID). FAS-mediated death occurs through a FADD-mediated activation of procaspase 8 or DAXX (death-associated protein )-mediated activation of JNK. JNK modifies BID to jBID, allowing its translocation to the mitochondrion and release of SMAC/DIABLO (second-mitochondrialderived activator of caspases). The intrinsic apoptotic pathway is initiated at the mitochondrion by diverse stimuli. Membrane permeabilization is mediated by BH3-only proteins, which sequester and inhibit the supression of BAX (B-cell lymphoma 2-associated protein X) by BCL2, allowing mitochondrial BAX translocation and the release of cytochrome c (Cyto c), SMAC/DIABLO, AIF (apoptosis-inducing factor) and HTRA2/OMI (high temperature requirement serine protease 2).

tloc(p(HGNC:AIFM1),GOCCACC:"GO:0005739",GOCCACC:"GO:0005737") -> bp(MESHPP:Apoptosis)

tloc(p(HGNC:HTRA2),MESHCL:Mitochondria,MESHCL:Cytoplasm) -> bp(MESHPP:Apoptosis)

kin(p(HGNC:MAP3K5)) -> kin(p(HGNC:MAPK8))

Figure 4 Anti-apoptotic brakes at the mitochondrion. Black lines represent apoptotic pathways, red lines indicate inhibition. BCL2 (B-cell leukaemia lymphoma-2) and ?B-crystallin prevent mitochondrial release of the apoptogenic factors AIF (apoptosisinducing factor), cytochrome c (cyto c), HTRA2/OMI (high temperature requirement serine protease 2) and SMAC/DIABLO (second-mitochondrial-derived activator of caspases) into the cytosol by the binding and sequestration of BAX (B-cell lymphoma 2-associated protein X) and pro-apoptic BCL2 BAX-like molecules, BAK (BCL2 agonist killer 1) and BOK (BCL2-related ovarian killer protein) in the cytosol. APC (activated protein C) might prevent AIF release by increasing BCL2 expression. BAX translocation to the outer mitochondrial membrane is prevented by HSP70 (heat shock protein 70) and its co-chaperone HSP40(DNAJL1/DNAJL2). Meanwhile, membrane depolarization is prevented by the uncoupling properties of UCP2 (uncoupling protein 2) and the free radical scavenging properties of GIF (growth inhibitory factor). BH3, BCL2 homology domain 3; cIAP1, cellular apoptosis inhibitor 1; ENDOG, endonuclease G; HSP27, heat shock protein 27; IAP, inhibitor of apoptosis protein; XIAP, X-chromosome linked inhibitor of apoptosis protein.

kin(p(HGNC:SRC)) -| bp(MESHPP:Apoptosis)

Oxaliplatin-induced apoptosis, potentiated by kinase-defective c-Src mutants, was dependent on activation of caspase 8 and associated with Bid cleavage.

a(SCHEM:Calcium) -> tscript(p(HGNC:CREB1))

CREB and NFkappaB were activated most likely in response to an observed elevation in cytosolic calcium

p(MGI:Nfatc2ip) -> tscript(p(MGI:Nfatc2))

Arginine methylation of the amino terminus of NIP45 modulated its interaction with NFAT and resulted in augmented cytokine production, while T cells from mice lacking NIP45 had impaired expression of IFNgamma and IL-4.

p(HGNC:PEBP1) -| (tscript(complex(NCH:"Nfkb Complex")) -| bp(MESHPP:Apoptosis))
tscript(complex(NCH:"Nfkb Complex")) -| bp(MESHPP:Apoptosis)

RKIP has been shown to disrupt the Raf-1-MEK1/2 [mitogen-activated protein kinase-ERK (extracellular signal-regulated kinase) kinase-1/2]-ERK1/2 and NF-kappaB signaling pathways, via physical interaction with Raf-1-MEK1/2 and NF-kappaB-inducing kinase or transforming growth factor beta-activated kinase-1, respectively, thereby abrogating the survival and antiapoptotic properties of these signaling pathways.

kin(p(HGNC:MAPK1)) -| bp(MESHPP:Apoptosis)

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

The recently discovered mitochondrial and nuclear Grx (Grx2) differs from the more abundant cytosolic Grx (Grx1) by its higher affinity toward S-glutathionylated proteins and by being a substrate for thioredoxin reductase. Here, we have successfully established a method to silence the expression of Grx2 in HeLa cells by using short interfering RNA to study its role in the cell. Cells with levels of Grx2 of the control were dramatically sensitized to cell death induced by doxorubicin/adriamycin and phenylarsine oxide but did not show signs of a general increase in oxidative damage with respect to carbonylation and glutathionylation.

wenty-eight of 150 serum-inducible genes were found to be MKL-dependent. The promoters of the serum-inducible genes were analyzed for SRF binding sites and other common regulatory elements. Putative SRF binding sites were found at a higher rate than in a mouse promoter database but were only identified in 12% of the serum-inducible promoters analyzed.

Treatment with progesterone (P4) resulted in the induction of CaBP-9k mRNA, and a co-treatment with estrogen (E2) plus P4 evoked a synergic effect on its mRNA level in this tissue. translation of CaBP-9k protein was enhanced by E2, while no difference was observed at the transcriptional level. E2 stimulated the expression levels of ERalpha and PR mRNAs and P4 inhibited the expression of these transcripts at an early time point (12 h) and increased them at 24 and 48 h

On the normal diet, serum leptin levels of Pik3r1(-/-) mice were significantly higher than in wild-type mice as a result of increased leptin secretion from adipocytes, presumably due to the increased PtdIns(3,4,5)P3 production in adipocytes.

KGF alone greatly stimulated proliferation and increased cyclin-dependent kinase (cdk) 2 kinase activity and Retinoblastoma susceptibility gene product (Rb) phosphorylation. Cyclin D1, cdk2, and cdc25A protein levels were increased, and p15(Ink4b) and p27(Kip1) protein levels were decreased. (KGF = FGF7)

p(RGD:Fgf7) -> bp(GO:"cell proliferation")

TGF-beta inhibits the proliferative effect of KGF in vitro and may be a biologic antagonist of KGF.

bp(GO:"response to hypoxia") -| r(RGD:Cdc25a)

In the current study, time-dependent (3 h-11 days) changes in fetal tissue gene expression in a rat model of in utero hypoxia compared with normoxic controls were investigated as an initial approach to understand molecular events underlying fetal development in response to hypoxia. # Table 3. Temporal- and tissue-specific genes related to growth down-regulated by hypoxia in the rat fetus

cat(p(RGD:Tlr4)) -> path(MESHD:Ischemia)

TLR4 and its partner molecule MD-2 may play an important role in Kupffer cell activation and IR injury.

gtp(p(HGNC:RHEB)) -> kin(p(HGNC:RPS6KB1))

Rheb to stimulate S6 kinase (S6K) phosphorylation

Fig. 3A. Genes identified in differentiation pattern 2

Fig. 5. Genes identified in differentiation pattern 4

p(HGNC:SPRY1) -| bp(GO:"cell proliferation")

We investigated Spry expression levels in various cancers and found that Spry1 and Spry2 were down-regulated consistently in breast cancers.

kin(complex(NCH:"AMP Activated Protein Kinase Complex")) -> tport(p(HGNC:KPNA2))

First, AMPK triggered the acetylation of importin alpha1 on Lys(22), a process dependent on the acetylase activity of p300. Second, AMPK phosphorylated importin alpha1 on Ser(105)

tloc(p(HGNC:ELAVL1),GOCCACC:"GO:0005737",GOCCACC:"GO:0005634") -> cat(p(HGNC:ELAVL1))

Here, we provide evidence that importin alpha1, an adaptor protein involved in nuclear import, contributes to the nuclear import of HuR through two AMPK-modulated mechanisms

TG (50 microM) induced GLUT4 and h-caldesmon expression in 24-h culture of explanted carotid arteries of DOCA salt-hypertensive rats,

Although total Rac1 protein was not changed in KO VSMCs, the level of the Rac guanine exchange factor (GEF), Sos1, was decreased.

we then determined the mRNA levels of Txn1 and the Txnrd3 genes and found that these levels also increased after E2 treatment, with approximately 4-fold induction at the 24-h point for Txn1 and 2.5-fold induction for Txnrd3

tscript(complex(NCH:"Nfkb Complex")) -> r(HGNC:NUAK2)

We demonstrate that up-regulation of SNARK in response to CD95 ligand and tumor necrosis factor alpha depends on activation of NF-kappaB.

cat(p(HGNC:BAK1)) -> bp(MESHPP:Apoptosis)

BID induces oligomerization of proapoptotic members BAX and BAK, resulting in release of cytochrome c from mitochondria and subsequent induction of apoptosis

The accumulation of the ST6Gal I transcript in response to activated Ras was accompanied by an increase of alpha2,6-sialyltransferase activity and of Neu5Acalpha2,6Gal at the cell surface.

p(HGNC:MAPK11,pmod(P)) -> tscript(p(HGNC:ATF2))

HDAC3 decreases the MAPK11 phosphorylation state and inhibits the activity of the MAPK11-dependent transcription factor, activating transcription factor-2 (ATF-2).

a(CHEBI:lipopolysaccharide) -> r(HGNC:TNF)
p(HGNC:HDAC3) -| (a(CHEBI:lipopolysaccharide) -> r(HGNC:TNF))

HDAC3-repressed TNF gene expression, and TNF protein production observed in response to LPS stimulation.

a(CHEBI:lipopolysaccharide) -> tscript(p(HGNC:ATF2))
p(HGNC:HDAC3) -| (a(CHEBI:lipopolysaccharide) -> tscript(p(HGNC:ATF2)))

LPS-mediated activation of ATF-2 was inhibited by HDAC3 in a time- and dose-dependent manner.

Pleiotropic G proteins are essential for the action of hormones and neurotransmitters and are activated by stimulation of G protein-coupled receptors (GPCR), which initiates heterotrimer dissociation of the G protein, exchange of GDP for GTP on its Galpha subunit and activation of effector proteins. Regulator of G protein signaling (RGS) proteins regulate this cascade and can be recruited to the membrane upon GPCR activation. Direct functional interaction between RGS and GPCR has been hypothesized. We show that recruitment of GAIP (RGS19) by the dopamine D2 receptor (D2R), a GPCR, required the scaffold protein GIPC (GAIP-interacting protein, C terminus) and that all three were coexpressed in neurons and neuroendocrine cells. Dynamic translocation of GAIP to the plasma membrane and coassembly in a protein complex in which GIPC was a required component was dictated by D2R activation and physical interactions. In addition, two different D2R-mediated responses were regulated by the GTPase activity of GAIP at the level of the G protein coupling in a GIPC-dependent manner. Since GIPC exclusively interacted with GAIP and selectively with subsets of GPCR, this mechanism may serve to sort GPCR signaling in cells that usually express a large repertoire of GPCRs, G proteins, and RGS.

cat(p(HGNC:TNFRSF10B)) -> bp(MESHPP:Apoptosis)

TRAIL (TNF-related apoptosis-inducing ligand) death receptors DR4 and DR5 facilitate the selective elimination of malignant cells through the induction of apoptosis. From previous studies the regulation of the DR4 and DR5 cell-death pathways appeared similar; nevertheless in this study we screened a library of small interfering RNA (siRNA) for genes, which when silenced, differentially affect DR4- vs. DR5-mediated apoptosis. These experiments revealed that expression of the signal recognition particle (SRP) complex is essential for apoptosis mediated by DR4, but not DR5. Selective diminution of SRP subunits by RNA interference resulted in a dramatic decrease in cell surface DR4 receptors that correlated with inhibition of DR4-dependent cell death. Conversely, SRP silencing had little influence on cell surface DR5 levels or DR5-mediated apoptosis. Although loss of SRP function in bacteria, yeast and protozoan parasites causes lethality or severe growth defects, we observed no overt phenotypes in the human cancer cells studied--even in stable cell lines with diminished expression of SRP components. The lack of severe phenotype after SRP depletion allowed us to delineate, for the first time, a mechanism for the differential regulation of the TRAIL death receptors DR4 and DR5--implicating the SRP complex as an essential component of the DR4 cell-death pathway.

siRNAs that inhibit or enhance DR4- or DR5-mediated cell death

complex(p(HGNC:PPARA),p(HGNC:RXRA)) => (tscript(p(HGNC:MEF2C)) => r(HGNC:CPT1B))

synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha

Inhibition of MEK1 significantly inhibited extracellularly regulated kinase (ERK)1/2 activation and insulin-regulated Gene33 transcription and protein

Transient transfection assay demonstrated that SHP inhibited the transcriptional activity of all three isoforms of HNF3, HNF3alpha, beta, and gamma.

Theseeffects were reversed by NS398, a COX-2-specific inhibitor, suggesting thatlipopolysaccharide-mediated inhibition of CUGBP2 is a PG-dependent mechanism.

path(SDIS:"food intake") -| r(MGI:Caprin1)

To investigate the mechanisms underlying long-term resistance of the A/J mouse strain to diet-induced obesity, we studied, over a period of 4 wk, the expression of uncoupling proteins in brown adipose tissue and the expression of hypothalamic neuropeptides known to regulate energy homeostasis and then used microarray analysis to identify other potentially important hypothalamic peptides. (Table 2- 1 week)

path(SDIS:"food intake") -| r(MGI:Tiam1)

We describe here identification of ITGA3 encoding integrin alpha(3) as a target of its trans-activating function, proposing that p51/p63 allows epidermal stem cells to express laminin receptor alpha(3)beta(1) for anchorage to the basement membrane.

bp(GO:"response to heat") -> tloc(p(HGNC:HSF1),GOCCACC:"GO:0005737",GOCCACC:"GO:0005634")

The effects of 14-3-3epsilon binding on HSF1 were complex, however, depending on extracellular conditions, in that HSF1-14-3-3 binding at 37 degrees C led to the cytoplasmic sequestration and repression of HSF1, whereas heat shock overrode these effects and caused quantitative nuclear localization of HSF1. Although the effects of 14-3-3epsilon binding to HSF1 were overridden acutely by stress

complex(p(HGNC:HSF1),p(HGNC:MAPK3)) -> kin(p(HGNC:MAPK1))

We have found that the two pathways interact directly and that heat shock causes the physical association of ERK1 with HSF1, an interaction that promotes the kinase activity of ERK in heat-shocked cells.

cat(p(MGI:Chd8)) =| tscript(p(MGI:Ctnnb1))

Duplin (axis duplication inhibitor) interacts with beta-catenin and prevents its binding to Tcf, thereby inhibiting downstream Wnt signaling.

kin(p(HGNC:ERBB2)) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

In this report we have explored the mechanism linking the loss of expression of ERalpha in breast cancer cells with overexpression of Her-2/neu, which signals constitutively via a phosphatidylinositol 3-kinase (PI3K)/Akt kinase pathway.

