Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The respiratory epithelium expresses the cholinergic system including nicotinic receptors (nAChRs). It was reported that normal human bronchial epithelial cells (BEC), which are the precursor for squamous cell carcinomas, and small airway epithelial cells (SAEC), which are the precursor for adenocarcinomas, have slightly different repertoires of nAChRs. Studies shown that nAChRs expressed on lung carcinoma or mesothelioma form a part of an autocrine-proliferative network facilitating the growth of neoplastic cells; others demonstrated that nicotine can promote the growth of colon, gastric, and lung cancers. Nicotine and structurally related carcinogens like NNK [4-(methylnitrosoamino)- 1-(3-pyridyl)-1-butanone] and NNN (N'-nitrosonornicotine) could induce the proliferation of a variety of small cell lung carcinoma cell lines and endothelial cells and nicotine in non-neuronal tissues -including lung- induces the secretion of growth factors (bFGF, TGF-alpha, VEGF and PDGF), up regulation of the calpain family proteins, COX-2 and VEGFR-2, causing the eventual activation of Raf/MAPK kinase/ERK (Raf/MEK/ERK) pathway contributing to the growth and progression of tumors exposed to nicotine through tobacco smoke or cigarette substitutes. It has been demonstrated that nicotine promotes the growth of solid tumors in vivo, suggesting that might induce the progression of tumors already initiated. While tobacco carcinogens can initiate and promote tumorigenesis, the exposure to nicotine could confer a proliferative advantage to early tumors but there is no evidence that nicotine itself provokes cancer. This is supported by the findings that nicotine can prevent apoptosis induced by various agents - such as chemotherapeutic in NSCLC, conferring a survival advantage as well.
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PMID:Nicotine, lung and cancer. 1763 Sep 20

In the renal medulla, cyclooxygenase (COX)-2 is induced by osmotic stress as present in this kidney region during antidiuresis. Increasing evidence suggests that EGF receptor (EGFR) signaling is involved in this process. The aim of the present study was to examine the mechanisms responsible for COX-2 expression and PGE(2) production during hypertonic conditions and to identify potential autocrine/paracrine EGFR ligands. Immunohistochemisty and Western blot analysis revealed abundant expression of the pro-EGFR ligand pro-transforming growth factor (TGF)-alpha in renal medullary cells in vivo and in cultured Madin-Darby canine kidney cells. In Madin-Darby canine kidney cells, hypertonicity rapidly increased TNF-alpha converting enzyme (TACE)-dependent ectodomain shedding of pro-TGF-alpha; phosphorylation of EGFR, p38, and ERK1/2; expression of COX-2; and production of PGE(2). Conversely, TACE inhibition prevented TGF-alpha release; EGFR, p38, and ERK1/2 activation; and COX-2 expression. Furthermore, cell survival was reduced substantially, a response that could be reversed by the addition of PGE(2). Simultaneous addition of recombinant TGF-alpha during TACE inhibition restored EGFR and MAPK phosphorylation, COX-2 expression, PGE(2) production, and cell survival during osmotic stress. These results indicate that hypertonicity induces TACE-mediated ectodomain shedding of pro-TGF-alpha, which subsequently activates COX-2 expression in an autocrine/paracrine fashion, via EGFR and MAPKs. We conclude that tonicity-induced TGF-alpha release is required for COX-2 expression, PGE(2) synthesis, and survival of renal medullary cells during osmotic stress.
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PMID:Ectodomain shedding of pro-TGF-alpha is required for COX-2 induction and cell survival in renal medullary cells exposed to osmotic stress. 1794 33

