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cat(p(MGI:Vav1)) -> p(MGI:Plcg1,pmod(P,Y))

a(CHEBI:estradiol) -> p(MGI:Raf1,pmod(P,S,259))

We demonstrated that lung myofibroblasts, incubated in the presence of E2, showed a rapid phosphorylation on serine-259 of Raf1 and tyrosine-204 of ERK1/2 MAP kinase at 15 min, by approximately 3- and 5-fold, respectively

kin(p(HGNC:MAPK3)) => p(HGNC:HSPB8,pmod(P,S,27))

kin(p(PFH:"PRKC Family")) => p(HGNC:HSPB8,pmod(P,S,14))

bp(GO:"response to hypoxia") -> r(HGNC:TFF3)

Hypoxia resulted in parallel induction of ITF mRNA and protein.

IL-10 decreased the optimal time of mRNA expression induced by LPS from 24 to 8 h. Blocking experiments indicated that endogenous IL-10 contributes to gene induction by LPS. Cooperation between IL-10 and LPS was not due to altered mRNA stability but was dependent on de novo protein synthesis. The region of the promoter involved was localized to a 178-bp fragment flanking the transcription start site of the gene. This region was also responsible for the suppressive effects of IL-4 and IL-13. Forskolin, CTP-cAMP, and PGE(2) also enhanced LPS- and IFN-induced A8 mRNA,

Up-regulation of the A8 gene by LPS (17), IFN-, IL-1, and TNF in elicited Mac (18) and by LPS and IL-1 in microvascular endothelial cells (MEC; 19) suggested a proinflammatory role.

p(HGNC:RB1) -| (a(CHEBI:troglitazone) -> p(HGNC:CDKN2C))

HLF, which was deficient in the protein product of the retinoblastoma tumor-suppressor gene (pRb), responded most profoundly to troglitazone, showing an increased expression in not only p21, but also in p27 and in p18.

a(CHEBI:acetaldehyde) -> (kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> kin(p(HGNC:RPS6KB1)))
kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> kin(p(HGNC:RPS6KB1))

As expected, acetaldehyde-elicited ERK1/2 phosphorylation was inhibited by PD98059, a MEK inhibitor, but not by wortmannin, a PI3K inhibitor. On the other hand, both of these inhibitors partially inhibited phosphorylation of pp70(S6K) induced by acetaldehyde suggesting that its activation is ERK1/2- and PI3K-dependent.

a(CHEBI:acetaldehyde) -> (kin(p(PFH:"PRKC Family")) -> kin(p(HGNC:MAPK3)))
kin(p(PFH:"PRKC Family")) -> kin(p(HGNC:MAPK3))

These effects were completely prevented by calphostin C, a protein kinase C inhibitor.

a(CHEBI:acetaldehyde) -> (kin(p(PFH:"PRKC Family")) -> kin(p(HGNC:RPS6KB1)))
kin(p(PFH:"PRKC Family")) -> kin(p(HGNC:RPS6KB1))

kin(p(PFH:"PRKC Family")) -> kin(p(HGNC:MAPK1))

a(CHEBI:lipopolysaccharide) -| r(RGD:Cyp4f4)

See Figure 1: Toxicogenomic patterns of gene expression. All changes correspond to the LPS, 6 hour timepoint and are greater than or equal to 2.

cat(p(MGI:Ptgs2)) -> sec(a(CHEBI:serotonin))

Pleckstrin phosphorylation and serotonin secretion in human platelets stimulated with vWF are blocked by the cyclooxygenase inhibitor acetylsalicylic acid

a(CHEBI:glucocorticoid) -> cat(p(HGNC:HSD11B1))

11betaHSD1 activity was sensitively up-regulated by increasing concentrations of glucocorticoid

PLCG1-mediated production of diacylglycerol leads to activation of PKC, and this pathway plays an important role in mediating VEGF-induced activation of ERKs ERK activation mediates cytosolic PLA2-mediated PGI2 synthesis

IFNA induced activation of STAT1 and STAT2.

kin(p(PFH:"AKT Family")) => p(HGNC:GSK3A,pmod(P,S,21))

these proliferators also induce simultaneously the expression of genes encoding acyl-CoA oxidase, enoyl-CoA hydratase-hydroxyacyl-CoA dehydrogenase [multifunctional enzyme] and thiolase [3-ketoacyl-CoA thiolase]

The enhancing effect of Pit-1 was much lower for the GHS-R promoter than for 344 nucleotides of the human GH promoter, in agreement with the significantly lower expression levels of the GHS-R in somatotroph pituitary cells.Thyroid hormone and estrogen lead to a significant stimulation; glucocorticoids lead to a significant inhibition.