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

the transcriptional activity of the ATF-2 transcription factor, as a direct p38 and JNK target in syndecan-4-null and wild type cells. In the absence of syndecan-4, both ATF-2 phosphorylation and transcriptional activity were significantly more elevated compared with wild type cells, and both activities were decreased either by the re-expression of syndecan-4 or by the expression of RacN17.

a(CHEBI:estradiol) -> bp(GO:"cell proliferation")

In these cells, exposure to the synthetic glucocorticoid dexamethasone (DEX) markedly decreases basal as well as 17 beta-estradiol (E2)-induced cellproliferation while causing a maximal 10-fold stimulation of apo-D secretion inthe presence or absence of E2.

bp(GO:"response to hypoxia") -| r(HGNC:BRCA1)

Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding angiogenic growth factors, which are secreted by hypoxic cells and stimulate endothelial cells, leading to angiogenesis. To determine whether HIF-1 also mediates cell-autonomous responses to hypoxia, we have compared gene expression profiles in arterial endothelial cells cultured under nonhypoxic versus hypoxic conditions and in nonhypoxic cells infected with adenovirus encoding beta-galactosidase versus a constitutively active form of HIF-1alpha (AdCA5). There were 245 gene probes that showed at least 1.5-fold increase in expression in response to hypoxia and in response to AdCA5; 325 gene probes showed at least 1.5-fold decrease in expression in response to hypoxia and in response to AdCA5. The largest category of genes down-regulated by both hypoxia and AdCA5 encoded proteins involved in cell growth/proliferation. Many genes up-regulated by both hypoxia and AdCA5 encoded cytokines/growth factors, receptors, and other signaling proteins. Transcription factors accounted for the largest group of HIF-1-regulated genes, indicating that HIF-1 controls a network of transcriptional responses to hypoxia in endothelial cells. Infection of endothelial cells with AdCA5 under nonhypoxic conditions was sufficient to induce increased basement membrane invasion and tube formation similar to the responses induced by hypoxia, indicating that HIF-1 mediates cell-autonomous activation of endothelial cells.

bp(GO:"response to hypoxia") -| r(HGNC:CDC6)

bp(GO:"response to hypoxia") -> r(HGNC:BHLHE40)

bp(GO:"response to hypoxia") -> r(HGNC:CDKN1C)

bp(GO:"response to hypoxia") -> r(HGNC:COL9A1)

bp(GO:"response to hypoxia") -> r(HGNC:CXCR4)

bp(GO:"response to hypoxia") -> r(HGNC:ERO1L)

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

bp(GO:"response to hypoxia") -> r(HGNC:P4HA2)

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

bp(GO:"response to hypoxia") -> r(HGNC:STC2)

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

tscript(complex(NCM:"Nfkb Complex")) -| r(MGI:Ccne2)

We reported previously that transcription factor nuclear factor (NF)-kappaB is constitutively activated in human and murine squamous cell carcinomas (SCCs). The role of NF-kappaB in the cumulative changes in gene expression with transformation and progression of the murine SCC Pam 212 and after switching off NF-kappaB by a dominant negative inhibitor kappaB mutant (IkappaBalphaM) was explored by profiling with a 15,000-element cDNA micoarrray. Remarkably, NF-kappaB modulated the expression of 60% of the 308 genes differentially expressed between normal keratinocytes and metastatic SCCs. NF-kappaB directly or indirectly modulated expression of programs of genes functionally linked to proliferation, apoptosis, adhesion, and angiogenesis. Among these, changes in expression of cyclin D1, inhibitor of apoptosis-1, mutant Trp53, and beta-catenin detected with modulation of NF-kappaB by microarray were confirmed by Western and Northern blot. NF-kappaB DNA binding motifs were detected in the promoter of approximately 63% of genes showing increased expression and 33% of the genes showing decreased expression. The ACTACAG motif implicated in the NF-kappaB-dependent down-regulation of mRNA expression of MyoD and Sox9 was detected in the coding portion of about 15% of genes showing increased or decreased expression. Inactivation of NF-kappaB inhibited malignant phenotypic features including proliferation, cell survival, migration, angiogenesis, and tumorigenesis. These results provide evidence that NF-kappaB is an important modulator of gene expression programs that contribute to the malignant phenotype of SCC.

tscript(complex(NCM:"Nfkb Complex")) -| r(MGI:Eif4g2)

tscript(complex(NCM:"Nfkb Complex")) -| r(MGI:Hmgb1)

tscript(complex(NCM:"Nfkb Complex")) -| r(MGI:Lcn2)

tscript(complex(NCM:"Nfkb Complex")) -| r(MGI:Nrk)

tscript(complex(NCM:"Nfkb Complex")) -| r(MGI:Rock1)

tscript(complex(NCM:"Nfkb Complex")) -| r(MGI:Rabep1)

tscript(complex(NCM:"Nfkb Complex")) -| r(MGI:Serinc1)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Bok)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Capza2)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Cd97)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Cdh3)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Ly6e)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Myc)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Nfkb1)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Pdlim1)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Ppp3cb)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Pik3r1)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Rpsa)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Rps2)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Sdc1)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Slc12a2)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Tgfb1i1)

p(HGNC:DCTN1) -> (p(HGNC:TNF) -> p(HGNC:MAP2K6,pmod(P)))

Similarly, the p150Glued siRNA could also specifically reduce the tumor necrosis factor -induced phosphorylation of MKK3/6 and p38 MAPK.

#------------------------------------------------------------------------------- Eleven genes were found to be upregulated by ANG II. These encode the proteins for ferredoxin, Nor1, Nurr1, c6orf37, CAT-1, A20, MBLL, M-Ras, RhoB, GADD45alpha, and a novel protein designated FLJ45273.

tscript(p(HGNC:TP53)) -> cat(p(PFH:"CASP Family"))

RNA interference and inducible gene expression approaches suggest that NDRG1 is necessary but not sufficient for p53-mediated caspase activation and apoptosis.

Together these studies identify S100A9 as a novel OM-regulated gene through the STAT3-signaling cascade and suggest its involvement in the growth regulation of breast cancer cells.

gtp(p(HGNC:RAC1)) -> tscript(p(PFH:"TCF/LEF Family"))

Taken together, our data demonstrate a novel mechanism of Wnt pathway regulation whereby activation of Rac1 amplifies the signaling activity of stabilized/mutated beta-catenin by promoting its accumulation in the nucleus, and synergizing with beta-catenin to augment TCF/LEF-dependent gene transcription.

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

VRK1 phosphorylates c-Jun in Ser63 and Ser73 in vitro, the same residues targeted by the N-terminal kinase of c-Jun (JNK). This phosphorylation induces the stabilization and accumulation of the c-Jun protein. VRK1 phosphorylates the endogenous c-Jun in Ser63. VRK1 activates c-Jun dependent transcription, which is dependent on phosphorylation of Ser63 and Ser73. The c-Jun with Ser63Ala and Ser73Ala substitutions is not transcriptionally active when cotransfected with VRK1. VRK1 interacts with c-Jun but not with JNK. The cotransfection of VRK1 and JNK has an additive effect on the transcriptional activation of c-Jun

We report here that CoCoA also binds the bHLH-PAS domains of AHR and ARNT and functions as a potent primary coactivator for them;

By contrast, serum- and glucocorticoid-inducible kinase 1 (SGK1) was significantly induced in a p53-dependent manner after DNA damage, and this induction was through extracellular signal-regulated kinase 1/2-mediated posttranslational regulation.

tscript(p(HGNC:TLX1)) -> r(HGNC:SMARCD3)

We focused on examining genes found to be up-regulated according to the microarray analysis and selected three putative target genes, NFKB2, SMARCD3, and NR4A3, for further investigation. We could not only confirm the up-regulation of NR4A3 by an independent method in all clones expressing HOX11, but luciferase reporter assays demonstrated that the effect that HOX11 exerted on the proximal promoter of NR4A3 was dependent on the presence of an intact homeodomain, providing support for the idea that HOX11 manifests its regulatory function via its action as a transcription factor.

bp(GO:"response to hypoxia") -| bp(GO:"ATP synthesis coupled electron transport")

Acute and 24-h hypoxia decreased JO2 of A549 cell mitochondrial complexes I, II, and III by 30-40%. Reoxygenation restored complex I activity after acute hypoxia but not after 24-h hypoxia. ATP was decreased 30% after 24-h hypoxia, but lactate production rate was not affected.

path(SDIS:"response to shear stress") -| r(HGNC:NOX4)

Furthermore, OS increased gp91phox (nox2) and nox1 mRNA levels while decreasing nox4. In contrast, BMP4 induced nox1 mRNA expression, whereas nox2 and nox4 were decreased or not affected, respectively

p(HGNC:BMP4) -> a(CHEBI:"hydrogen peroxide")

Similar to OS, BMP4 stimulated H2O2 and O2- production in ECs.

p(HGNC:CLU) -| bp(GO:"response to oxidative stress")

These findings suggest that clusterin may contribute to conferring resistance to oxidative stress-mediated cellular injury on prostate cancer cells, especially in the presence of androgen.

a(CHEBI:androgen) -> (p(HGNC:CLU) -| bp(GO:"response to oxidative stress"))

cat(p(HGNC:PRDX6)) -| a(CHEBI:"hydrogen peroxide")

Finally, depletion of human Srx by RNA interference suggested that Srx is largely responsible for reduction of the Cys-SO2H of Prx in A549 human cells.

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

These data indicate that in BMMC, Lyn contributes to SCF-induced phosphorylation of Kit, as well as phosphorylation of Jnks and Stat3.

kin(p(HGNC:LYN)) -> tscript(p(HGNC:STAT3))

Endothelial cells expressing human HO-1 via retroviral transfer exhibit approximately 7-fold higher levels of PGT RNA and equivalently elevated uptake of [(3)H]PGE(2).

tport(p(HGNC:SLCO2A1)) -> a(SCHEM:Dinoprostone)

table 4: gene expressions altered in foxa2 deletion A: genes downregulated in foxa2 deletion

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

The microarray analysis revealed that 8 genes including collagen type 1, alpha2 (COL1A2), insulin-like growth factor binding protein 2 (IGFBP2), integrin, alpha7 (ITGA7), basigin (BSG), quiescin Q6 (QSCN6), superoxide dismutase 3, extracellular (SOD3), nerve growth factor receptor (NGFR), and p53-induced protein (PIG11) exhibited substantial induction (ratio >2.0) after TSA treatment in multiple cell lines.

a(CHEBI:"trichostatin A") -> r(HGNC:QSOX1)

a(CHEBI:"trichostatin A") -> r(HGNC:SOD3)

a(CHEBI:"hydrogen peroxide") -| cat(p(PFH:"HDAC Family"))

H2O2 and CSC decrease HDAC activity and histone deacetylase 2 levels

Surprisingly, CSC (1, 2.5, and 5%) treatments did not cause any appreciable increase in NF-kB transactivation at 24 h in A549 cells. In preliminary studies, treatment of rat type II epithelial (L2) cells with CSC (1, 5, and 10%) for 4 h did not increase NF-kB DNA binding as assessed by electrophoretic mobility gel shift assay (data not shown) suggesting that CSC has no effect on NF-kB activation or transactivation in epithelial cells as revealed by various techniques. We also assessed the translocation of the p65 subunit of NF-?B from the cytoplasm to nucleus using the Cellomics Arrayscan technology. Using this technique, we showed increased nuclear p65 in response to IL-1b treatment (Fig. 7B), whereas CSC did not result in translocation of p65 from the cytoplasm to nucleus (data not shown).

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

Notch activation inhibits proliferation of endothelial cells in a cell-autonomous manner by inhibiting phosphorylation of the retinoblastoma protein (Rb)

p(HGNC:JAG1) => tscript(p(PFH:"NOTCH Family"))

we show that activation of the Notch pathway by the ligand Jagged1 reduces the proliferation of endothelial cells.

complex(p(HGNC:IRS1),p(HGNC:MDM2)) -> bp(MESHPP:"Insulin Resistance")

In summary, we have found the following: (i) beta-arrestin-1 can alter insulin signaling by inhibiting insulin-induced proteasomal degradation of IRS-1; (ii) beta-arrestin-1 decreases the rate of ubiquitination of IRS-1 by competitively binding to endogenous Mdm2, an E3 ligase that can ubiquitinate IRS-1; (iii) dephosphorylation of S412 on beta-arrestin and the amino terminus of beta-arrestin-1 are required for this effect of beta-arrestin on IRS-1 degradation; and (iv) inhibition of beta-arrestin-1 leads to enhanced IRS-1 degradation and accentuated cellular insulin resistance.

Table 1. Genes regulated >2-fold in the Cln5-/- mice (3- and 4.5-month-old) upregulated

Ninjurin1-overexpressing clones exhibited strong growth inhibition due to G1 cell cycle arrest, which is associated with a posttranscriptional increase in p21WAF1/Cip1, a decrease of cyclin-dependent kinase 2 activity and the hypophosphorylation of Rb.

These data suggest that Spred-1 negatively regulates hematopoiesis by suppressing not only SCF-induced but also IL-3-induced ERK activation.

a(SCHEM:Calcium) -> kin(p(PFR:"Camk2 Family"))

We show that histamine synthesis stimulation by depolarization with 30 mM K(+) requires extracellular calcium entry, mostly through N-type channels, and subsequent activation of calcium/calmodulin-dependent protein kinase type II. In vitro, this kinase phosphorylated and activated histidine decarboxylase, the histamine-synthesizing enzyme.

Coexpression of MEF2A and PITX2a or Pitx2c resulted in a strong synergistic activation of the ANF promoter

the activity of lecithin-cholesterol acyltransferase was severely impaired in CBS(-/-) mice.

95387_f_at Sema4b NM_013659 20352 semaphorin 4B

95611_at Lpl NM_008509 16956 lipoprotein lipase

a(SCHEM:Tretinoin) -> r(MGI:2810025M15Rik)

Other 93333_at Tbca NM_009321 21371 tubulin cofactor a

Table 2. Group 1: Genes downregulated by RA at 6 h

Table 3. Group 2: Genes induced by RA at all times

Table 4. Group 3: Genes suppressed by RA

Transcription factor 102380_s_at Hoxd4 NM_010469 15436 HoxD4

Transport 160544_at Fabp5 NM_010634 16592 mal1; Mus musculus Fabpe gene

kin(p(HGNC:PRKCZ)) -> complex(p(HGNC:UBE4B),p(HGNC:FEZ1))

Interaction between E4B and FEZ1 in mammalian cells was enhanced by coexpression of constitutively active PKCzeta.

p(HGNC:NRG1) -> bp(GO:"cell proliferation")

proliferation caused by heregulin-beta1 treatment of T47D cells was inhibited by all-trans retinoic acid and this effect was mediated by HES-1.

tscript(p(HGNC:HES1)) -> (p(HGNC:NRG1) -> bp(GO:"cell proliferation"))

kin(p(HGNC:AKT1)) -> p(HGNC:GSK3A,pmod(P))

kin(p(HGNC:AKT1)) -> tscript(p(HGNC:RELA))

bp(GO:"DNA methylation") -| r(HGNC:HAND1)

Treatment of a cancer cell line with a demethylating agent, 5-aza-2'-deoxycytidine, restored the expression of 13 genes, RASGRF2, ADAM23, NEF3, NKX2-8, HAND1, EGR4, PRG2, FBN2, CDH2, TLL1, NPTX1, NTSR1 and THBD, showing their silencing by methylation of their 5' CGIs.

bp(GO:"DNA methylation") -| r(HGNC:NPTX1)

activation of ERK-MAPK pathway and Sp1 transcription factor play a pivotal role in the induction of TIMP-3 by TGF-beta in chondrocytes

cat(p(HGNC:SIRT1)) -| p(PFH:"Histone H3 Family",pmod(M,K,79))

Gal4-SirT1 expression resulted in the deacetylation of H4-K16 and H3-K9, recruitment of H1 within the promoter vicinity, drastically reduced reporter expression, and loss of H3-K79 methylation, a mark restricting silenced chromatin...recruitment and deacetylation of histone H1,

Ceramide, the hydrolysis product of sphingomyelin, seems to be a key mediator as it mimics mmLDL by inducing activation of the same signaling components

a(SCHEM:"Oxidized Low Density Lipoprotein") -> cat(p(HGNC:SMPD2))

minimally modified LDL (mmLDL) mainly activated components involved in stress response and apoptotic cell death including p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK) as well as neutral and acid sphingomyelinase

Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment

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

In order to investigate the mechanisms of hypoxic regulation of PFKFB4 gene expression, we used dimethyloxalylglycine, which has the ability to mimic effect of hypoxia by significant induction of hypoxia-inducible factor (HIF-1alpha) protein levels.

See table 6: Genes regulated by gefitinib or cetuximab in A431 cells and with fold change of at least 1.5.

PHA-665752 effectively blocked the biological responses to HGF in all assays, with 50% inhibition at 5 to 15 nmol/L concentration and complete inhibition at around 100 nmol/L.

a(SCHEM:"smoke condensate, cigarette (particulate phase)") -> p(RGD:Cxcl1)

The mean CINC-1 concentration was higher in PPexposed animals compared with gas phase-and shamexposed animals (Table 1). Interestingly, gas phaseexposed animals had a lower mean CINC-1 concentration compared with sham animals ( p = .005, Table 1).

path(SDIS:"viral infection") -| r(HGNC:GSN)

TABLE 2. Statistically significant cytoskeleton-, extracellular matrix-, and adhesion-related genes consistently upmodulated (positive fold change) or downmodulated (negative fold change) across late times of infection [in response to CMV infection]

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

Trx facilitates the transcriptional activities of nuclear factor NFkB and the glucocorticoidrecept or via direct associations with their DNA-binding domains (Matthews et al., 1992; Hayashi et al., 1993; Qin et al., 1995; Makino et al., 1999).

kin(p(HGNC:ATM)) -> p(PFH:"PRKAA Family",pmod(P))

Immunoprecipitates of ATM collected from IGF-1-stimulated cells also caused the phosphorylation of the AMPK-alpha subunit in vitro.

complex(p(MGI:Npm1),p(MGI:Cdkn2a)) -| bp(GO:"cell proliferation")

NPM is released from ARF-containing protein complexes, and in vivo S phase progression ensues.

kin(p(HGNC:RAF1)) => p(HGNC:RB1,pmod(P))

Disruption of the Rb-Raf-1 interaction by a nine-amino-acid peptide inhibits Rb phosphorylation, cell proliferation, and vascular endothelial growth factor-mediated capillary tubule formation.

tscript(p(HGNC:KLF6)) -| bp(GO:"cell proliferation")

Functionally, wild-type KLF6 decreased cellular proliferation of HepG2 cells, while patient-derived mutants did not.