Recent studies in the hen ovary have linked the initiation of granulosa cell differentiation at follicle selection to the alleviation of inhibitory MAPK signaling. The present studies assessed a role for individual inhibitor of differentiation (Id) protein isoforms as modulators of key transcriptional events occurring within granulosa cells at or immediately subsequent to differentiation. Findings from freshly collected granulosa cells collected at different stages of follicle development demonstrated a negative association between expression levels for Id2 mRNA compared with levels of Id1, Id3, and Id4. Elevated levels of Id2 are related to a differentiating/differentiated phenotype, whereas elevated Id1, Id3, and Id4 are associated with an undifferentiated phenotype. This negative relationship extends to cell signal transduction, because factors that promote inhibitory MAPK signaling (TGF-alpha and betacellulin) block expression of Id2 mRNA but increase levels of Id1, Id3, and Id4. Furthermore, overexpression of Gallus Id2 in cultured granulosa was found to significantly decrease levels of Id1, Id3, and Id4 mRNA but facilitate FSHR mRNA expression and, importantly, initiate LHR mRNA expression plus LH-induced progesterone production. Finally, knockdown studies using small interfering RNA specific for Id2 revealed reduced expression of FSHR and LHR mRNA and attenuated FSH- and LH-induced levels of StAR and p450 cholesterol side-chain cleavage enzyme mRNA plus progesterone production. Collectively, these data demonstrate that Id2 expression is both sufficient and necessary for increasing LHR expression and, as a result, promoting gonadotropin-induced differentiation in hen granulosa cells subsequent to follicle selection.
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PMID:Role for inhibitor of differentiation/deoxyribonucleic acid-binding (Id) proteins in granulosa cell differentiation. 1832 89

Epidermal growth factor receptor (EGFR) is an activated oncogene in many cancers. It can be transactivated by ligands of G protein-coupled receptors (GPCRs). We show here that a novel gene, human rhomboid family-1 (RHBDF1), which was recently reported to have a pivotal role in epithelial cancer cell growth in culture and in xenograft tumors, participates in the modulation of GPCR-mediated EGFR transactivation. The RHBDF1 protein localizes mainly in the endoplasmic reticulum. Silencing the RHBDF1 gene in head and neck squamous cancer cell line 1483 cells with siRNA causes an inhibition of gastrin-releasing peptide (GRP) -induced phosphorylation of EGFR and EGFR-dependent signaling proteins p44/42 MAPK and AKT, accompanied by an inhibition of GRP-induced survival, proliferation, and invasion of the cells. The EGFR signaling pathway itself remains intact, however, as the cells remain responsive to exogenous EGF. In addition, RHBDF1 gene silencing disrupts GRP-stimulated secretion of EGFR ligand TGF-alpha, but not the production of latent TGF-alpha, whereas engineered overexpression of RHBDF1 markedly accelerates the secretion of TGF-alpha. These findings are consistent with the view that RHBDF1 is critically involved in a GPCR ligand-stimulated process leading to the activation of latent EGFR ligands.
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PMID:Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells. 1883 97

Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-kappaB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-alpha transgenic mice. iNOS, IKK/NF-kappaB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
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PMID:Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis. 1903 60

We investigated the effects of tumor necrosis factor (TNF)-alpha on DNA synthesis and proliferation, and its signal transduction pathways in primary cultures of adult rat hepatocytes. TNF-alpha induced time- and dose-dependent increases in hepatocyte DNA synthesis and proliferation. The hepatocyte proliferation stimulated by 30 ng/ml TNF-alpha was significantly inhibited by anti-TNF receptor 2 antibody, but not by anti-TNF receptor 1 antibody. TNF-alpha-induced hepatocyte DNA synthesis and proliferation were blocked by AG1478 (10(-7) M), PD98059 (10(-6) M), LY 294002 (10(-7) M), and rapamycin (100 ng/ml). TNF-alpha at 30 ng/ml significantly increased phosphorylation of receptor tyrosine kinase (175 kDa) and p42 mitogen-activated protein (MAP) kinase. This data suggests that the proliferative signal for primary cultured hepatocytes induced by TNF-alpha is mediated by TNF receptor 2 and the receptor tyrosine kinase/MAP kinase pathway. In addition, TNF-alpha-induced hepatocyte mitogenesis was significantly blocked by somatostatin (10(-6) M), adenylate cyclase inhibitor dideoxyadenosine (10(-7) M), protein kinase A inhibitor H-89 (10(-7) M), and neutralizing antibody to transforming growth factor (TGF)-alpha in culture. Indeed, 30 ng/ml TNF-alpha was found to rapidly stimulate secretion of TGF-alpha, and this secretion was also blocked by anti-TNF receptor 2 antibody. Moreover, TGF-alpha secretion induced by TNF-alpha was suppressed by dideoxyadenosine, H-89, and somatostatin. Together, these results indicate that stimulation of TNF receptor 2 by 30 ng/ml TNF-alpha induces autocrine secretion of TGF-alpha via the adenylate cyclase/protein kinase A pathway, after which TGF-alpha induces hepatocyte DNA synthesis and proliferation through the TGF-alpha receptor-linked tyrosine kinase (175 kDa)/MAP kinase signaling system.
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PMID:Tumor necrosis factor (TNF) receptor-2-mediated DNA synthesis and proliferation in primary cultures of adult rat hepatocytes: The involvement of endogenous transforming growth factor-alpha. 1910 Jul 31