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

After treating NSCLC cells containing active Akt/PKB with LY294002 for 48 h, typical morphological changes of apoptosis were observed, including membrane blebbing, increased refractoriness, and chromatin condensation (data not shown).

TGF-beta1 stimulation of COLO-357, PANC-1, and IMIM-PC1 cells lead to a down-regulation of cytokeratins 8 and 19 mRNA levels in PANC-1 and IMIM-PC1 (responsive cell lines)cells and to a minor extent in COLO-357 cells. The mesenchymal differentiation marker vimentin and collagen1alpha is strongly up-regulated in all responsive cell lines. The TGF-beta1 mediated regulation of differentiation markers occurs in a time-dependent manner. In contrast, TGF-beta1 treatment failed to induce any significant change in the expression pattern of differentiation markers in cell lines with a nonfunctional TGF-beta1 signaling pathway (IMIM-PC2 and CAPAN-1). The TGF-beta1 mediated changes of gene expression were also reproducibly observed on the protein level in all responsive cell lines in multiple experiments; however, down-regulation of epithelial marker proteins was less prominent on the RNA level.

a(CHEBI:cisplatin) -| path(SDIS:"tumor growth")
p(HGNC:DNAJC15) -> (a(CHEBI:cisplatin) -| path(SDIS:"tumor growth"))

Loss of expression of a new member of the DNAJ protein family confers resistance to chemotherapeutic agents used in the treatment of ovarian cancer. MCJ expression was associated with enhanced sensitivity to paclitaxel, topotecan, and cisplatin, suggesting that MCJ loss may play a role in de novo chemoresistance in ovarian carcinoma.

kin(p(PFH:"PRKC Family")) -> cat(p(HGNC:FCGR3B))

Treatment of PMN with phosphatidylinositol-specific phospholipase C to remove FcgammaRIIIb also decreased phagocytosis of SAP-opsonized zymosan, but not CRP-opsonized zymosan.

complex(p(HGNC:APCS),p(HGNC:FCGR3B)) -> bp(GO:phagocytosis)

Zymosan was used to test the functional consequences of SAP and CRP binding to FcgammaR. Both SAP and CRP bound to zymosan and enhanced its uptake by PMN. This enhanced phagocytosis was abrogated by treatment of PMN with wortmannin, a phosphatidylinositol-3 kinase inhibitor, or with piceatannol, a Syk inhibitor, consistent with uptake through FcgammaR.

These results demonstrate that NGF increases APP gene expression at transcriptional level.

p(HGNC:IGF1) -> kin(p(PFH:"AKT Family"))

Activation of Akt is stimulated by a variety of growth factors, such as insulin, insulin-like growth factor 1 (IGF-1), platelet-derived growth factor, and epidermal growth factor

a(SCHEM:"serum insulin") -> kin(p(PFH:"AKT Family"))
phos(p(HGNC:PTEN)) -| (a(SCHEM:"serum insulin") -> kin(p(PFH:"AKT Family")))

PTEN has been shown to downregulate insulin, IGF-1, and epidermal growth factor- stimulated activation of Akt,

Angiotensin-II (A-II) induces proliferation of zona glomerulosa cells and stimulates expression of cytochrome P-450 aldosterone synthase.

a(SCHEM:"AG-490") -| (p(HGNC:CXCR4) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex")))
p(HGNC:CXCR4) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

Furthermore, pretreatment of CTS cells with AG490 significantly inhibited SDF-1alpha-induced PI3-kinase activity, and inhibition of JAK2 with AG490 ablated the SDF-1alpha-induced tyrosine phosphorylation of multiple focal adhesion proteins (including focal adhesion kinase, related adhesion focal tyrosine kinase, paxillin, CrkII, CrkL, and p130Cas).

a(CHEBI:lipopolysaccharide) -> cat(p(MGI:Casp3))
p(MGI:Bid) -> (a(CHEBI:lipopolysaccharide) -> cat(p(MGI:Casp3)))

caspase 3 activities are much higher in treated wild-type mice than in treated bid-deficient mice. Wild-type (solid bar) or bid-deficient (open bar) C57BL/6J or 129/SvJ mice were treated with 2 ?g/kg TNF? or LPS (50 or 25 ?g/kg) in the presence of 20 mg of GalN per mouse for 4 or 6 h as indicated.

galectin-8 triggers integrin-mediated signaling cascades including Tyr phosphorylation of focal adhesion kinase and paxillin

bp(GO:"response to osmotic stress") -> r(RGD:Akr1b1)