31 genes were confirmed to be up- or down-regulated during replicative senescence by semi-quantitative RT-PCR. The overexpressions of several genes including CD36, putative lymphocyte G0/G1 switch gene (G0S2), tumor protein D52-like 1 (TPD52L1), chemokine (C-X-C motif) ligand 6, myxovirus resistant gene 1 (MX1), and the down-regulation of the immunoglobulin superfamily containing leucine-rich repeat (ISLR), neurotrimin, insulin-like growth factor 2 associated protein (IGF2A), and apoptosis-related RNA binding protein (NAPOR3) were newly identified.

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

TNF-? stimulated NF-?B-dependent promoter activity (Fig. 5D), that rottlerin had little effect on TNF-?-induced NF-?B-dependent promoter activity, and that PDTC diminished NF-?B-dependent promoter activity

TNF-alpha induced both phosphorylation and degradation of IKappaB-alpha in A549 cells within several minutes

p(HGNC:ID1) -> bp(GO:"cell proliferation")

ectopic expression of Id1, but not Id2, allowed continued proliferation of immortalized mammary epithelial cells and breast cancer cells. Conversely, downregulation of Id1 impaired proliferation

Stimulation of PKCs in U-251 cells for 30 min with 100 nM PMA, showed an increased phosphorylation of mTOR at ser-2448 by 43+/-10-fold compared with untreated cells. Expression of PKC-etaKR, a kinase dead mutant of PKCeta significantly reduced PMA stimulated ser-2448 phosphorylation of mTOR by 54+/-12%. In U-1242 PKCdeltaNPS, a catalytically active PKC expression increased phosphorylation on ser-2448 of mTOR by 322+/-58% as compared to the empty vector, suggesting that PKCeta activates mTOR.

complex(p(HGNC:YWHAZ),p(HGNC:CTNNB1)) => tscript(p(HGNC:CTNNB1))

14-3-3zeta Interacts with beta-Catenin and Activates beta-Catenin-Dependent Promoters in HEK293T cells and Colon Carcinoma cells.

gtp(p(PFM:"Ras Family")) -> r(MGI:Alkbh3)

Extensive data indicate that oncoproteins, such as oncogenic H-Ras, initiate signal transduction cascades that ultimately lead to the activation of specific transcription factors. We and others have previously demonstrated that Ras activates the inherent transcriptional activation function of the transcription factor nuclear factor kappaB (NF-kappaB). Supportive of the importance of NF-kappaB in transformation, Ras-induced cellular transformation can be suppressed by expression of IkappaBalpha, an inhibitor of NF-kappaB, or by dominant-negative forms of the upstream activator IkappaB kinase (IKK). However, conclusive evidence for a requirement for NF-kappaB subunits in oncogenic transformation has not been reported. Furthermore, there is little understanding of the gene targets controlled by NF-kappaB that might support oncogenic conversion. The data presented here demonstrate that, although both p65 and c-Rel enhance the frequency of Ras-induced cellular transformation, these NF-kappaB subunits are not essential for Ras to transform spontaneously immortalized murine fibroblasts. Microarray analysis identified a set of genes induced by Ras that is dependent on NF-kappaB for their expression and that likely play contributory roles in promoting Ras-induced oncogenic transformation.

gtp(p(PFM:"Ras Family")) -> r(MGI:Col18a1)

gtp(p(PFM:"Ras Family")) -> r(MGI:Crisp1)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Crisp1)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Klf3)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Rnf19b)

tscript(complex(NCM:"Nfkb Complex")) -> r(MGI:Sh3rf1)

kin(p(HGNC:MAPK3)) -> tscript(p(HGNC:ETS1))

cat(p(HGNC:AKR1C1)) -| a(CHEBI:progesterone)

Suppression of ARK1C1 and AKR1C2 by selective small interfering RNAs inhibited production of 20alpha-dihydroprogesterone and was associated with increased progesterone in MCF-10A cells

cat(p(HGNC:AKR1C2)) -| a(CHEBI:progesterone)

cat(p(HGNC:RNF43)) -> bp(GO:"cell growth")

Its exogenous expression conferred a growth-promoting effect in COS7 and NIH3T3 cells, and suppression of its expression by specific short interfering RNAs retarded the growth of colon cancer cells.

The Wnt/Ca(2+)/cGMP pathway mediated by Frizzled-2 was discovered recently. Activation of this pathway leads to increased intracellular concentrations of Ca(2+) and decreased intracellular concentrations of cGMP. On the basis of results from these three analyses, the cGMP-specific phosphodiesterase, PDE6, is demonstrated to be an effector for the Wnt/Ca(2+)/cGMP signalling pathway of development, which is mediated by Frizzled-2.

p(HGNC:SMAD3,pmod(P)) => tscript(p(HGNC:SMAD3))

TGF-beta phosphorylation of Smad2/3, an obligatory step of intracellular TGF-beta signaling, was also suppressed by VEGF. VEGF attenuation of TGF-beta action was also demonstrated in two other endothelial cell lines. In conclusion, VEGF attenuates TGF-beta action in the human endothelial cell, specifically at the level of transcription of PAI-1 gene and Smad2/3 phosphorylation

As a result of alpha4 deletion, multiple proapoptotic genes were transcribed.

p(HGNC:PTK2B,pmod(P,Y)) -> kin(p(PFH:"MAPK Erk1/3 Family"))

Our data show that in a glioma-derived cell line the cytoplasmic tyrosine kinase PYK2 is constitutively associated with HER3 and that stimulation with Heregulin results in PYK2 tyrosine phosphorylation. HER3, but not HER2, mediates the phosphorylation of the C-terminal region of PYK2 to promote a mitogenic response through activation of the MAPK pathway.

leptin decreased CA III expression while insulin increased it which suggests that the decrease in CA III expression observed in obesity in rat adipose tissue may be related to hyperleptinemia.

kin(p(HGNC:SRC)) => p(HGNC:SRC,pmod(P,Y,530))

The chief phosphorylation sites of Src include tyrosine 416 that results in activation from autophosphorylation and tyrosine 527 that results in inhibition from phosphorylation by C-terminal Src kinase

IMPA2 promoter activity in both cell lines is downregulated, in a dose-dependent manner, by lithium

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> r(HGNC:EN1)

Five DNA replication and repair-related genes (FEN1, PCNA, RFC4, TOP2A, and TYMS) were suppressed by LY294002 treatment as detected by real time PCR (Fig. 6C).

kin(p(PFH:"AKT Family")) -> r(HGNC:TYMS)

The expression of active mAKT1 blocked the down-regulation of CKS2, HEC, UBE2C, and ZWINT genes (cell cycle-related, Fig. 7B); of RFC4 and TYMS genes (DNA replication and repair-related, Fig. 7B); and of HMGB2 and HIST1H4C genes (chromatin-related, Fig. 7, B and C) induced by the anti-HER2 antibody.

kin(p(PFH:"AKT Family")) -> r(HGNC:ZWINT)

kin(p(PFM:"Prka Family")) -> p(MGI:Tnni3,pmod(P,S,24))

Within the cardiac isoform's amino-terminal extension, serines are present at residues 23 and 24 (Ser23/Ser24), which serve as substrates for protein kinase A (PKA), which is activated in response to ?-adrenergic stimulation of the heart (3). Several investigations report that PKA-mediated phosphorylation of cTnI results in a reduction in myofilament Ca2+ sensitivity (4), an increase in cross-bridge cycling (5), and increased binding of cTnI to the thin filament. Cardiac TnI is also a substrate for protein kinase C (PKC) phosphorylation at Ser43/Ser45 and Thr144 (position 143 in the human protein) (6). However, the substrate specificity of these sites is not absolute, since PKC can phosphorylate the PKA sites (7-9).

results indicate that BCL-6 negatively regulates proliferation of the monocytic/macrophage lineage by suppressing an autocrine IL-6/STAT3-mediated gene expression program.

tscript(p(MGI:Bcl6)) -| bp(GO:"cell proliferation")

a(SCHEM:"Adenosine triphosphate") -| kin(complex(NCH:"AMP Activated Protein Kinase Complex"))

AMPK is therefore activated by any stress that depletes cellular ATP

p(HGNC:EP300,pmod(P,S,89)) =| cat(p(HGNC:EP300))

Finally, it (AMPK) phosphorylates the ubiquitous co-activator p300 at a specific site (Ser89), reducing its ability to bind to nuclear hormone receptors and thus activate their target genes

kin(complex(NCH:"AMP Activated Protein Kinase Complex")) -| cat(p(HGNC:EP300))

kin(complex(NCH:"AMP Activated Protein Kinase Complex")) -> p(HGNC:EP300,pmod(P,S,89))

kin(complex(NCH:"AMP Activated Protein Kinase Complex")) -| cat(p(HGNC:GYS1))

the mechanism for AMPK activation by stresses involves an upstream kinase... The upstream kinase purified from rat liver is a complex between LKB1, STRAD and MO25 and all three subunits are required for full activity

kin(complex(NCH:"AMP Activated Protein Kinase Complex")) -| cat(p(HGNC:PCK1))

kin(p(MGI:Ntrk1)) -> p(MGI:Rasgrf1,pmod(P))

Previously, we demonstrated a novel interaction between the intracellular domain of the nerve growth factor-regulated TrkA receptor tyrosine kinase and an N-terminal fragment of RasGrf1. We now show that RasGrf1 is phosphorylated and interacts with TrkA, -B, and -C in co-transfection studies.

composite(a(CHEBI:estradiol),complex(NCH:"AP-1 Complex")) -> r(HGNC:AHCYL1)

Table 2. Estrogen-Induced/AP-1-Dependent Genes

composite(a(CHEBI:estradiol),complex(NCH:"AP-1 Complex")) -> r(HGNC:B4GALT1)

composite(a(CHEBI:estradiol),complex(NCH:"AP-1 Complex")) -> r(HGNC:BRCA1)

composite(a(CHEBI:estradiol),complex(NCH:"AP-1 Complex")) -> r(HGNC:PRKAR1A)

composite(a(CHEBI:estradiol),complex(NCH:"AP-1 Complex")) -> r(HGNC:PRSS23)

Their actions have been shown to be mediated by three different receptor subtypes: PAC1-R, which has exclusive affinity for PACAP, and VPAC1-R and VPAC2-R, which have equal affinity for PACAP and VIP.

Collagen synthesis is activated via the angiotensin II type 1 (AT1) receptor. We demonstrate that transforming growth factor-beta1, a major product of stimulated AT1 receptor, does not activate solely collagen synthesis but synergistically the synthesis of hnRNP A1, E1, and K as well.

Reporter gene cell transfection experiments and RNA stability assays show that hnRNPs A1, E1, and K stimulate collagen expression by stabilizing mRNAs We report identification of three mRNA-binding proteins, heterogeneous nuclear ribonucleoprote (hnRNP) A1, E1, and K, as positive effectors of collagen synthesis acting at the post-transcriptional level by interaction with the 3'-untranslated regions (3'-UTRs) of COL1A1, 1A2, and 3A1 mRNAs

Table 4. Gene ontology biological process groupings for differentially expressed genes in FR (food restriction) mice

tscript(p(HGNC:SMAD1)) -| bp(GO:"cell proliferation")

Furthermore, p38(MAPK), ERK1/2, JNK, and Smad1 were phosphorylated by BMP4. Using specific MAPK inhibitors, a dominant negative Smad1 construct, and Smad1 siRNA, we found that the antiproliferative and prodifferentiation effects of BMP4 were Smad1 dependent with JNK also contributing to differentiation.

Ectopic expression of Dkk-3/REIC in HeLa, Hep3B and Huh 7 cells led to suppression of cell growth, which was primarily attributable to induction of cell apoptosis.

a(SCHEM:"Thioctic acid") -> a(CHEBI:glutathione)

LA pretreatment maintains the intracellular level of reduced glutathione

tscript(p(HGNC:PPARD)) -| bp(MESHPP:"Insulin Resistance")

activation of PPARd is associated with an anti-obesity and more insulin sensitive phenotype

tscript(p(HGNC:PPARD)) -| bp(MESHPP:Obesity)

kin(complex(NCH:"AMP Activated Protein Kinase Complex")) -| bp(MESHPP:"Insulin Resistance")

adiponectin and leptin contribute to an insulin-sensitive phenotype via their ability to activate AMP-activated kinase and increase fatty acid oxidation

a(CHEBI:ceramide) -| kin(p(PFH:"AKT Family"))

ceramide, diacylglyceride and long chain acyl-coenzyme A esters can also suppress the insulin signaling pathway, as reported for the ceramide induced inhibition of protein kinase B phosphorylation

p(HGNC:SMAD2,pmod(P)) => tscript(p(HGNC:SMAD2))

Western blotting revealed higher expression of phosphorylated SMAD2 in wt-ACVR2 transfectants versus controls, suggesting cells deficient in ACVR2 had impaired SMAD signaling.

kin(p(HGNC:ACVR2A)) -> tscript(p(HGNC:SMAD2))

a(CHEBI:progesterone) -| path(SDIS:"invasive cancer")

% Boyden chamber invasion assay revealed that PR-transfected MDA-MB231 cells also lost most of their invasive properties after Pg treatment.

Table 1 Rosiglitazone-induced mitochondrial gene expression in ob/ob mouse adipocytes

p(MGI:Csf3) -> bp(GO:"neutrophil differentiation")

G-CSF-induced differentiation was accompanied by up-regulation of genes associated with neutrophil differentiation, including gp91pHOX and matrix metalloproteinase (MMP9; gelatinase b), whereas expression of macrophage scavenger receptor 2 (MSR2), a marker of monocytic differentiation, was down-regulated.39,45 Conversely, M-CSF-induced differentiation was accompanied by up-regulation of MSR2.

cat(p(HGNC:TGFBR2)) -> tscript(p(HGNC:SMAD3))

Furthermore, acute and long-term pretreatment of ECs with thrombin or PAR1 peptide agonist suppressed the TGF-beta-induced serine phosphorylation of Smad2, a critical mediator of TGF-beta signaling. Moreover, activation of PAR1 led to a profound and spread cytosolic clustering formation of Smad2/3 and markedly prevented Smad2/3 nuclear translocation evoked by TGF-beta1.

Tables 2-8 - effects of dihydrotestosterone on gene expression in adipose tissue

a(SCHEM:Stanolone) -> bp(GO:"cell proliferation")

The present results provide global genomic evidence for a stimulation of glycolysis, fatty acids and triacylglycerol production, lipolysis and cell shape reorganization, as well as cell proliferation and differentiation, by DHT.

transcripts involved in adipogenesis, and cell cycle and cell shape organization, such as DDX5, C/EBPalpha, cyclin I, procollagen types I, III, IV, V and VI, SPARC and matrix metalloproteinase 2, were upregulated by DHT.

p(HGNC:KIT,pmod(P,Y,721)) -> kin(p(PFH:"AKT Family"))

Activation of PI3-kinase by c-Kit has been linked to mitogenesis, differentiation, survival, adhesion, secretion and actin cytoskeletal reorganization . In c-Kit, Y721 has been found to directly interact with PI3-kinase [82]. c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo.

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

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

The c-Kit ligand SCF is expressed as a glycosylated transmembrane protein. Binding of SCF to c-Kit results in dimerization of the receptors followed by activation of its intrinsic tyrosine kinase activity

The protein tyrosine phosphatase SHP-1 interacts with Y570 of c-Kit and negatively regulates c-Kit signaling

cat(complex(p(HGNC:ITGA2),p(HGNC:ITGB1))) -> bp(GO:phagocytosis)

Other functions associated with Fc receptor-mediated phagocytosis, such as the activation of NADPH-oxidase, were not affected in Gsn-/- mice [55]. An impairment of complement- opsonized phagocytosis was observed in capG/Gsn double-null mice, providing evidence for distinctive and non-overlapping functions of capG and gelsolin in phagocytic processes [50]. Finally, binding and internalization of collagen beads, a process dependent on a2 b1 integrin [53], was also shown to be affected in Gsn-/- fibroblasts [56].