Viral infection is a major trigger for exacerbation of asthma and induces overproduction of mucins. We investigated whether dsRNA could amplify the induction of mucin by TGF-alpha in human bronchial epithelial cells, as well as the molecular mechanisms regulating MUC5AC expression. Human pulmonary mucoepidermoid carcinoma (NCI-H292) cells and normal human bronchial epithelial cells were exposed to polyinosinic-cytidyric acid (poly(I:C)) and TGF-alpha. Then, MUC5AC protein production, mRNA expression, and promoter activity were evaluated. Cells were pretreated with a selective inhibitor of ERK, and phosphorylation of ERK was examined by Western blotting. Furthermore, the expression of MAPK phosphatase 3 (MKP3) mRNA was evaluated and the effect of MKP3 overexpression was assessed. Poly(I:C) synergistically increased MUC5AC induction by TGF-alpha in both NCI-H292 and normal human bronchial epithelial cells. This increase was dependent on MUC5AC gene transcription. A MEK1/2 inhibitor (U0126) significantly inhibited MUC5AC production. Phosphorylation of ERK was enhanced by poly(I:C). TGF-alpha stimulation up-regulated MKP3 mRNA expression, while costimulation with poly(I:C) inhibited this up-regulation dose-dependently. Enhanced expression of MUC5AC mRNA by poly(I:C) in wild-type cells was completely suppressed in cells transfected with the MKP3 expression vector. dsRNA can synergistically amplify the induction of MUC5AC mucin by TGF-alpha. This synergistic effect on MUC5AC production may be due to enhanced activation of ERK through inhibition of MKP3 by poly(I:C).
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PMID:Double-stranded RNA and TGF-alpha promote MUC5AC induction in respiratory cells. 1910 60

Bacterial products (e.g., LPS) are viewed as critical stimuli in inflammation-associated cancer. Cyclooxygenase 2 (COX-2), a major effector of LPS, and EGFR, are key to carcinogenesis, notably in the hepatobiliary tract. In this study, we tested the hypothesis that LPS can initiate an interaction between the epidermal growth factor receptor (EGFR) and COX-2 pathways. We examined the effect of LPS in biliary carcinoma cells that displayed constitutive COX-2 expression and PGE(2) production and in normal human biliary epithelial cells in which COX-2/PGE(2) expression was virtually absent. LPS induced early phosphorylation of EGFR and ERK1/2 in both types of cells, which reached maximum levels within 30 min (first phase). However, only the carcinoma cells showed a second significant rise in both EGFR and ERK phosphorylation 6 h after exposure to LPS (second phase). Inhibition of COX-2/PGE(2) production prevented the second, but not the first, phase of EGFR and ERK1/2 phosphorylation, implicating COX-2/PGE(2) in the second phase of phosphorylation. LPS induced COX-2-derived PGE2 production at 4 h, which was before the rise in the second phosphorylation that occurred at 6 h. Exogenous PGE(2) also caused EGFR activation via a signaling pathway involving TACE-dependent TGF-alpha release. Inhibition of the second phase of EGFR phosphorylation with EGFR or COX-2 inhibitor prevented LPS-induced cell invasion in vitro, demonstrating the biological importance of this COX-2 feedback signaling in cancer cells. We conclude that LPS triggers a positive feedback loop involving COX-2/PGE(2) in biliary carcinoma cells and that this second phase of EGFR phosphorylation is implicated in cell invasion by LPS.
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PMID:Lipopolysaccharide initiates a positive feedback of epidermal growth factor receptor signaling by prostaglandin E2 in human biliary carcinoma cells. 1920 81