Like SMIT, BGT1 and AR genes, TauT, CDO and CSD genes appear to be tonicity-sensitive genes which can be activated in vivo by hypertonicity in the rat kidney

bp(GO:"response to osmotic stress") -> r(RGD:Slc5a3)

These effects were markedly attenuated in Rat2-Rac(N17) cells expressing a dominant negative Rac1 mutant. Pretreatment with SB203580, a specific inhibitor of p38 MAP kinase

CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK)

kin(p(HGNC:SRC)) => p(HGNC:CTNND1,pmod(P,Y,112))

Here, as a first step toward pinpointing this role, we have employed two-dimensional tryptic mapping to directly identify the major sites of Src-induced p120 phosphorylation. Eight sites were identified by direct mutation of candidate tyrosines to phenylalanine and elimination of the accompanying spots on the two-dimensional maps. Identical sites were observed in vitro and in vivo, strongly suggesting that the physiologically important sites have been correctly identified. (Next section taken from Results - Fig 4) Mutation of tyrosines 112, 228, and 280 to phenylalanine resulted in elimination of phosphopeptide spots 6, 7, and 8, respectively. Mutation of tyrosine 96 eliminated spots 9 and 10, whereas mutation of tyrosine 257 eliminated spots 4 and 5...These results suggest that peptides 1, 2, and 3 represent singly, doubly, and triply phosphorylated variants, respectively, of the same peptide, containing Tyr291, Tyr296, and Tyr302.

The expression of wild-type Etk in a non-invasive human breast cancer MCF-7 cells significantly increased proliferation and anchorage-independent growth of epithelial cancer cells.

p(HGNC:MYL9,pmod(P,T,18)) -> cat(p(HGNC:TNFRSF1B))

Treatment of cells with either ionomycin or endotoxin (lipopolysaccharide) leads to activation of myosin II and increased translocation of TNFR-1 to the plasma membrane independent of TNF signaling.

p(HGNC:PGR) -> (a(CHEBI:progesterone) -| r(HGNC:LEPR))

These results indicate that, in the human endometrium, progestins act via the progesterone receptors to suppress functional OB-R(L) mRNA expression, and may thereby alter the sensitivity of the endometrium to leptin.

whereas oestradiol plus progesterone (10(-8), 10(-7) and 10(-6) mol/l) or medroxyprogesterone acetate (10(-8) and 10(-7) mol/l) suppressed the expression by approximately 50%.

Gas2 is a caspase-3 substrate that plays a role in regulating microfilament and cell shape changes during apoptosis. Here we provide evidence that overexpression of Gas2 efficiently increases cell susceptibility to apoptosis following UV irradiation, etoposide and methyl methanesulfonate treatments, and that these effects are dependent on increased p53 stability and transcription activity.

p(HGNC:TGFB1) -> complex(p(HGNC:DAB2),p(HGNC:SMAD3))

TGFbeta stimulation triggers a transient increase in association of Dab2 with Smad2 and Smad3

p(HGNC:TGFB1) -> complex(p(HGNC:DAB2),p(HGNC:SMAD2))

TGFbeta stimulation triggers a transient increase in association of Dab2 with Smad2 and Smad3,

p(HGNC:AKT3,pmod(P,T,305)) => kin(p(HGNC:AKT3))

When Thr-305 of HA-PKB?1 was mutated to an alanine that cannot be phosphorylated (HA-PKB?1T305A), the activation was abolished (Fig. 4 A).

p(MGI:Akt2) -| a(SCHEM:"D-Glucose, anhydrous")

ablation of Akt2 in mice results in mild, but statistically significant fasting hyperglycemia due to peripheral insulin resistance and nonsuppressible hepatic glucose production accompanied by inadequate compensatory hyperinsulinemia

complex(p(HGNC:TNFAIP3),p(HGNC:TAX1BP1)) -| bp(MESHPP:Apoptosis)

A similar functional redundancy of the A20 zinc fingers was also observed for binding of A20 to a number of other proteins, including two novel NF-kappaB inhibitory proteins (ABIN-1, ABIN-2), A20 itself, the anti-apoptotic protein TXBP151, and a regulatory component of the IkappaB kinase complex, IKKgamma.