Recently, a third isoform (gelsolin-3) has been described [9]. Gelsolin-3 is cytoplasmic and is characterized by 11 additional residues at the N-terminus. Gelsolin-3 is expressed in oligodendrocytes and mainly in the brain, lungs and testis [9], but its specific function is still unknown. Gelsolin contains six gelsolin-like (G) domains and was first described as a protein able to bind and sever actin filaments, and to control polymerization of barbed ends. Furthermore, this protein also initiates formation of actin filaments by binding two monomeric actin molecules. Gelsolin activity is regulated by Ca2+, intracellular pH, phosphoinositides and tyrosine phosphorylation. Crystallographic studies of gelsolin complexed with its substrate have been recently performed [10-14]. Results have been reviewed in [15] and will not be discussed here. The other gelsolin superfamily members; villin, advillin, supervillin and flightless, have additional domains beyond the sixfold repeat. Villin has been demonstrated to participate in cytoskeleton remodeling in response to various stimuli in the intestine [16]. Flightless is the only member of gelsolin superfamily that has been shown to be essential for mouse development [17]. Among all of the proteins forming the gelsolin superfamily, adseverin (also named scinderin) is the one that shares the highest degree of homology with gelsolin. Indeed, adseverin shares 60% amino acid homology with gelsolin [18], and displays Ca2+-regulated actin filament severing activity. As compared to gelsolin, adseverin has a more restricted expression. Adseverin was first discovered in platelets, megakaryocytes and chromaffin cells [19]. This protein is present in all secretory cells and is involved in actin cytoskeleton remodeling occurring during exocytosis [19-22]. With flightless [23] and supervillin [24, 25], capG (also named gCap39, Mbh1 or macrophage capping protein) is the only other protein of gelsolin family sharing a nuclear localization [26, 27]. CapG only contains three G domains and can bind and cap actin filaments but cannot sever them [28]. CapG has been demonstrated to play an important role as a mediator of endothelial cell response to mechanical forces [29]. Actin filament remodeling In the absence of Ca2+, gelsolin exists in a globular conformation. Crystal structure analysis has revealed the existence of a C-terminal tail ('latch helix') which is in close contact with the actin binding region of G2 domain. The importance of this latch helix in Ca2+ regulation of gelsolin-actin interactions was first revealed by the demonstration that a lack of 20 residues in the C-terminus tail abrogates the Ca2+ regulation of actin binding [30, 31]. The latch hypothesis suggests that Ca2+ binding to G6 domain induces a first conformational change in the gelsolin structure, releasing tail latch inhibition of G2 binding to actin. G2 binding to actin directs the G1 domain to its actin binding site. In the absence of Ca2+, G4 and G6 domains are close together. Ca2+ opens this structure, and the G6 domain forms new contacts with the G5 domain, releasing the G4 domain, which now can form a Ca2+ binding domain coordinated by actin and G4 itself. The actin binding sites at the N- and C-terminal parts bind to two adjacent actin filaments. Slowly, gelsolin severs the two actin filaments, remaining bound to the newly formed actin + end (barbed end) of one of the two shorter filaments (fig. 1B).

tscript(p(HGNC:SREBF2)) -| tscript(p(HGNC:SMAD3))

Interactions of AGP7, sex-determining region Y protein, actin beta and sterol regulatory element binding protein-2 (SREBP-2) proteins with Smad3 constructs were confirmed by immunoblotting with specific antibodies. Interaction of Smad3 with SREBP-2 was also confirmed by co-immunoprecipitation of myc-Smad3 and Flag-SREBP-2 upon expression in mammalian cells. We found that SREBP-2 inhibited the transcriptional activity of Smad3 in luciferase reporter assays

bp(GO:"macrophage activation") -| r(HGNC:IL1RN)

\"Differential gene expression modulated by the cytoplasmic domain of Fc gamma RIa (CD64) alpha-chain.\" Expression of M-CSF, MIC-1, and LSP1 was greater after stimulation of WT-Fc{gamma}RI relative to the TL-Fc{gamma}RI, while expression of MIP-2 and IL-1Ra were lower after stimulation of WT-Fc{gamma}RI relative to the TL-Fc{gamma}RI (Table II).

cat(p(PFH:"CD64 Family")) -> r(HGNC:GDF15)

a(SCHEM:Hydrocortisone) -> r(HGNC:CXCR4)

Cortisol dose- and time-dependently augmented CXCR4 expression on T lymphocytes

path(SDIS:Diabetes) positiveCorrelation a(SCHEM:"3-Nitrotyrosine")

Moreover, because metformin has protective effects on nondiabetic beta-cells exposed to high glucose or free fatty acid levels, we investigated its direct action on T2D islet cells. Diabetic islets were characterized by reduced insulin content, decreased amount of mature insulin granules, impaired glucose-induced insulin secretion, reduced insulin mRNA expression, and increased apoptosis with enhanced caspase-3 and -8 activity. These alterations were associated with increased oxidative stress, as shown by higher nitrotyrosine concentrations, increased expression of protein kinase C-beta2 and nicotinamide adenine dinucleotide phosphate reduced-oxidase,

a(CHEBI:metformin) -| bp(MESHPP:Apoptosis)

Twenty-four-hour incubation of T2D islets with metformin was associated with increased insulin content, increased number and density of mature insulin granules, improved glucose-induced insulin release, and increased insulin mRNA expression. Moreover, apoptosis was reduced, with concomitant decrease of caspase-3 and -8 activity. These changes were accompanied by reduction or normalization of several markers of oxidative stress. Thus, T2D islets have several functional and survival defects, which can be ameliorated by metformin; the beneficial effects of the drug are mediated, at least in part, by a reduction of oxidative stress.

IL6 induces phosphorylation of STAT3 on Tyr705 and activates STAT3.

TNF-alpha treatment results in a temporary release of IkappaBalpha from the hes1 promoter that correlates with increased histone acetylation and transcriptional activation

tscript(p(MGI:Tbx5)) -| (tscript(p(MGI:"Nkx2-5")) -> r(MGI:Gja5))

Furthermore, co-transfection experiments showed the ability of Nkx2-5 and GATA4 to transactivate the minimal Cx40 promoter while Tbx5 repressed Nkx2-5/GATA4-mediated activation.

cat(p(HGNC:FTH1)) -| a(CHEBI:"reactive oxygen species")

FHC is induced downstream of NF-kappaB and is required to prevent sustained JNK activation and, thereby, apoptosis triggered by TNFalpha. FHC-mediated inhibition of JNK signaling depends on suppressing ROS accumulation and is achieved through iron sequestration.

pharmacological doses of testosterone simultaneously down-regulated the level of OAT protein and up-regulated the expression of arginase II and ODC genes

complex(p(HGNC:ERBB3),p(HGNC:ERBB2)) -> cat(p(HGNC:ERBB3))

Additional genetic and pharmacologic experiments show that this modulation of AR function is mediated by the HER2/ERBB3 pathway, not by EGFR.

This HER2/ERBB3 signal stabilizes AR protein levels and optimizes binding of AR to promoter/enhancer regions of androgen-regulated genes.

IL-6 infusion resulted in muscle atrophy characterized by a preferential loss of myofibrillar protein (-17%). IL-6 induced a decrease in the phosphorylation of ribosomal S6 kinase (-60%) and STAT5 (-33%), whereas that of STAT3 was increased approximately twofold.

A GRK2-specific small interfering RNA effectively reduced GRK2 expression and resulted in a significant increase in histamine-promoted calcium flux.

p(HGNC:VRK1) -> bp(GO:"cell proliferation")

Suppression of VRK1 expression by specific small interfering RNA provokes several defects in proliferation, situating the protein in the regulation of this process.

In contrast to Sox7, exogenous expression of Gata-4 or Gata-6 induced the expression of laminin alpha1 and Hnf1b in undifferentiated F9 and F9H1Sox7 cells without RA/Bt2cAMP treatment (Fig. 5 and 6 ).

tscript(complex(NCM:"AP-1 Complex")) -> r(MGI:Pon2)

PON2 expression was found to be regulated, at least in part, by the transcription factor AP-1, as suggested by decreased JDP2 (AP-1 repressor) protein expression in the nucleus and by decreased PON2 expression in the presence of a Jun N-terminal kinase inhibitor (SP600125)

bp(GO:"response to oxidative stress") -| cat(p(MGI:Ndufs2))

we determined whether the oxidative stress that occurs in response to T. cruzi infection contributes to the catalytic impairment of respiratory complexes and to subsequent mitochondrial dysfunction in murine myocardium. Our data show that oxidative injuries, as determined by the levels of lipid peroxides and protein carbonyls, are incurred in cardiac mitochondria as early as 3 days postinfection and persist throughout the infection and disease. We observed substantial carbonylation of the specific subunits of mitochondrial respiratory complexes in infected murine hearts. Of note is the oxidative modification of NDUFS1, NDUFS2, and NDUFV1, which form the catalytic core of the CI complex; UQCRC1, UQCRC2, and UQCRQ, the subunits of the core subcomplex, and UQCRH and CYC1, which form the cyt c(1) subcomplex of CIII; and a gamma chain that is essential for ATP synthesis by CV complex. The extent of oxidative modifications of the subunits correlated with the catalytic defects of the respiratory complexes in the infected myocardium. Taken together, our data demonstrate that respiratory complexes are oxidatively damaged in response to the stress of T. cruzi infection. These data also suggest involvement of the specific susceptibility of the protein subunits, and not generalized mitochondrial oxidative damage in respiratory chain impairment of chagasic hearts.

P-Rex1 is a guanine-nucleotide exchange factor (GEF) for the small GTPase Rac.

kin(p(HGNC:ROCK1)) -| phos(p(HGNC:PPP1CB))

The gene silencing of p116Rip consistently and significantly increased myosin phosphorylation as well as stress fiber formation in cells.

p(EGID:23164) -| (kin(p(HGNC:ROCK1)) -| phos(p(HGNC:PPP1CB)))

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

Increased expression of the NF-kB target genes GADD45? (De Smaele et al. 2001; Papa et al. 2004) and XIAP (Tang et al. 2001) has been implicated in this process and it appears that NF-kB functions to suppress the TNF-stimulated ROS production that causes sustained JNK activation (Sakon et al. 2003).

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

Wild-type and Jnk1-/- Jnk2-/- (Jnk-/-) fibroblasts....Furthermore, TNF-stimulated NF-kB DNA binding activity was detected in nuclear extracts prepared from wild-type and Jnk-/- fibroblasts, but not from wild-type (N-IkBa) or Jnk-/- (N-IkBa) fibroblasts,

bp(MESHPP:"Liver Regeneration") -> r(MGI:Ctgf)

We performed microarray-based expression profiling on livers 0-40 h post-hepatectomy corresponding to G0, G1, and S phases. # supplemental data table

bp(GO:"response to endoplasmic reticulum stress") -> bp(MESHPP:Apoptosis)

Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate.

ARAP3 causes a Rho GAP-dependent decrease in active RhoA and Rac1 in vivo. ARAP3 stimulated a marked decrease in active RhoA levels in cells.ARAP3 showed GAP activity towards RhoA in vitro (our results) (Krugmann et al., 2002Go), and when overexpressed, inhibited actin stress fibre formation in PAE (Krugmann et al., 2002Go) and NIH3T3 cells

kin(p(HGNC:MAP2K6)) => kin(p(HGNC:PAK7))

PAK4 and PAK5 were similarly activated by MKK6, consistent with a conserved TPY motif in their activation domains.

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

\"Critical regulation of genes for tumor cell migration by AP-1.\" Strikingly, at low levels GFP-aFos, but not GFP-TAM67, caused a change in colony morphology, impairment of directional motility in a monolayer wound healing assay, as well as inhibition of chemotaxis and haptotaxis. Microarray analysis identified a novel set of AP-1 target genes, including the tumor suppressor TSCL-1 and regulators of actin cytoskeletal dynamics, including the gelsolin-like actin capping protein CapG.

p(EGID:313729) -| (p(RGD:Egf) -> kin(p(PFR:"Mapk JNK Family")))
p(RGD:Egf) -> kin(p(PFR:"Mapk JNK Family"))

Gene 33 inhibits EGFR autophosphorylation and specifically blunts epidermal growth factor (EGF)-induced activation and/or phosphorylation of Ras, ERK, JNK, Akt/PKB, and retinoblastoma protein.

Our results demonstrated that levels of Fli-1 protein, but not RNA, were higher in extracts from cells treated with G-CSF.

TABLE 3. Gene Expression Prediction Profile [changed in ischemic cardiomyopathy vs. non-ischemic] upregulated

a(CHEBI:lipopolysaccharide) -> r(MGI:Fcer2a)

a(CHEBI:lipopolysaccharide) -> r(MGI:Nfkb2)

a(CHEBI:lipopolysaccharide) -> r(MGI:Saa1)

Fgr increased Rac GTP loading, and phosphorylation of the Rac GEF Vav2, and bound to a protein complex formed by the Rho inhibitor p190RhoGAP and FAK, increasing p190RhoGAP phosphorylation, in a manner absolutely dependent on membrane localization.

a(SCHEM:Epinephrine) -> path(SDIS:"adipocyte lipolysis")

E2 can indirectly affect - by inducing the lipolytic enzyme hormone-sensitive lipase (31) or by increasing the lipolytic effects of epinephrine (32).

cat(p(HGNC:LPL)) -> path(SDIS:"fatty acid import")

This action happens principally through decreasing activity of lipoprotein lipase (LPL), an enzyme that regulates lipid uptake by adipocytes. Ovariectomy increases LPL and lipid deposition within the adipocyte and administering physiological doses of E2 reverses this deposition (29). Recently, work on a 3T3 adipocyte cell line transfected with estrogen receptor showed that the LPL gene has a negatively controlled estrogen response element (30).

complex(p(HGNC:CDKN2A),p(HGNC:BCL6)) -| tscript(p(HGNC:BCL6))

Either mouse p19(ARF) or human p14(ARF) binds to BCL6 and downregulates BCL6-induced transcriptional repression.ARF-mediated downregulation of the BCL6 activity may account in part for ARF-mediated tumor suppression.

a(SCHEM:"Phosphatidylinositol-3,4,5-trisphosphate") => kin(p(HGNC:AKT3))

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

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

a(SCHEM:Geldanamycin) -> (p(HGNC:EGF) -> kin(p(HGNC:MAPK1)))

the activation of Erk and phospholipase C (PLC)-g observed following stimulation of HeLa cells with a low dose of EGF was accelerated and potentiated following co-treatment with a low dose of GA (Fig 2E).

kin(p(HGNC:MAPK3)) -> kin(p(HGNC:RPS6KA5))

In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38,

p(HGNC:PXN,pmod(P,Y,31)) -> gtp(p(HGNC:RAC1))

We show that EGF stimulation activates the catalytic activity of Brk, which in turn phosphorylates paxillin at Y31 and Y118. These phosphorylation events promote the activation of small GTPase Rac1 via the function of CrkII

tscript(p(MGI:Ep300)) -> tscript(p(PFM:"Tcf/Lef Family"))

It has been shown that the LIM protein FHL2 and the acetyltransferase CBP/p300 individually stimulate beta-catenin transactivating activity

kin(p(MGI:Raf1)) -> kin(p(PFM:"MEK1/2 Family"))

Although activation of RAF and AKT is clearly sufficient to repress p27Kip1 expression, these experiments do not address whether the PI3'-kinase-PDK1-AKT and the RAF-MEK- ERK pathways are required for the repression of p27Kip1 in response to mitogenic stimulation or oncogenic transformation. To address this, we used pharmacological inhibitors of the signaling proteins PI3'-kinase (LY294002), mTor (rapamycin), and MEK (PD98059, U0126, or CI-1040) either alone or in combination with one another. PDGF stimulation of quiescent NIH 3T3 cells leads to activation of both the PI3'-kinase- PDK1-AKT and the RAF-MEK-ERK signaling pathways and repression of p27Kip1 expression (Fig. 3A).

kin(p(MGI:Raf1)) -| bp(GO:"G1/S transition of mitotic cell cycle")

Moreover, AKT was able to bypass RAF-induced G1 cell cycle arrest mediated by CKI-dependent inhibition of cyclin E/cdk2 (64).

gtp(p(MGI:Rhoa)) -| (gtp(p(PFM:"Ras Family")) -> r(MGI:Cdkn1a))
gtp(p(PFM:"Ras Family")) -> r(MGI:Cdkn1a)

Under these circumstances activated RhoA is reported to prevent the expression of the CKI p21Cip1, a major mediator of RAS- or RAF-induced cell cycle arrest in mouse fibroblasts (43).

kin(p(HGNC:ROCK1)) => kin(p(HGNC:LIMK1))

ROCK1 and -2, alternatively, activate LIM domain-containing protein kinase 1 (LIMK1) and 2 (LIMK2), which phosphorylate and inhibit the actin depolymerization factor cofilin (cofilin-P). This increases actin polymerization and results in the stabilization of actin stress fibres27. The phosphatase slingshot dephosphorylates cofilin, which blocks actin polymerization.

