Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the epidermal growth factor receptor (EGFR) and/or its family member(s) stimulates many processes of carcinogenesis, including cell invasion and the formation of new blood vessels, events that are critically involved in angiogenesis. Interference with the activation of EGFRs, therefore, represents a promising strategy for the development of novel and selective anticancer therapies. Previously, we reported that EGFR-related protein (ERRP), which we have isolated and characterized as a pan-erbB inhibitor, is a potential therapeutic agent for colorectal and other epithelial cancers. The present investigation was undertaken to determine whether ERRP would affect the invasion of colon cancer cells and formation of tubules, and the regulation of these processes. ERRP inhibited tubule formation by aortic endothelial cells and invasion of HCT-116 colon cancer cells through matrigel. These changes were associated with marked reductions in the synthesis and secretion of bFGF, VEGF and TGF-alpha by HCT-116 cells. Secretion of bFGF and VEGF by aortic endothelial cells was also inhibited by ERRP. Microarray analysis of ERRP-treated HCT-116 cells showed reduced levels of several growth regulatory proteins such as p21Rac1, Stratifin (14-3-3 Sigma), focal adhesion kinase (FAK) and mediators of the Ras-Raf-ERK pathway. ERRP treatments resulted in reduced expression of p21Rac1 and inhibited the constitutive activation of FAK and MEK2 in HCT-116 cells. Transfection of constitutively activate p21Rac1 or MEK2 into HCT-116 cells abrogated ERRP-induced inhibition of growth. In summary, it was demonstrated that ERRP not only inhibits cell growth, but also the processes of cell invasion and blood vessel formation that are critical for the development and progression of carcinogenesis.
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PMID:EGF receptor-related protein (ERRP) inhibits invasion of colon cancer cells and tubule formation by endothelial cells in vitro. 1661 3

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

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

Amiloride-sensitive sodium entry, via the epithelial sodium channel (ENaC), is the rate-limiting step for Na(+) absorption. Epidermal growth factor (EGF) is involved in the regulation of Na(+) transport and ENaC activity. However it is still controversial exactly how EGF regulates ENaC and Na(+) absorption. The aim of the present study was to characterize the EGF regulation of Na(+) transport in cultured mouse renal collecting duct principal mpkCCD(c14) cells, a highly differentiated cell line which retains many characteristics of the cortical collecting duct (CCD). EGF dose dependently regulates basal transepithelial Na(+) transport in two phases: an acute phase (<4 h) and a chronic phase (>8 h). Similar effects were observed with TGF-alpha, HB-EGF, and amphiregulin which also belong to the EGF-related peptide growth factor family. Inhibition of MEK1/2 by PD98059 or U0126 increased acute effects and disrupted chronic effects of EGF on Na(+) reabsorption. Inhibition of PI3-kinase with LY294002 abolished acute effect of EGF. As assessed by Western blotting, ErbB2 is the most predominant member of the ErbB family detected in mpkCCD(c14) cells. Immunohistochemistry analysis revealed localization of ErbB2 in the CCD in Sprague-Dawley rat kidneys. Both acute and long-term effects of EGF were abolished when cells were treated with tyrphostin AG-825 and ErbB2 inhibitor II, chemically dissimilar selective inhibitors of the ErbB2 receptor. Thus, we conclude that EGF and its related growth factors are important for maintaining transepithelial Na(+) transport and that EGF biphasically modulates sodium transport in mpkCCD(c14) cells via the ErbB2 receptor.
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PMID:EGF and its related growth factors mediate sodium transport in mpkCCDc14 cells via ErbB2 (neu/HER-2) receptor. 2004 96


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