Phospholipid scramblase 1 (PLSCR1) is a plasma membrane protein that has been proposed to play a role in the transbilayer movement of plasma membrane phospholipids. PLSCR1 contains multiple proline-rich motifs resembling Src homology 3 (SH3) domain-binding sites, which highly specific for binding to the Abl SH3 domain. Endogenous PLSCR1 was immunoprecipitated from either Abl-/- or Abl+/+ murine fibroblasts using antibody specific for murine PLSCR1 the data indicated that Tyr phosphorylation of PLSCR1 detected in the Abl+/+ fibroblasts was virtually abolished in the Abl-/- fibroblasts, implying that the c-Abl kinase accounts for most, if not all, of the Tyr phosphorylation of PLSCR1 detected in mammalian cells.

cat(p(HGNC:GFPT1)) -| tscript(p(HGNC:PDX1))

Overexpression of GFAT or treatment with glucosamine results in impaired glucose-stimulated insulin secretion and reduction in the expression levels of several beta-cell specific genes (insulin, GLUT2, and glucokinase). Additionally, the DNA binding activity of PDX-1, an important transcription factor for these three genes, was markedly reduced.

cat(p(HGNC:FRS2)) -> (kin(p(HGNC:RET)) -> kin(p(PFH:"MAPK Erk1/3 Family")))
kin(p(HGNC:RET)) -> kin(p(PFH:"MAPK Erk1/3 Family"))

However, overexpression of FRS2 but not Shc potentiates mitogen-activated protein (MAP) kinase activation by RET oncoproteins.

complex(NCH:"Catalytic Activity of T-cell receptor complex") -> kin(p(HGNC:MAPK3))

The P-1 domain mediates a constitutive interaction of SLP-76 with the SH3 domain of PLC-gamma1 and is required for TCR-mediated activation of Erk, PLC-gamma1, and NFAT (nuclear factor of activated T cells).

Here we describe that epidermal growth factor stimulates the ACK1/Dbl pathway, leading to actin cytoskeletal rearrangements. The role of the two ACK1-binding proteins Cdc42 and Grb2 was assessed by overexpression of the Cdc42/Rac interactive binding domain and a dominant-negative Grb2 mutant, respectively.

Consistent with these results, BMP-2 increases caspase-9 and caspase-3, -6, and -7 activity, and an anti-caspase-9 agent suppresses BMP-2-induced apoptosis.

glucocorticoid-induced inhibition of interleukin-2 mRNA expression

cat(p(RGD:Adra2c)) -> kin(p(PFR:"Prkc Family"))

The alpha2 adrenoceptor agonist, UK14,304-induced sustained contraction and Ca2+ oscillations may be due to PKC activation and opening

Recently, we reported that tumstatin (the NC1 domain of alpha 3 chain of type IV collagen) and its deletion mutant tum-5 possess anti-angiogenic activity. In the present study, we confirm that the anti-angiogenic activity of tumstatin and tum-5 is independent of disulfide bond requirement.

Here we show that exposure to FGF-1 and FGF-2 leads to significant and dose-dependent increase in E-cadherin-dependent cell-cell adhesion, tubular differentiation, and a reduced capacity to invade collagen gels. FGF stimulation produces phosphorylation of E-cadherin and beta-catenin on tyrosine residues, as well as increased E-cadherin localisation to the cytoplasmic membrane and association with FGFR1 demonstrable by coimmunoprecipitation

p(HGNC:FGF1) -> p(HGNC:CTNNB1,pmod(P,Y))

p(HGNC:FGF1) -> complex(p(HGNC:CDH1),p(HGNC:FGFR1))

p(HGNC:FGF1) -> tscript(p(PFH:"TCF/LEF Family"))

p(HGNC:FGF2) -> p(HGNC:CTNNB1,pmod(P,Y))

p(HGNC:FGF2) -> complex(p(HGNC:CDH1),p(HGNC:FGFR1))

p(MGI:Bmp4) -> bp(GO:"cell differentiation")

Recombinant CHL protein inhibited the BMP4-dependent differentiation of embryonic stem cells in vitro and interacted directly with BMPs, similar to chordin.

p(MGI:Chrdl1) -| (p(MGI:Bmp4) -> bp(GO:"cell differentiation"))

Androgens upregulate the expression of tra-2alpha, an enhancer of RNA splicing homologous to Drosophila tra-2, and promote redistribution of the protein from a diffuse to a speckled pattern within the nucleus. Similarly, androgens upregulate the expression of a novel gene homologous to Caenorhabditis elegans fox-1

p(HGNC:HSPD1) -> complex(p(HGNC:TLR4),p(HGNC:LY96))

Human fibroblasts transfected with TLR2 or TLR4 plus MD-2 gain responsiveness to HSP60, while TLR2- or TLR4-defective cells display impaired responses.