Whereas the function of CKIs as tumour suppressors is well characterized in the nucleus, they also seem to function in the cytoplasm,where they regulate cytoskeletal functions. This occurs through the modulation of the Rho signalling pathway. This cytoplasmic function could be oncogenic, as inhibition of the Rho pathway can result in increased migratory capacity. Phosphorylation of p21 on Thr145 by protein kinase B (PKB)/Akt48 or Pim1 inhibits the nuclear localization of p21. In the cytoplasm, p21 can protect the cell from apoptosis, as well as bind and inhibit the Rho kinases ROCK1 and -2 to modulate actin cytoskeleton organization46,47.

tloc(p(HGNC:CDKN1A),GOCCACC:"GO:0005634",GOCCACC:"GO:0005737") -| bp(MESHPP:Apoptosis)

Table 3 Gene expression in normal old cells relative to normal young cells: selection of genes that are differently expressed and that may specifically contribute to aneuploidy, cell cycle regulation, and proliferation upregulated

kin(p(HGNC:PRKCD)) -> tloc(p(HGNC:FGF1),GOCCACC:"GO:0005634",GOCCACC:"GO:0005737")

Fibroblast growth factor-1 (FGF-1), which stimulates cell growth, differentiation, and migration, is capable of crossing cellular membranes to reach the cytosol and the nucleus in cells containing specific FGF receptors. The cell entry process can be monitored by phosphorylation of the translocated FGF-1. We present evidence that phosphorylation of FGF-1 occurs in the nucleus by protein kinase C (PKC)delta. The phosphorylated FGF-1 is subsequently exported to the cytosol

p(HGNC:STXBP3,pmod(P)) -> bp(GO:"cell adhesion")

Thus, protease-activated receptor-1-induced protein kinase Calpha activation and phosphorylation of syntaxin 4 and Munc18c are required for the cell surface expression of P-selectin and the consequent binding of neutrophils to endothelial cells.

bp(GO:"muscle contraction") -| r(RGD:Mmp2)

In a rat tail-suspension experimental model, we show that after fourteen days of non-weight bearing there is increased expression of MMP-2 in the atrophic soleus and gastrocnemius and decreased expression of TIMP-2.

Data presented here demonstrate that epidermal growth factor (EGF) receptor ligands promote the tyrosine phosphorylation of endogenous and adenovirally transduced Srcasm in keratinocytes, and that increased levels of Srcasm activate endogenous SFKs, with a preference for Fyn and Src.

a(CHEBI:"vitamin E") -| (p(EGID:2357) -> a(CHEBI:"leukotriene B4"))
p(EGID:2357) -> a(CHEBI:"leukotriene B4")

Furthermore, whereas LTB4 production by neutrophils from control subjects was concentration dependently inhibited by the lipophilic antioxidant -tocopherol (Figure 3),

kin(p(HGNC:ERBB2)) -> bp(GO:"cell-cell adhesion")

erbB2, the ligand-less member of the epidermal growth factor receptor family, was shown to form a complex with the hemidesmosomal integrin alpha6beta4. These results indicate that stimulation of alpha6beta4 increases E-cadherin-mediated cell-cell adhesion and that this mechanism depends on erbB2 activation.

p(HGNC:NLRC4) -> (p(HGNC:TP53) -> bp(MESHPP:Apoptosis))

A dominant-negative mutant of Ipaf inhibited p53-induced and doxorubicin-induced apoptosis by about 50%.

The accurate killing is assured by a vectorial movement of secretory lysosomes along microtubules and focused secretion within the immunological synapse. Here we present an over view of how these key regulators such as AP-3 adaptor protein, RabGGTase enzyme, Rab27a small GTP binding protein, Lyst and Munc13-4 act in a very orchestrated way to deliver the kiss of the death.

p(HGNC:NF1) -| kin(p(PFH:"MAPK JNK Family"))

Alternatively, Kit signaling may also activate JNK kinase, a MAP kinase activated in response to stress [35]. NF1, a GTPase activating protein, is considered to be involved in modulating Ras activation through Kit signaling [36]. NF1 deficiency that occurs in cases of neurofibromatosis may induce an increase in MAP kinase activity. Pathways with JAK/STAT or with Src family members may be involved in Kit signaling [33] (fig. 1). Some studies showed the association of JAK2 with Kit and also its activation by Kit signaling [37]. Other reports also indicated the increased activity of Lyn, a Src family member, by Kit signaling [38].

p(PFH:"AKT Family",pmod(P,Y)) -| bp(MESHPP:Apoptosis)

Binding of dimerized KitL induces the dimerization of Kit [32]. This leads to the autophosphorylation of Kit on tyrosine and its association with substrates of various kinds. The phophatidylinositol-3-kinase (PI3K)/Akt system is one of the major pathways [33] (fig. 1). PI3K is composed of an 85-kDa regulatory subunit and a 110-kDa catalytic subunit. The 85-kDa regulatory subunit is associated with activated Kit through an SH2 domain, and then is phosphorylated on tyrosine. The 110-kDa catalytic subunit of the activated PI3K produces phosphatidylinositol-3,4-bisphosphate, which in turn is used for phosphorylation of Akt, a serine-threonine kinase. The activated Akt is involved in the inhibition of apoptosis of cells whose survival depends on Kit signaling. A tyrosine kinase inhibitor, imatinib mesylate blocks not only autophosphorylation of Kit but also phosphorylation of Akt [34]. Induction of apoptosis in Kit signaling-dependent cells by imatinib mesylate may be mediated through the inhibition of Akt activity.

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

p(HGNC:KIT,pmod(P,Y)) => kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

In human mast cell leukemia cell line, HMC-1, Kit was const phosphorylated on tyrosine, activated and then could associate with PI3K without addition of KitL.

EDNRB activation enhances the effects of RET signaling on the proliferation of uncommitted ENS neurons but inhibits RET-mediated chemoattractive effects [19].

cat(p(HGNC:EDNRB)) -| a(SCHEM:"cyclic AMP")

EDNRB reduces cyclic AMP (cAMP) production via Gai, thus leading to protein kinase A (PKA) inhibition. Since chemical PKA blockade mimics the effects exerted by ET-3 on ENS progenitors, it is likely that the RET-EDNRB interaction is mediated by PKA (fig. 1) [19]. This is supported by the finding that serine 686 in the juxtamembrane domain of RET is phosphorylated by PKA, thereby enhancing RET-mediated lamellipodia formation [20].

GDNF signaling needs heparan sulphate glycosaminoglycans, such as syndecans and glypicans, probably to ensure local concentration of GDNF [26]. GDNF is able to trigger intracellular signaling events that are mediated by GFR-a but not by RET [27]. Stimulated GFR-a can trigger c-Src activation; in turn, c-Src induces phosphorylation of Met, the tyrosine kinase receptor of hepatocyte growth factor (HGF) [28]. Thus, Met may contribute to RET-independent GDNF signaling (fig. 2).

gtp(p(PFH:"RAS Family")) -> tscript(complex(NCH:"Nfkb Complex"))

RET stimulation triggers many other signaling intermediates, including CREB [42], p38MAPK [42], NFkB [43], ERK5 (BMK1) [44], phosphoinositide-dependent kinase 1 (PDK1) 45, cyclin-dependent kinase 5 (CDK5) [46] and PKC isoforms [47 48] (fig. 3). Although the mechanism of activation of these pathways remains to be elucidated, Y1062 is important for most of them. In particular, Ras/ERK- and PI3K-triggering by Y1062 is essential for full activation of CREB and NFkB [42]. A novel RET interactor designated Grap-2 has been found to negatively regulate NFkB activation [43].

p(HGNC:SPRY4) -| gtp(p(PFH:"RAS Family"))

We previously showed that TESK1 interacts with Sprouty-4 (referred to as Spry4), an inhibitor of growth factor-induced Ras/MAP (mitogen-activated protein) kinase signalling, but the functional role of this interaction has remained unknown.

We and others have shown that ER stress can induce intracellular lipid accumulation through the activation of the sterol responsive element binding proteins (SREBPs) and initiate programmed cell death by activation of caspases

while seven chemokines (CCL6, CCL8, CCL12, CCL22, CXCL9, CXCL12, and CXCL13) were increased only after a second allergen exposure.

Binding of (pro)renin to the receptor mediates (pro)renin cellular effects by activating MAP kinases ERK1/2.

p(HGNC:SREBF2,pmod(P,S,432)) => tscript(p(HGNC:SREBF2))

insulin also stimulates the transcriptional activity of nSREB2 and nSREB1A through a mitogen activated protein kinase pathway. The ser117 residue has been identified as the major phosphorylation site for MAPK in SREB1A. Ser432 and Ser455 are described as the MAPK phosphorylation sites in viro and in vivo in SREBP2. These phosphorylations do not modify DNA binding but enhance SREBP2 transactivation capacity. A role for MAPK in the modification of SREB1C transcriptional activity remains controversial. Although the ser117 target of MAPK in SREBP1A is also present in the SREBP1C isoform, the use of inhibitors of teh MAPK pathway in cultured hepatocytes do not antagonize the effect of insulin on SREBP1C target genes, suggesting that SREBP1C is not phosphorylated by MAPK in hepatocytes. We have shown that PKB is able to phosphorylate purified nSREBP1C in vitro. Cotransfection experiments in cultured hepatocytes indicate that phosphorylation by insulin and PKB stimulates the transcriptional activity of nuclear SREBP1C

kin(complex(NCM:"p85/p110 PI3Kinase Complex")) -| r(MGI:Saa3)

complex(p(HGNC:FKBP5),p(PFH:"HSP90 Family")) -| tscript(p(HGNC:NR3C1))

The Inhibitory Activity of FKBP51 Requires Interaction with Hsp90

dynamitin, which disrupts the transport complex and reduces receptor activity;

kin(p(HGNC:ABL1)) => p(EGID:5424,pmod(P,Y,15))

We show that Abi promotes Abl-mediated phosphorylation of Cdc2 at tyrosine 15 and inactivation of Cdc2 kinase activity.

kin(p(MGI:Src)) -> p(MGI:Crkl,pmod(P,Y,251))

kin(p(MGI:Src)) -> p(MGI:Anxa2,pmod(P,Y,238))

To investigate this, we used the immunoaffinity profiling approach to identify phosphotyrosine sites in NIH/3T3 cells expressing consitutively active c-Src Y527F tyrosine kinase (Fig 2a). (159 statements)

kin(p(MGI:Src)) -> p(MGI:Cdc42bpb,pmod(P,Y,954))

kin(p(MGI:Src)) -> p(MGI:Ctnnd1,pmod(P,Y,221))

kin(p(MGI:Src)) -> p(MGI:D8Ertd82e,pmod(P,Y,437))

kin(p(MGI:Src)) -> p(MGI:Dok1,pmod(P,Y,361))

kin(p(MGI:Src)) -> p(MGI:Dok1,pmod(P,Y,408))

kin(p(MGI:Src)) -> p(MGI:Eps8,pmod(P,Y,490))

kin(p(MGI:Src)) -> p(MGI:Mgrn1,pmod(P,Y,394))

kin(p(MGI:Src)) -> p(MGI:Pcdh1,pmod(P,Y,79))

kin(p(MGI:Src)) -> p(MGI:Phldb2,pmod(P,Y,130))

kin(p(MGI:Src)) -> p(MGI:Ptpn11,pmod(P,Y,62))

kin(p(MGI:Src)) -> p(MGI:Rab7,pmod(P,Y,183))

kin(p(MGI:Src)) -> p(MGI:Scarf2,pmod(P,Y,615))

kin(p(MGI:Src)) -> p(MGI:Skap2,pmod(P,Y,260))

kin(p(MGI:Src)) -> p(MGI:Tjp1,pmod(P,Y,1164))

kin(p(MGI:Src)) -> p(MGI:Tjp1,pmod(P,Y,1177))

kin(p(MGI:Src)) -> p(MGI:Tkt,pmod(P,Y,275))

kin(p(MGI:Src)) -> p(MGI:Twf2,pmod(P,Y,309))

kin(p(HGNC:PRKDC)) -| cat(p(HGNC:PARP1))

kin(p(HGNC:PRKDC)) -> tscript(p(HGNC:SRF))

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

Transfection results showed that overexpression of ERRs inhibited cell proliferation

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

kin(p(HGNC:PTK2)) => p(HGNC:PTK2,pmod(P,Y,397))

CrkII overexpression enhanced the autophosphorylation of FAK at Tyr-397 and tyrosine phosphorylation of p130(Cas) (Crk-associated substrate, Cas) upon stimulation of integrin by fibronectin.

DCs inducing levels of PU.1 inhibited MafB expression in monocytes, which appeared to be required for DC specification, since constitutive MafB expression inhibited DC differentiation. Consistent with this, PU.1 directly bound to MafB, inhibited its transcriptional activity in macrophages, and repressed its ability to induce macrophage differentiation

path(SDIS:"bacterial infection") -> r(HGNC:PTGS2)

Activation of the inducible form of cyclooxygenase, COX-2, and of the interleukins IL-1, IL-6, and IL-8, as well as of the NF-kappaB pathway, was observed preferentially in cells in contact with bacterial supernatant.

path(SDIS:"bacterial infection") -> r(HGNC:JUN)

Among others, Fos, Jun, and EGR-1 were upregulated by the bacterial supernatant and by live bacteria

path(SDIS:"bacterial infection") -> r(HGNC:JUNB)

Early infection was characterized by an upregulation of anti-apoptotic genes and a downregulation of pro-apoptotic genes. This correlated with a necrotic, rather than apoptotic cell death.

path(SDIS:"bacterial infection") -> r(HGNC:KLF6)

path(SDIS:"bacterial infection") -> r(HGNC:MYC)

path(SDIS:"bacterial infection") -> r(HGNC:PIM1)

path(SDIS:"bacterial infection") -> r(HGNC:YARS)

bp(GO:"response to endoplasmic reticulum stress") -> tscript(p(MGI:Atf6))

% ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress.

bp(GO:"response to endoplasmic reticulum stress") -> tscript(p(MGI:Xbp1))

a(CHEBI:"reactive oxygen species") -> r(MGI:Ccl2)
cat(complex(NCM:"NADPH Oxidase Complex")) -> (a(CHEBI:"reactive oxygen species") -> r(MGI:Ccl2))

Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis.

a(CHEBI:"reactive oxygen species") -| r(MGI:Adipoq)

The mRNA expression levels of adiponectin and PPARg were diminished by incubation with H2O2 (Figure 6A) in a dose-dependent manner. In contrast, ROS increased the mRNA expression levels of PAI-1, IL-6, and monocyte chemotactic protein-1 (MCP-1) in 3T3-L1 adipocytes

T cells in peripheral airways of COPD patients show increased expression of CXCR3, a receptor activated by interferon-{gamma} inducible protein of 10 kDa (IP-10; CXCL10), monokine induced by interferon-{gamma} (Mig; CXCL9), and interferon-inducible T cell-{alpha} chemoattractant (I-TAC; CXCL11). All three cytokines activate CXCR3, although CXCL11 has the highest affinity.

Apoptosis signal-regulating kinase-1 (MAP3K5) is held in an inactive conformation by thioredoxin and when oxidized by ROS, this triggers the apoptotic pathway.

a(CHEBI:"reactive oxygen species") -| r(MGI:Pon1)

PON1 expression is downregulated by oxidative stress. In contrast, more recent studies have shown that PON2 expression is upregulated in response to oxidative stress-inducing agents

bp(GO:"response to hypoxia") -> tscript(p(HGNC:TP53))

During hypoxia, Bnip3L is highly induced in wild-type p53-expressing cells, in part due to increased recruitment of p53 and CBP to Bnip3L.

cat(p(PFH:"HSP90 Family")) -> tscript(complex(NCH:"Nfkb Complex"))

Stress-induced transient insolubilization of the IkappaB kinase complex following its dissociation from Hsp90 represents a novel mechanism by which the activation of the stress response inhibits the NF-kappaB signaling pathway in response to proinflammatory stimuli.