To elucidate the mechanism of action of prostaglandin I(2) (PGI(2)) and carbaprostacyclin, we studied their effect on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. Hepatocyte parenchymal cells, maintained in a serum-free, defined medium, synthesized DNA and proliferated in the presence of PGI(2) or carbaprostacyclin in a time- and dose-dependent manner. PGI(2) was less potent than carbaprostacyclin in stimulating hepatocyte mitogenesis. These effects of PGI(2) and carbaprostacyclin were abolished by treatment with a specific IP-receptor antagonist, CAY10441 (10(-9) - 10(-7) M). Hepatocyte mitogenesis induced by the IP-receptor agonists was almost completely blocked by specific inhibitors of growth-related signal transducers such as AG1478 (5 x 10(-7) M), LY294002 (10(-7) M), PD98059 (10(-6) M), and rapamycin (10 ng/ml). In addition, PGI(2) or carbaprostacyclin significantly increased the kinase activity of a (p175 kDa) receptor tyrosine kinase and the phosphorylation of extracellular signal-regulated kinase (ERK) 2. Addition of a monoclonal antibody against transforming growth factor (TGF)-alpha, but not insulin-like growth factor-I, to the culture dose-dependently inhibited the PGI(2)- or carbaprostacyclin-induced hepatocyte mitogenesis. Furthermore, treatment with the IP-receptor agonists significantly increased the secretion of TGF-alpha to the culture medium. These results indicate that the IP receptor agonist-induced hepatocyte mitogenesis is mediated by autocrine secretion of TGF-alpha followed by activation of a receptor tyrosine kinase / ERK pathway.
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PMID:IP receptor agonist-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes: the involvement of endogenous transforming growth factor-alpha. 1934 70

Mucous hypersecretion is a serious feature of chronic airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Although mucins are produced via activation of an EGF receptor (EGFR) signaling cascade, the mechanisms leading to exaggerated mucin production in mucous hypersecretory diseases are unknown. Because expression of ICAM-1 and of the ICAM-1 ligand fibrinogen is increased in the airways of subjects with mucous hypersecretory diseases, we hypothesized that fibrinogen binding to ICAM-1 could increase EGFR-dependent mucin production in human airway (NCI-H292) epithelial cells. Consistent with this hypothesis, we found that an ICAM-1 neutralizing antibody and an ICAM-1(8-22) peptide that binds fibrinogen decreased mucin production induced by the EGFR ligand transforming growth factor (TGF)-alpha dose-dependently. Exogenous fibrinogen and a fibrinogen(117-133) peptide that binds ICAM-1 rescued mucin production in cells treated with the ICAM-1(8-22) peptide. Surprisingly, the ICAM-1(8-22) peptide increased EGFR phosphotyrosine and phospho-ERK1/2 in cells treated with TGF-alpha. The ICAM-1(8-22) peptide-induced increases in EGFR phosphotyrosine and phospho-ERK1/2 were prevented by exogenous fibrinogen, by the fibrinogen(117-133) peptide, and by selective inhibitors of phospholipase C (PLC), protein kinase C (PKC)-alpha/beta, and metalloproteases. These results suggest that fibrinogen binding to ICAM-1 promotes mucin production by decreasing TGF-alpha-induced EGFR and ERK1/2 activation and that the fibrinogen-ICAM-1-dependent decrease in EGFR and ERK1/2 activation occurs via inhibition of an early positive feedback pathway involving PLC- and PKC-alpha/beta-dependent metalloprotease activation and subsequent metalloprotease-dependent EGFR reactivation.
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PMID:Fibrinogen binding to ICAM-1 promotes EGFR-dependent mucin production in human airway epithelial cells. 1942 76


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