Nicotine (500 microM) activated 42 kDa isoform of MAPK in hippocampi from L250T animals. Stimulation of ERK2 was dependent on alpha7 nAChR function because an alpha7-selective antagonist, methyllycaconitine (MLA, 1 microM), attenuated nicotine-induced activation of ERK2 MAPK in L250T hippocampal slices. These results suggested that nicotine induced the alpha7 nAChR activation in hippocampus.

p(PFH:"AKT Family") -| tscript(p(HGNC:AR))

A mutation at AR Ser-210 results in the reversal of Akt-mediated suppression of AR transactivation.

kin(p(HGNC:AKT1)) => p(HGNC:AR,pmod(P,S,210))

Here, we demonstrate that Akt phosphorylates the androgen receptor (AR) at Ser-210 and Ser-790.

p(HGNC:AR,pmod(P,S,790)) =| tscript(p(HGNC:AR))

we demonstrate that Akt phosphorylates the androgen receptor (AR) at Ser-210 and Ser-790.

HGF induces the expression of uPA. When the HGF antibody or the tyrosine kinase inhibitor was introduced the uPA expression was decreased.

Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (138+/-7% of control) and an enhanced ecNOS activity in the vessel wall (209+/-46% of control).

PC-12 cells over expressing SH2-Bbeta when treated with 100 ng/ml of NGF for 10 minutes and immunoblotted with TrkA anti-phosphotyrosine antibody, showed normal NGF induced tyrosine phosphorylation of TrkA.

Pretreatment of LNCaP cells with SB202190, PD98059, or tyrphostin AG879 [p38 mitogen-activated protein kinase (MAPK), MAP/extracellular signal-regulated protein kinase kinase 1/2, and ErbB2 MAPK inhibitors, respectively) but not wortmannin (PI3-kinase inhibitor) blocked IL-6-mediated induction of the PSA promoter, which demonstrates that IL-6 activity is dependent on a MAPK pathway.

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

IKK-beta brought about the activation of NFkB.

# Ariadne: UO-44 gene expression in the uterus is strictly regulated by estrogens, tamoxifen, and GH, whereas the pure antiestrogen ICI 182780 is inhibitory. [Expression]

PC-3 cells overexpressing FADD dominant negative form were found to be resistant to cell death induced by TRAIL.

Thus, Raf-1 may promote cell survival through its protein-protein interactions in addition to its established MEK kinase function

a(CHEBI:androgen) -> (tscript(p(HGNC:AR)) -> tscript(p(HGNC:CREBBP)))
tscript(p(HGNC:AR)) -> tscript(p(HGNC:CREBBP))

AR dramatically increased the intrinsic transcriptional activity of the nuclear receptor coactivators glucocorticoid receptor-interacting protein-1 (GRIP1), cAMP response element-binding protein-binding protein, and p300 that are tethered to DNA.

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

In addition, liganded AR can interfere with the activity of other transcription factors, such as activator protein-1 and nuclear factor kappaB, for which DNA binding by AR is not necessary.

p(HGNC:TP53,sub(F,134,I)) =| tscript(p(HGNC:TP53))

Table 2 p53 mutants unable to discriminate between diÂ?erent p53 responsive elements

p(HGNC:TP53,sub(Y,205,N)) =| tscript(p(HGNC:TP53))

p(HGNC:TP53,sub(A,276,G)) =| tscript(p(HGNC:TP53))

Table 2 p53 mutants unable to discriminate between diÃ???erent p53 responsive elements

p(HGNC:TP53,sub(E,286,K)) =| tscript(p(HGNC:TP53))

p(HGNC:TP53,sub(G,244,S)) =| tscript(p(HGNC:TP53))

Table 2 p53 mutants unable to discriminate between diÃ??erent p53 responsive elements

p(HGNC:TP53,sub(N,239,S)) =| tscript(p(HGNC:TP53))

p(HGNC:TP53,sub(S,241,T)) =| tscript(p(HGNC:TP53))

Table 3 EÂ?ect of temperature on the ability of p53 mutants to discriminate between diÂ?erent p53 responsive elements

kin(p(HGNC:STK11)) => p(HGNC:STK11,pmod(P,T,189))

After stimulation of the thrombin receptor, PAR1, or overexpression of a constitutively active variant of G alpha(q), PIP5K I alpha translocated to the plasma membrane. Movement of PIP5K I alpha to the cell membrane was dependent on both GTP-bound Rac and Rho

p(HGNC:HBEGF) -> bp(GO:"cell migration")
p(HGNC:NRD1) -> (p(HGNC:HBEGF) -> bp(GO:"cell migration"))

When overexpressed in cells, NRDc enhanced their migration in response to HB-EGF but not to EGF

The RBP-Jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated Notch1 through RBP-Jkappa-dependent transcription.