TSC1 inhibits Rac1, and TSC2 blocks this activity of TSC1.

complex(p(MGI:Tsc1),p(MGI:Tsc2)) -| (p(MGI:Tsc1) -| gtp(p(MGI:Rac1)))

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

Activation of FGF receptors can activate multiple signal transduction pathways including the phospholipase Cgamma, phosphatidyl inositol 3-kinase, mitogen-activated protein kinase and signal transducers and activators of transcription (STAT) pathways

Pharmacological intervention to inhibit phosphorylation of Foxa2 may be an effective treatment for type 2 diabetes.

gtp(p(PFH:"RAS Family")) -> bp(GO:"DNA methylation")

We tested the hypothesis that up-regulation of DNA methyltransferase 1 (DNMT1) will lead to methylation and silencing of uPA and inhibition of the invasiveness of metastatic breast cancer cells. Since RAS was previously shown to up-regulate DNA methylation, we examined the effects of ectopic expression of constitutively active RAS on methylation and expression of uPA.

Table II. Changes in expression in liver determined by QRT-PCR after treatment for 2 weeks with different known carcinogens and non-carcinogens

INTERPRETED FROM TEXT: Genes downregulated by stable sphingosine 1-phosphate knockdown in an angiosarcoma cell line using Affymetrix Human Genome U133A GeneChips.

tscript(p(HGNC:SMAD3)) -> complex(p(HGNC:CREBBP),p(HGNC:SOX9))

Interestingly, the association between Sox9 and CBP/p300 was increased by Smad3 overexpression and was suppressed by si-Smad3

complex(p(MGI:Lum),p(MGI:Fasl)) => cat(p(MGI:Fas))

The data suggest that lumican binds FasL and facilitates induction of Fas.

RT-PCR at d 0 and 28. At d 28, SLC19A3 expression had decreased to 33% of d 0 (P < 0.02 by two-tailed, paired t test). Expression of MCCA, PCCA, PC, ACCA, ACCB, HCS, biotinidase, and SMVT decreased to approximately 80% of d 0 (P < 0.05).

a(CHEBI:"hyaluronic acid") -> bp(GO:"cellular extravasation")

The extracellular matrix glycosaminoglycan hyaluronan (HA)1 is a large polymer of N-acetyl-D-glucosamine and D-glucuronic acid (molecular mass 105-107 Da) which plays an important role in maintaining tissue integrity as well as facilitating the migration of cells during inflammation, wound repair, and embryonic development (1, 2).

p(MGI:Slc3a2) -> (cat(p(MGI:Itgb1)) -> kin(p(MGI:Ptk2)))

beta1 integrins play an important role in cell proliferation and in some cancers and we report here that CD98hc enhances beta1 activation of signaling pathways such as FAK, Rac and Akt

Differential inhibition of signaling pathways suggested that FGF-1 stimulates apoE synthesis via the phosphoinositide 3-OH kinase for PI3K/Akt pathway

kin(complex(NCR:"p85/p110 PI3Kinase Complex")) -> r(RGD:Apoe)

TGF-beta suppression of the Phase II genes correlated with a decrease in cellular glutathione and an increase in cellular reactive oxygen species

cat(p(HGNC:HRH1)) -> cat(p(EGID:115557))

Here we report that p63RhoGEF, a recently identified RhoA-specific guanine nucleotide exchange factor, enhances the Rho-dependent gene transcription induced by agonist-stimulated G(q/11)-coupled receptors (M3-cholinoceptor, histamine H1 receptor) or GTPase-deficient mutants of G alpha(q) and G alpha11.

consequence of an intracellular signal triggered by interleukin-4 deprivation. Growth factor deprivation in turn induces PP1alpha phosphatase activation

phos(p(MGI:Ppp1ca)) -> bp(MESHPP:Apoptosis)

translocation of Bad from rafts to mitochondria, which correlates with apoptosis

tloc(p(MGI:Casp3),GOCCACC:"GO:0005737",GOCCACC:"GO:0005886") -> bp(MESHPP:Apoptosis)

tloc(p(MGI:Casp9),GOCCACC:"GO:0005737",GOCCACC:"GO:0005886") -> bp(MESHPP:Apoptosis)

Examples of genes whose expression was increased or decreased by E2 are provided in Tables 3 and 4, respectively. TABLE 3. Examples of genes up-regulated by E2

Table 5. genes upregulated by estrogen in MCF-7 cells

Table 6. genes downregulated by estrogen in MCF-7 cells

a(SCHEM:"8-Isoprostane") -> kin(p(PFH:"MAPK JNK Family"))

Signal transduction pathway inhibitors (SB203580, curcumin, and PD98059) implicated p38 and JNK

cat(p(HGNC:TBXA2R)) -> kin(p(PFH:"MAPK JNK Family"))

complex(p(MGI:S100a8),p(MGI:S100a9),a(CHEBI:"arachidonic acid")) -> cat(complex(NCM:"NADPH Oxidase Complex"))

Moreover, S100A8/A9 transferred the cofactor arachidonic acid to NADPH oxidase as shown by the impotence of a mutant S100A8/A9 complex unable to bind arachidonic acid to enhance NADPH oxidase activity.

p(MGI:Map2k3) -> (p(PFM:"Ifna Family") -> kin(p(MGI:Mapk14)))
p(PFM:"Ifna Family") -> kin(p(MGI:Mapk14))

IFN-dependent activation of the downstream effectors of p38, MAPKAPK-2 and MAPKAPK-3, is not detectable in cells lacking Mkk3 and Mkk6

p(MGI:Map2k3) -> (p(PFM:"Ifna Family") -> kin(p(MGI:Mapkapk2)))
p(PFM:"Ifna Family") -> kin(p(MGI:Mapkapk2))

p(MGI:Map2k6) -> (p(PFM:"Ifna Family") -> kin(p(MGI:Mapkapk2)))

p(MGI:Map2k3) -> (p(PFM:"Ifna Family") -> r(MGI:Irf9))

IFN-dependent induction of two genes known to be of importance in the generation of IFN responses, Isg15 and Irf-9, was diminished in the absence of Mkk3 and Mkk6.

p(PFM:"Ifna Family") -> kin(p(MGI:Map2k6))

IFNalpha- and IFNbeta-dependent transcription via either interferon-stimulated response element or IFNgamma activated site elements was defective in MKK3 -/-/MKK6 -/- MEFs

complex(p(HGNC:IHH),p(HGNC:PTCH1)) -> tscript(p(HGNC:GLI1))

Sonic hedgehog (SHH), Desert hedgehog (DHH) and Indian hedgehog (IHH) bind to Patched family receptors (PTCH1 and PTCH2) to transduce signals to GLI1, GLI2 and GLI3. GLI family transcription factors then activate transcription of Hedgehog target genes, such as FOXE1 and FOXM1 encoding Forkhead-box transcription factors.

complex(p(HGNC:SHH),p(HGNC:PTCH1)) -> tscript(p(HGNC:GLI2))

complex(p(HGNC:SHH),p(HGNC:PTCH2)) -> tscript(p(HGNC:GLI1))

p(MGI:Tgfb1) -> bp(GO:"actin filament polymerization")

TGF-beta1 induced rapid actin polymerization into stress fibers and concomitantly activated RhoA and RhoB small GTPases.

cat(p(HGNC:BMP2)) -> complex(p(HGNC:ITGAV),p(HGNC:ITGB3))

Human osteoblasts (HOBs) express alphabeta1, alphavbeta3, alphavbeta5, alphavbeta6, and alphavbeta8 integrins at focal adhesion sites. BMP-2 increases the levels of these integrins on osteoblast surface

A fraction of growth factors showed a steady increase in the mRNA expression reaching between fourfold and eightfold 30 days after castration, including amphiregulin (P < 0.005) and epiregulin (P < 0.001).

Although both IFN-beta and IFN-gamma strongly enhance HLA-G1 and HLA-G5 expression by monocytes in vitro, IFN-beta leads to a stronger relative upregulation of HLA-G compared to classical MHC class I molecules than stimulation with IFN-gamma.

bp(GO:"myoblast differentiation") -> p(MGI:Socs3)
SOCS-3 mRNA levels and SOCS-3 transcriptional activity increase during myoblast differentiation.
cat(p(HGNC:GRN)) -> bp(GO:"cell proliferation")
GEP can substitute for estradiol in stimulating DNA synthesis in breast cancer cells, rendering them estrogen independent and tamoxifen resistant
bp(GO:"inflammatory response") -> r(HGNC:GRN)
The granulins are emerging as multifunctional regulators of cell growth, development, wound repair and transcription. In normal tissues full-length granulin and individual granulins mediate the wound response and coordinate host defense and wound repair (11,12). High levels of GEP expression are found in several human cancers and its involvement in breast cancer has
complex(a(CHEBI:"hyaluronic acid"),p(HGNC:CD44)) -> gtp(p(HGNC:CDC42))
In particular, we demonstrated that the addition of HA to CD44-containing SK-OV-3.ipl cells caused almost a 3-fold increase in the binding of [35S]GTP{gamma}S to Cdc42 compared with the amount of binding present in untreated SK-OV-3.ipl cells.
a(CHEBI:"hyaluronic acid") => complex(p(HGNC:CD44),p(HGNC:IQGAP1))
Ovarian cancer cells express CD44 isoforms that cause very strong cell adhesion to HA-enriched peritoneal mesothelium. The binding of HA to CD44 isoforms triggers direct \"cross-talk\" between two different tyrosine kinase (e.g. p185HER2 tyrosine kinase (5) and c-Src kinase (6))-linked signaling pathways (cell growth versus cell migration, respectively) in ovarian tumor cells. Our results indicate that HA treatment caused the recruitment of a significant amount of IQGAP1 (Fig. 1C, panel a, lane 2) into the CD44 complex (panel c, lane 2).
a(SCHEM:"LY 294002") -| kin(p(HGNC:PIM1))
kin(p(HGNC:SRC)) -> p(HGNC:PLCG1,pmod(P,Y))
Adhesion to fibronectin induced PLC-gamma1 tyrosine phosphorylation that was inhibited by a Src-kinase inhibitor
kin(p(HGNC:MAPK1)) => p(HGNC:NFATC4,pmod(P,S,676))
kin(p(PFH:"MAPK JNK Family")) -> p(HGNC:RARA,pmod(P,S,445))
Analysis of RARalpha mutants and phosphopeptide mapping revealed that RARalpha residues Thr181, Ser445, and Ser461 are phosphorylated by JNK.
kin(p(PFH:"MAPK JNK Family")) -> p(HGNC:RARA,pmod(P,T,181))
kin(p(PFH:"PRKA Family")) -> (p(HGNC:PAWR) -> bp(MESHPP:Apoptosis))
Elevated protein kinase A (PKA) activity noted in cancer cells activated the apoptotic function of ectopic Par-4 or its SAC (selective for apoptosis induction in cancer cells) domain, which induces apoptosis selectively in cancer cells and not in normal or immortalized cells. PKA preferentially phosphorylated Par-4 at the T155 residue within the SAC domain in cancer cells
a(CHEBI:galactosylceramide) -| bp(MESHPP:Apoptosis)
Ceramide is an important apoptosis activator, whereas galactosylcerebroside functions as an inhibitor.
cat(p(HGNC:GALC)) -| bp(GO:"cell proliferation")
The resulting accumulation of galactosylcerebroside promotes a reduction of cellular adhesion and inhibits apoptosis, leading to increased cellular growth, migration and prolonged cell survival
galactocerebrosidase gene. Galactocerebrosidase is the enzyme responsible for degrading galactosylcerebroside to ceramide.
As single agents, FAS blocker C75 and Taxol induced a significant stimulation of the proliferation and cell survival mitogen-activated protein kinase extracellular signal-regulated kinase (ERK1/ERK2 MAPK) activity, whereas, in combination, they interfered with ERK1/ERK2 activation
a(CHEBI:paclitaxel) -> kin(p(HGNC:MAPK1))
kin(p(HGNC:MAPK14)) -> p(HGNC:TP53,pmod(P,S,46))
Co-exposure to C75 and Taxol induced a remarkable nuclear accumulation of activated p38 mitogen-activated protein kinase (p38 MAPK), which was accompanied by a synergistic nuclear accumulation of the p53 tumor-suppressor protein that was phosphorylated at Ser46, a p38 MAPK-regulated pro-apoptotic modification of p53
a(CHEBI:paclitaxel) -> bp(MESHPP:Apoptosis)
a(SCHEM:C75) -> (a(CHEBI:paclitaxel) -> bp(MESHPP:Apoptosis))
We examined the ability of C75, a synthetic slow-binding inhibitor of FAS activity, to modulate the cytotoxic activity of the microtubule-interfering agent Taxol (paclitaxel) in SK-Br3, MDA-MB-231, MCF-7 and multidrug-resistant MDR-1 (P-Glycoprotein)-overexpressing MCF-7/AdrR breast cancer cells.Because the nature of the cytotoxic interactions was definitely schedule-dependent in MCF-7 cells, we next evaluated the effects of C75 on Taxol-induced apoptosis as well as Taxol-activated cell death and cell survival-signaling pathways in this breast cancer cell model. An ELISA for histone-associated DNA fragments demonstrated that C75 and Taxol co-exposure caused a synergistic enhancement of apoptotic cell death, whereas C75 pre-treatment did not enhance the apoptosis-inducing activity of Taxol
p(HGNC:CDKN1B) -| bp(GO:"G1/S transition of mitotic cell cycle")
Adenovirus expressing the constitutively active FKHRL1... FKHRL1 overexpression in cultured VSMCs increased p27 expression, leading to G1 phase cell-cycle arrest and increased apoptosis.
kin(p(PFH:"MAPK JNK Family")) -> p(HGNC:SMAD2,pmod(P))
c-Jun NH(2)-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence (phosphorylation increases formation of SMAD234 complex)
kin(p(PFH:"MAPK JNK Family")) -> tscript(p(HGNC:SMAD2))
kin(p(HGNC:MAPK8)) -> p(HGNC:SMAD2,pmod(P))
TSP1 expression was inversely correlated with blood vessel density
Ang II-stimulated StAR transcription in H295R cells is dependent upon both influx of external Ca2+ and tyrosine kinase signaling and is enhanced by protein kinase C and mitogen-activated protein kinase (ERK1/2) activation. In particular, Janus tyrosine kinase-2 (Jak2) activation was increased with Ang-II treatment of H295R cells
In 1986 we postulated that this disorder might be due to mutations in P450 oxidoreductase (POR), the flavoprotein that donates electron to these and all other microsomal P450 enzymes,
cat(p(HGNC:POR)) -> cat(p(HGNC:CYP2C19))
complex(p(HGNC:INPPL1),p(HGNC:BCAR1)) -> bp(GO:"cell adhesion")
SHIP2 associates with p130Cas and filamin, regulators of cell adhesion/migration and cytoskeleton, influencing cell adhesion/spreading.
kin(p(HGNC:SRC)) -> p(HGNC:INPPL1,pmod(P,Y))
p(PFH:"COL1 Family") -> (kin(p(HGNC:SRC)) -> p(HGNC:INPPL1,pmod(P,Y)))
Type I collagen specifically induces Src-mediated tyrosine phosphorylation of SHIP2.
tscript(p(HGNC:FOXO3)) -> bp(MESHPP:Apoptosis)
Forkhead family members FOXO1, FOXO3a, and FOXO4 are multifunctional transcription factors, which regulate transcription of a number of genes that play critical roles in inducing either cell cycle arrest or apoptosis. Activation of each member of this family in transformed and nontransformed cells results in up-regulation of the cyclin-dependent kinase inhibitor p27KIP1 and/or down-regulation of D-type cyclins, thereby arresting cells at G1
we found that CTCF plays a major role in IRAK2 transcription. The presence of the CTCF protein in human IRAK2 promoter was confirmed by chromatin immunoprecipitation assay. In all cell lines analyzed, including cells of lung, renal, monocytic and T-cell origin, the IRAK2 luciferase reporter construct, containing an intact CTCF-binding site, showed strong promoter activity.
from full text - In AngII-stimulated, control siRNA-transfected cells, ERK1/2 activation reached maximal levels (typically, 20- to 30-fold over basal) rapidly and remained stable for up to 10 min, decreasing very slowly (Fig. 3).
a(SCHEM:"LY 294002") -| (p(HGNC:BCAR3) -> gtp(p(PFH:"RAC Family")))
p(HGNC:BCAR3) -> gtp(p(PFH:"RAC Family"))
Treatment with 10 Ã‚Âµmol/L LY294002 inhibited both AND-34-mediated Rac activation and Akt Ser473 phosphorylation in MCF-7 cells (Fig. 3A). # AND-34 = BCAR3
kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> (p(HGNC:BCAR3) -> gtp(p(PFH:"RAC Family")))
Motoneurons are important for regulating the function and properties of skeletal muscle. In the present study high-density oligonucleotide arrays have been used to compare gene expression in innervated and six-days denervated NMRI mouse skeletal muscle. To avoid looking at genes mainly participating in the process of atrophy, both hind-limb muscles (atrophic after denervation) and hemidiaphragm muscle (transiently hypertrophic after denervation) were used. Only genes previously not known to respond to denervation and with potential roles in DNA/RNA interactions/transcription and/or cellular communication/signalling are presented. Data for additional genes are provided as supplementary material. Thirty-two genes, up-regulated by a factor of two or down-regulated to the same extent after denervation, are presented. These include genes that may act through chromatin remodelling and/or as transcription factors/regulators (Cdkn1a, Cdr2, Hrmt1l2, Idb2, Myc/c-myc, L-myc1, Rb1, Sap30 and Tgif), genes possibly involved in the regulation of muscle membrane properties and/or excitation-contraction coupling (Cacng1, Camk2d, Hrmt1l2, Kcnj12, Kcna7 and Rrad) and genes potentially involved in neuromuscular interactions and/or receptor signalling (Acvr2b, Adam19, D0H4S114, Kai1, Maged1, Mt2, Prkcabp, Ptp4a3, Ramp1, Rras, Timp1, Vegfa and Zfp145). A set of five genes with altered expression after denervation (Fzd9, Nr4a1, Frat2, Ctgf and Cyr61) indicate that Wnt signalling may be reduced in denervated skeletal muscle.
Using a constitutively active form for Mer (CDMer) or Gas6 as a ligand to stimulate Mer, we found that Mer activation induced a post-receptor signaling cascade involving Src-mediated tyrosine phosphorylation of FAK on Tyr(861), the recruitment of FAK(Tyr861) to the alphavbeta5 integrin, and increased formation of p130(CAS)/CrkII/Dock180 complex to activate Rac1.
In cultured myoblasts, we found that BTG1 stimulates the transcriptional activity of nuclear receptors (T3 and all-trans retinoic acid receptors but not RXRalpha and PPARgamma), c-Jun and myogenic factors (CMD1, Myf5, myogenin).
We also found that HER2/neu engages Akt to regulate WT1 levels since inhibition of Akt reduced WT1 levels.
cat(p(HGNC:LMO4)) -> tscript(p(HGNC:STAT3))
Together, our data reveal a positive regulatory role of LMO4 in IL-6 signaling, possibly by acting as a scaffold for stabilization of the gp130 complex.
Surprisingly, the association of STAT3 with the Cdc25A promoter does not necessarily lead to transcriptional induction because this protein also functions as a transcriptional repressor of the Cdc25A gene. In coimmunoprecipitations and ChIP experiments, Rb was found to associate with STAT3 on DNA and we provide evidence that Rb binds directly to the transcription factor. Thus, we propose that Myc and STAT3 cooperate to induce the expression of Cdc25A and that their transcriptional activity is normally regulated by the Rb tumor suppressor gene.
complex(p(HGNC:RB1),p(HGNC:STAT3)) -| tscript(p(HGNC:STAT3))
p(HGNC:SOCS7) -| (p(HGNC:PRL) -> p(HGNC:STAT3,pmod(P)))
SOCS-7 inhibits PRL- and leptin-induced STAT5 and STAT3 phosphorylation and prevented the nuclear translocation of activated STAT3
We demonstrate that SOCS-7 inhibits prolactin (PRL), growth hormone (GH), or leptin (LEP) signaling mediated through STAT3 and STAT5
p(HGNC:SOCS7) -| (p(HGNC:GH1) -> tscript(p(HGNC:STAT3)))
a(CHEBI:fulvestrant) -> sec(p(RGD:Wfdc1))
ps20 secretion was enhanced by ICI 182,780, but was inhibited by estrogens and tamoxifen
We show here that high-fat feeding, which induces hyperlipidemia and atherogenesis, stimulates the expression of both PGC-1beta and SREBP1c and 1a in liver.
Over expression of Gax is demonstrated to inhibit VSMC growth. We previously reported that Ang II down-regulated Gax expression
tscript(complex(NCH:"AP-1 Complex")) -> r(HGNC:GCLM)
Downstream, MAPK activation leads to increased AP-1 binding, which mediates GCL induction
a(CHEBI:"reactive oxygen species") -> cat(p(HGNC:CYBA))
# GeneRif: These findings suggest a positive feedback mechanism whereby reactive oxygen species (ROS), possibly generated by the NADPH oxidase, lead to elevated levels of p22phox and, thus, sustained ROS generation as is observed in endothelial dysfunction.
a(SCHEM:Tetrahydrogestrinone) -> tscript(p(MGI:Ar))
From full text As can be seen in Fig. 1Go, R1881, DHT and testosterone have relative potencies of 72%, 58% and 7% compared with the 100% value set for THG, the compound showing the highest affinity for AR
p(MGI:Cdkn1b) positiveCorrelation path(MESHD:Hyperglycemia)
Here we show that p27(Kip1) progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2(-/-)) or the long form of the leptin receptor (Lepr(-/-) or db/db). Deletion of the gene encoding p27(Kip1) (Cdkn1b) ameliorated hyperglycemia
See Supplemental Table 1. All genes are downregulated by greater than or equal to 1.5.
See Supplemental Table 2. All genes are downregulated by greater than or equal to 1.5.
Table 5. Genes downregulated posttraining
p(HGNC:CENPJ) -> (p(HGNC:TNF) -> tscript(complex(NCH:"Nfkb Complex")))
When overexpressed, CPAP enhanced NF-kappaB-dependent transcription induced by tumor necrosis factor-alpha (TNFalpha).
RUNX3 repressed the RUNX1 P1 promoter by binding specifically to conserved RUNX sites near the transcription start of the promoter.
p(MGI:Arnt) -> surf(complex(p(MGI:Itgav),p(MGI:Itgb3)))
Furthermore, this defect is associated with decreased cell surface expression of integrin alphavbeta3 and significantly decreased expression of this integrin in focal adhesions.
there is a specific decrease in the expression of the IR-B isoform, as well as both mRNA and protein levels of IR, IRS-1 and IRS-3 being significantly decreased, in epididymal adipose tissue from old compared with adult rats.
a(SCHEM:"Oxidized Low Density Lipoprotein") -| cat(complex(p(HGNC:ITGA2),p(HGNC:ITGB3)))
binding of oxLDL to the scavenger receptor CD36, which is associated with the fibrinogen receptor, alphaIIbbeta3
a(SCHEM:"Oxidized Low Density Lipoprotein") -> a(SCHEM:Calcium)
increase in LDL oxidation enhances platelet activation via 2 independent pathways, 1 signaling via p38(MAPK) phosphorylation and 1 via Ca(2+) mobilization. Between 0% and 15% oxidation, the p38(MAPK) route enhances fibrinogen binding induced by thrombin receptor (PAR-1)-activating peptide (TRAP), and signaling via Ca(2+) is absent. At 30% oxidation, p38(MAPK) signaling increases further and is accompanied by Ca(2+) mobilization and platelet aggregation in the absence of a second agonist
a(SCHEM:"Oxidized Low Density Lipoprotein") -> kin(p(HGNC:MAPK14))
Fig. 2. Pim-1 is post-transcriptionally regulated by stabilization on the mRNA and protein level and degraded by PP2A.The phosphorylation by Pim-1 results in an inactivation of repressors or activation of transcription factors or regulatory proteins, in the stabilization of proteins, which are involved in signaling pathways and in the inactivation of pro-apoptotic proteins.
p(HGNC:CSF3) -> tscript(p(PFH:"STAT5 Family"))
STAT3 is activated by many interleukins, IFNg,c-Kit, SCF, GCSF and EGF (for a review, see Heinrich et al., 2003) similar to STAT5, which is activated in particular by IL-2 and IL-7, Prolactin, G-CSF and GM-CSF.
p(HGNC:PRL) -> tscript(p(PFH:"STAT5 Family"))
Additionally Nkx2.2 recruited a histone deacetylase 1-mSin3A complex to the myelin basic protein promoter. We also found that the transcription factor Sp1 was able to compete off the binding of Nkx2.2 to its consensus binding site in vitro and reversed the repressive effect of Nkx2.2 in vivo.
p(MGI:Il13) -> bp(GO:"inflammatory response")
They also demonstrate that IL-13 is a potent stimulator of inflammation, fibrosis, hyaluronic acid accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure and death in mice with wild-type IL-11Ralpha loci and that these alterations are ameliorated in the absence of IL-11Ralpha.
Table 2. Table of genes deregulated by overexpression of Hoxc8 in C57BL6J MEF cell lines
path(SDIS:"laminar shear stress") -> r(HGNC:HMOX1)
Among genes responding to high shear were HMOX1 (up) and PPARG (down)
cat(p(HGNC:SENP1)) -> (tscript(p(HGNC:EP300)) -> tscript(p(HGNC:JUN)))
tscript(p(HGNC:EP300)) -> tscript(p(HGNC:JUN))
We further show that p300 is essential for SENP1 to enhance c-Jun-dependent transcription because SENP1 can desumoylate the CRD1 domain of p300, thereby releasing the cis-repression of CRD1 on p300.
phos(p(HGNC:PTEN)) -| kin(complex(NCH:"p85/p110 PI3Kinase Complex"))
Recent studies have demonstrated that the tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10), the antagonist of the phosphosphoinositol-3-kinase (PI3K) signaling cascade, is susceptible to H2O2-dependent oxidative inactivation
Finally, treatment of myotubes with PD-98059 or dnMEK1 adenovirus before TNF + INS addition resulted in a derepression of protein synthesis and the association of eIF4G with eIF4E. These findings suggest that TNF abrogates insulin-induced stimulation of protein synthesis in myotubes through a decrease in eIF4F complex assembly independently of S6K1 and 4E-BP1 signaling and dependently on a MEK1-sensitive signaling pathway.
a(SCHEM:"serum insulin") -> tscript(complex(p(MGI:Eif4e),p(MGI:Eif4g1)))
title := \"Acute treatment with TNF-alpha attenuates insulin-stimulated protein synthesis in cultures of C2C12 myotubes through a MEK1-sensitive mechanism.\" INS stimulated protein synthesis, enhanced eIF4E.eIF4G association, and eIF4G phosphorylation and repressed eIF4E.4E-BP1 association vs. control.
p(HGNC:TP53,sub(R,249,S)) =| tscript(p(HGNC:TP53))
Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity.
We have combined genome-wide transcription factor binding and expression profiling to assemble a regulatory network controlling the myogenic differentiation program in mammalian cells. We identified a cadre of overlapping and distinct targets of the key myogenic regulatory factors (MRFs)--MyoD and myogenin--and Myocyte Enhancer Factor 2 (MEF2). We discovered that MRFs and MEF2 regulate a remarkably extensive array of transcription factor genes that propagate and amplify the signals initiated by MRFs. We found that MRFs play an unexpectedly wide-ranging role in directing the assembly and usage of the neuromuscular junction. Interestingly, these factors also prepare myoblasts to respond to diverse types of stress. Computational analyses identified novel combinations of factors that, depending on the differentiation state, might collaborate with MRFs. Our studies suggest unanticipated biological insights into muscle development and highlight new directions for further studies of genes involved in muscle repair and responses to stress and damage.
complex(p(PFM:"Mef2 Family"),g(MGI:Cited2))
complex(p(PFM:"Mef2 Family"),g(MGI:Jun))
complex(p(PFM:"Mef2 Family"),g(MGI:Klf6))
bp(GO:"myoblast differentiation") -| r(MGI:Angpt1)
bp(GO:"myoblast differentiation") -| r(MGI:Dnajb1)
bp(GO:"myoblast differentiation") -| r(MGI:Htra1)
bp(GO:"myoblast differentiation") -> r(MGI:Ankrd2)
bp(GO:"myoblast differentiation") -> r(MGI:Chrng)
bp(GO:"myoblast differentiation") -> r(MGI:Ckm)
bp(GO:"myoblast differentiation") -> r(MGI:Cacng1)
bp(GO:"myoblast differentiation") -> r(MGI:Cav3)
bp(GO:"myoblast differentiation") -> r(MGI:Chrnb1)
bp(GO:"myoblast differentiation") -> r(MGI:Ckb)
bp(GO:"myoblast differentiation") -> r(MGI:Musk)
bp(GO:"myoblast differentiation") -> r(MGI:Tnnt2)
bp(GO:"myoblast differentiation") -> r(MGI:Tbc1d1)
bp(GO:"myoblast differentiation") -> r(MGI:Tead4)
bp(GO:"myoblast differentiation") -> r(MGI:Tnni2)
complex(p(HGNC:JUN),p(HGNC:PLEKHO1)) -| tscript(p(HGNC:JUN))
Here we show that the pleckstrin homology domain-containing protein CKIP-1 (casein kinase 2-interacting protein-1) functions as a plasma membrane-bound AP-1 regulator.
path(SDIS:"cyclic stretch") -> p(HGNC:PTK2,pmod(P,Y,397))
CS significantly increased FAK phosphorylation at Y397 (Fig. 3B), whereas SS stimulation was without effect (Fig. 3A).
bp(GO:"response to hypoxia") -> r(MGI:Anxa2)
Gene profiling of greater than 2-fold increase between the normal treatment and the hypoxic treatment
bp(GO:"response to hypoxia") -> r(MGI:Aplp2)
bp(GO:"response to hypoxia") -> r(MGI:Aqp1)
bp(GO:"response to hypoxia") -> r(MGI:Adm)
bp(GO:"response to hypoxia") -> r(MGI:Aldoart1)
bp(GO:"response to hypoxia") -> r(MGI:Cd72)
bp(GO:"response to hypoxia") -> r(MGI:Comp)
bp(GO:"response to hypoxia") -> r(MGI:Crabp1)
bp(GO:"response to hypoxia") -> r(MGI:Dpf1)
bp(GO:"response to hypoxia") -> r(MGI:Fbn1)
bp(GO:"response to hypoxia") -> r(EGID:14980)
bp(GO:"response to hypoxia") -> r(MGI:"H2-T23")
bp(GO:"response to hypoxia") -> r(MGI:Hsp90ab1)
bp(GO:"response to hypoxia") -> r(MGI:Kitl)
bp(GO:"response to hypoxia") -> r(MGI:Lmnb2)
bp(GO:"response to hypoxia") -> r(MGI:Ndrg2)
bp(GO:"response to hypoxia") -> r(MGI:Olfr571)
bp(GO:"response to hypoxia") -> r(MGI:Pgk1)
bp(GO:"response to hypoxia") -> r(MGI:Rpl8)
bp(GO:"response to hypoxia") -> r(MGI:Rpsa)
bp(GO:"response to hypoxia") -> r(MGI:Sdc4)
bp(GO:"response to hypoxia") -> r(MGI:Slc6a12)
bp(GO:"response to hypoxia") -> r(MGI:Sorbs3)
bp(GO:"response to hypoxia") -> r(MGI:Sprr2b)
bp(GO:"response to hypoxia") -> r(MGI:Tpt1)
bp(GO:"response to hypoxia") -> r(MGI:Timp3)
a(CHEBI:"S-(2,4-dinitrophenyl)glutathione") -> bp(MESHPP:Apoptosis)
These results show for the first time that POB1 can regulate the transport function of RLIP76 and are consistent with our previous studies showing that inhibition of RLIP76 induces apoptosis in cancer cells through the accumulation of endogenously formed GSH-conjugates.
kin(p(HGNC:EGFR)) => p(HGNC:PLCG1,pmod(P,Y))
From Fig. 4: Using the same time and dose strategies as before, a mean 6.2-fold induction of PLC{gamma} phosphorylation was observed following radiation treatment (Fig. 4). Increases in phosphorylation of Shc family members were observed following irradiation; the mean -fold changes (n = 3) were 2.3, 3.0, and 3.5 for the 66-, 52-, and 46-kDa isoforms, respectively. For both PLC{gamma} and Shc, EGF at 10 ng/ml induced a significantly greater increase in phosphorylation than IR (p < 0.05). Pretreatment of cells with 500 nM AG1478, a specific inhibitor of EGFR Tyr phosphorylation (29), abolished the radiation- and EGF-induced activation of both PLC{gamma} and Shc in A431 cells.
Brn-1 efficiently induced Krox-20 expression as a prerequisite for myelination.
p(HGNC:HGF) -> p(HGNC:SPSB1,pmod(P,Y,31))
in response to HGF stimulation, the SSB-1 protein became phosphorylated at tyrosine residue 31. The phosphorylated SSB-1 protein bound to p120Ras-GTPase-activating protein (GAP)
p(HGNC:SERPINF1) -| (p(HGNC:FGF2) -> kin(p(HGNC:FYN)))
We examined the effect of PEDF on kinase activity of Fyn and found that PEDF downregulated FGF-2-promoted Fyn activity by tyrosine phosphorylation at the C-terminus in a Fes-dependent manner.
# GeneRif: Glucocorticoids stimulate lipolysis through an increase in azgo1 expression, and they are responsible for the increase in azgp1 expression seen in adipose tissue of cachectic mice.
Zinc-alpha2-glycoprotein also increased its own expression and this was attenuated by SR59230A, suggesting that it was mediated through the beta3-AR
tscript(p(HGNC:ESR1)) -| tscript(p(HGNC:CEBPD))
tscript(p(RGD:Cebpd)) -| tscript(p(RGD:Esr1))
complex between hormone-activated ERalpha and C/EBPdelta inhibits transcription by each factor
Serum testosterone and oestradiol levels were lowered, accompanied by significantly decreased expression of Hsd3b2 (3beta-hydroxy-Delta5-steroid dehydrogenase-2), Hsd3b5 (3beta-hydroxy-Delta5-steroid dehydrogenase-5) and Hsd11b1 (11beta-hydroxysteroid dehydrogenase type 1), key enzymes in steroid hormone metabolism
p(PFH:"AKT Family",pmod(P,T,308)) => kin(p(PFH:"AKT Family"))
Akt/PKB activation requires the phosphorylation of Thr308
tscript(p(HGNC:KLF2)) -| bp(GO:"blood coagulation")
KLF2 overexpression increased blood clotting time
cat(p(HGNC:P2RY6)) -| bp(MESHPP:Apoptosis)
nucleotides, following their release at sites of inflammation and mechanical stimulation, can act through P2Y6 receptors to initiate NF-kappaB signaling and enhance osteoclast survival.
Homeobox (Hox) genes encode a family of transcription factors that regulate embryonic patterning and organogenesis. In embryos, alterations of the normal pattern of Hox gene expression result in homeotic transformations and malformations. Disruption of the Hoxa1 gene, the most 3' member of the Hoxa cluster and a retinoic acid (RA) direct target gene, results in abnormal ossification of the skull, hindbrain, and inner ear deficiencies, and neonatal death. We have generated Hoxa1(-/-) embryonic stem (ES) cells (named Hoxa1-15) from Hoxa1(-/-) mutant blastocysts to study the Hoxa1 signaling pathway. We have characterized in detail these Hoxa1(-/-) ES cells by performing microarray analyses, and by this technique we have identified a number of putative Hoxa-1 target genes, including genes involved in bone development (e.g. Col1a1, Postn/Osf2, and the bone sialoprotein gene or BSP), genes that are expressed in the developing brain (e.g. Nnat, Wnt3a, BDNF, RhoB, and Gbx2), and genes involved in various cellular processes (e.g. M-RAS, Sox17, Cdkn2b, LamA1, Col4a1, Foxa2, Foxq1, Klf5, and Igf2). Cell proliferation assays and Northern blot analyses of a number of ES cell markers (e.g. Rex1, Oct3/4, Fgf4, and Bmp4) suggest that the Hoxa1 protein plays a role in the inhibition of cell proliferation by RA in ES cells. Additionally, Hoxa1(-/-) ES cells express high levels of various endodermal markers, including Gata4 and Dab2, and express much less Fgf5 after leukemia inhibitory factor (LIF) withdrawal. Finally, we propose a model in which the Hoxa1 protein mediates repression of endodermal differentiation while promoting expression of ectodermal and mesodermal characteristics.
complex(p(RGD:Crebbp),p(RGD:Sox9)) -> tscript(p(RGD:Sox9))
binding of CBP/p300 to the transcriptional activator Sox9 increases Sox9 DNA binding to the Cd-rap promoter leading to further stimulation of gene transcription
cat(p(HGNC:CDC42)) -> a(SCHEM:Lamellipodiae)
Here, we found that PAR-3 directly interacted with STEF/Tiam1, which are Rac-specific guanine nucleotide-exchange factors, and that STEF formed a complex with PAR-3-aPKC-PAR-6-Cdc42-GTP. Cdc42 induces lamellipodia in a Rac-dependent manner in N1E-115 neuroblastoma cells. Disruption of Cdc42-PAR-6 or PAR-3-STEF binding inhibited Cdc42-induced lamellipodia but not filopodia.
a(SCHEM:Chymostatin) -| bp(GO:angiogenesis)
Chymostatin (5-10 nmol(-1) site(-1) day(-1)) reduced granuloma-associated angiogenesis by 57.3 and 70.0%. RT-PCR analysis showed that rMCP-5 mRNA amounts were significantly reduced by rMCP-5 AS-ODN (1.25-2.5-5.0 nmol site(-1)) by 69.5, 72.5 and 81.8%. In parallel experiments, rMCP-5 AS-ODN (1.25, 2.5, 5.0 nmol site(-1)) strongly reduced granuloma weight (26.1, 45.0 and 56.3%) and haemoglobin content (22.2, 50.4, 62.03%), suggesting that the observed effect is mediated through an antisense mechanism. In conclusion, these data suggest that: (i) inhibition of mast cell mediators release may represent a novel strategy to modulate angiogenesis; (ii) among the chymase family, rMCP-5 is a key promoter of angiogenesis in the rat.
kin(p(PFR:"Prkc Family")) -> r(RGD:Actb)
Pretreatment of cells with phorbol ester for 24 h, reducing functional protein kinase C activity, abolished the ability of phorbol esters to increase beta-actin transcription.
p(MGI:Spp1) -> tscript(complex(NCM:"Nfkb Complex"))
secretion of osteopontin resulted in enhanced degradation of I kappa B, the inhibitor of NF-kappa B.
a(CHEBI:"hydrogen peroxide") -> tscript(p(HGNC:IFI16))
Induction of IFI16 by H2O2 was concentration- and time-dependent (maximum at 50 microM, 6 h after treatment) and down-regulated by pretreatment with N-acetyl-L-cysteine, which acts as an antioxidant.
cat(p(HGNC:PLCB1)) -> kin(p(HGNC:MAPK3))
LPA mediated Akt activation was inhibited by pertussis toxin (PTX), whereas Erk1/2 activation was completely inhibited by a blocker of phospholipase Cbeta, U-73122.
cat(p(HGNC:PLCB2)) -> kin(p(HGNC:MAPK1))
bp(GO:"response to hypoxia") -| p(HGNC:PARP1)
HX/RO-induced increases in nuclear AIF translocation, as well as PARP-1 cleavage, were also reduced dose-dependently at 4 h after insult by the inhibitors.
a(CHEBI:gefitinib) -| bp(GO:"cell growth")
As demonstrated in Fig. 1A, H1299, A549, and H23 cells all have an IC50 > 1 uM (\"gefitinibresistant\"), whereas Calu-3, H358, and A431 cells all have an IC50 < 1 uM (\"gefitinib-sensitive\").
a(CHEBI:gefitinib) -| (p(HGNC:EGF) -> complex(p(HGNC:ERBB3),p(HGNC:PIK3R1)))
p(HGNC:EGF) -> complex(p(HGNC:ERBB3),p(HGNC:PIK3R1))
As shown in Fig. 3A, EGF stimulated an association between p85 and ErbB-3 (also observed as the 210-kDa PTyr protein). This association was blocked by exposing the cells to 1 uM gefitinib. Assessment of ErbB-3 immunoprecipitations reveals that gefitinib leads to a decrease in ErbB-3 tyrosine phosphorylation (Fig. 3B Top) and the amount of coprecipitated p85 (Fig. 3B Middle).
As shown in Fig. 1B, gefitinib leads to a reduction in phospho-Akt only in the gefitinib-sensitive NSCLC cell lines.
path(MESHD:Hypertension) -> r(RGD:Serpinh1)
In the transcriptomic arm, we studied differential gene expression in kidneys of SBH/y and SBN/y rats that had been fed regular diet or salt-loaded. The microarray identified 2470 transcripts that were differentially expressed between the study groups. Cluster analysis identified genome-wide 192 genes that were relevant to salt-susceptibility and/or hypertension, 19 of which mapped to chromosome 1. Eight of these genes mapped within the boundaries of QTLs SS1a and SS1b. RT-PCR confirmed 7 genes, leaving TcTex1, Myadm, Lisch7, Axl-like, Fah, PRC1-like, and Serpinh1. None of these genes has been implicated in hypertension before.
kin(p(HGNC:STK11)) -| tscript(p(PFH:"TCF/LEF Family"))
In addition-and in contrast to the wild type protein-these LKB1 mutants fail to activate the GSK-3beta kinase, which otherwise phosphorylates beta-catenin. The increase in beta-catenin phosphorylation that occurs upon expression of wild-type LKB1 results in transcriptional inhibition of a canonical Wnt reporter gene.
complex(p(HGNC:VTN),p(HGNC:ITGAV),p(HGNC:ITGB3)) => cat(complex(p(HGNC:ITGAV),p(HGNC:ITGB3)))
HKa can potentially disrupt the binding of vitronectin to integrins that utilize vitronectin as ligand, such as avb3. As a result of either of these mechanisms, cells will not be able to adhere to vitronectin properly and will eventually undergo apoptosis.
Hox genes encode transcription factors that regulate the morphogenesis of developing embryos. In mammals, knowledge of the genetic pathways, including the possible direct or indirect targets, regulated by HOX proteins is extremely limited. To identify the downstream genes regulated by posterior HOX proteins, we expressed HOXA13 in mouse embryonic fibroblasts lacking paralog group 13 expression using a bicistronic HOXA13/EGFP retroviral vector. Microarray analysis identified 68 genes with significant, reproducible RNA expression changes (50 activated; 18 repressed) in stable HOXA13-expressing cells. Genes with the GO annotation terms \"extracellular matrix\" and \"basement membran\" were greatly overrepresented, and several were shown to be regulated by HOX proteins in other studies. Among the genes strongly activated by HOXA13 were Enpp2, a bifunctional enzyme known to modulate tumor and normal cell motility and which is expressed in precartilaginous condensations; Fhl1, a transcription factor implicated in muscle cell differentiation and development; and M32486, a putative integral membrane molecule expressed in the female reproductive tract. Expression differences in the HOXA13-expressing cells were confirmed for selected downstream genes using semi-quantitative RT-PCR, and in vivo coexpression with Hoxa13 in the limb interdigital mesenchyme was demonstrated for many. For two candidates, Igfbp4 and Fstl, interdigital limb bud expression was reduced in Hoxa13 mutants. To explore whether paralogous and nonparalogous HOX proteins could regulate the same genes, we created new HOX cell lines and examined the expression of selected genes identified by the HOXA13 screen. HOXD13 similarly activatedrepressed 6 tested candidates, demonstrating that multiple downstream genetic pathways may be regulated by paralog HOX proteins. In contrast, HOXA9 was only able to repress expression of some gene targets. A HOXD13 mutant, HOXD13(IQN >)(AAA), incapable of monomeric DNA-binding, activated the expression of 5 HOXA13-upregulated genes; but was incapable of repressing the expression of Ngef and Casp8ap2. Our results suggest that HOX protein-protein interactions without direct HOX DNA-binding may play a larger role in HOX transcriptional regulation than generally assumed, and DNA-binding appears critical for repression.
a(SCHEM:"serum leptin") -> path(SDIS:"adipocyte lipolysis")
A bolus infusion of 1 microg/rat leptin into the third cerebroventricle increased the expression of mRNA for hormone-sensitive lipase (HSL), an indicator of lipolysis, in white adipose tissue (WAT).
leptin treatment increased expression of mRNA for uncoupling protein 1 (UCP1) in brown adipose tissue (BAT), UCP2 in WAT, and UCP3 in quadriceps skeletal muscle
a(CHEBI:budesonide) -| (a(CHEBI:lipopolysaccharide) -> r(RGD:Cxcl2))
a(CHEBI:lipopolysaccharide) -> r(RGD:Cxcl2)
Exposure to aerosolized LPS resulted in a significant increase in gene expression of a range of pro-inflammatory mediators in the lung tissue (Table 1). Treatment with resveratrol did not impact on any of the LPS-induced increases in gene expression measured. The positive control, budesonide, however caused dose-related inhibition of all of the pro-inflammatory genes measured (Table 1).
a(CHEBI:lipopolysaccharide) -> r(RGD:Ccl12)
a(CHEBI:budesonide) -| (a(CHEBI:lipopolysaccharide) -> tscript(complex(NCR:"Nfkb Complex")))
a(CHEBI:lipopolysaccharide) -> tscript(complex(NCR:"Nfkb Complex"))
Following LPS challenge, levels of NF-?B p65 able to bind to DNA were significantly increased compared with control levels, indicating an increase activity of this transcription factor pathway. Resveratrol appeared to have no impact on the LPS-induced increase in NF-?B pathway activity at any dose used in this experiment, whereas budesonide caused a significant, dose-dependent reduction in NF-?B p65 levels (Fig. 2A).
a(CHEBI:budesonide) -| (a(CHEBI:lipopolysaccharide) -> p(RGD:Cxcl2))
a(CHEBI:lipopolysaccharide) -> p(RGD:Cxcl2)
LPS exposure caused a significant increase in pro-inflammatory mediators in the lung tissue (Fig. 3 and Table 2). Although resveratrol did not have a general inhibitory effect on proinflammatory mediators, it did cause a dose-related inhibition of TNF-?, IL-1?, MPO, and CINC-1 levels in the lung tissue (Fig. 3 and Table 2). The positive control, budesonide, caused similar dose-related inhibition of all of the pro-inflammatory proteins increased by LPS treatment (Fig. 3 and Table 2).
a(CHEBI:budesonide) -| (a(CHEBI:lipopolysaccharide) -> p(RGD:Mpo))
a(CHEBI:lipopolysaccharide) -> p(RGD:Mpo)
a(CHEBI:budesonide) -| (a(CHEBI:lipopolysaccharide) -> p(RGD:Tnf))
a(CHEBI:lipopolysaccharide) -> p(RGD:Tnf)
a(CHEBI:lipopolysaccharide) -> p(RGD:Il1b)
Prednisolone-induced changes in dystrophic skeletal muscle. delta-sarcoglycan, myosin Va, FK506-binding protein 51 (FKBP51), the potassium channel regulator potassium inwardly-rectifying channel Isk-like (IRK2) and ADAM 10 were overexpressed differentially overexpressed genes included kallikreins (13, 16, and 26), FKBP51, PI3K alpha regulatory subunit, and IGFBP6
whereas growth hormone-releasing hormone receptor (GHRHR) and Homer-2 were underexpressed underexpressed genes included NeuroD and nicotinic cholinergic receptor gamma.
a(SCHEM:Thiazolidinedione) -| r(HGNC:ENG)
Effect of TZDs on gene expression. TZD treatment of the eight patients with type 2 diabetes (Table 1) was associated with a statistically significant twofold or greater increase in the expression (by microarray) of 107 gene sequences and a twofold or greater decrease in the expression of six gene sequences (online appendix [available at http://diabetes.diabetesjournals.org]).
a(SCHEM:Thiazolidinedione) -> r(HGNC:CTNNAL1)
a(SCHEM:Thiazolidinedione) -> r(HGNC:EDNRB)
a(SCHEM:Thiazolidinedione) -> r(HGNC:FOXC1)
a(SCHEM:Thiazolidinedione) -> r(HGNC:GCN1L1)
a(SCHEM:Thiazolidinedione) -> r(HGNC:GPM6A)
a(SCHEM:Thiazolidinedione) -> r(HGNC:HMGB2)
a(SCHEM:Thiazolidinedione) -> r(HGNC:LONP1)
a(SCHEM:Thiazolidinedione) -> r(HGNC:NDUFB5)
a(SCHEM:Thiazolidinedione) -> r(HGNC:NCKIPSD)
a(SCHEM:Thiazolidinedione) -> r(HGNC:PDIA4)
a(SCHEM:Thiazolidinedione) -> r(HGNC:PKD2L1)
a(SCHEM:Thiazolidinedione) -> r(HGNC:SHFM1)
a(SCHEM:Thiazolidinedione) -> r(HGNC:UBE2E4P)
tscript(p(HGNC:PPARG)) -| bp(MESHPP:"Insulin Resistance")
Thiazolidinediones (TZDs) are a new class of insulin-sensitizing drugs
tscript(p(HGNC:MEOX2)) -> r(HGNC:ALDH1A3)
Table 1. Genes regulated by Gax expression upregulated
tscript(p(HGNC:MEOX2)) -> r(HGNC:CDKN1C)
tscript(p(HGNC:MEOX2)) -| r(HGNC:SLC7A11)
tscript(p(HGNC:MEOX2)) -| r(HGNC:TNFSF4)