Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell adhesion promotes cellular proliferation through the regulation of gene expression, including the immediate early genes. However, the precise role of cell adhesion in the regulation of the c-Myc proto-oncogene is not clear, and the adhesion-dependent signaling pathway(s) regulating the expression of c-Myc has yet to be defined. We now show that integrin signaling directly regulates the expression of c-Myc in the mammary epithelial cell line 184A1N4 (A1N4). Adhesion of quiescent A1N4 cells to fibronectin, and to collagen types IV or I, induces the expression of c-Myc in an ECM concentration-dependent fashion. Cytoskeletal rearrangement, and integrin engagement and integrin clustering are required for the induction of c-Myc by fibronectin. Furthermore, beta1 integrin function-blocking antibodies prevent the adhesion-dependent induction of c-Myc. Adhesion of A1N4 cells results in the activation both of c-Src and of the Erk 1/2 mitogen-activated protein kinase (MAPK), each of which precedes the induction of c-Myc. Pharmacological inhibitors specific for either the c-Src family of kinases or for MEK1 block the adhesion-dependent induction of c-Myc. These observations indicate that beta1 integrins regulate the expression of c-Myc through the activation of the Src family of tyrosine kinases and the MAK kinase pathway.
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PMID:Regulation of the expression of c-Myc by beta1 integrins in epithelial cells. 1131 9

Initiation of translation of the proto-oncogene c-myc can occur by either the cap-dependent scanning mechanism or by internal ribosome entry. The latter mechanism requires a complex RNA structural element that is located in the 5' untranslated region of c-myc, termed an internal ribosome entry segment (IRES). Recent work has shown that IRESs are used to maintain protein expression under conditions when cap-dependent translation initiation is compromised; for example, during mitosis, apoptosis and under conditions of cell stress, such as hypoxia or heat shock. Induction of genotoxic stress also results in a large reduction in global protein synthesis rates and therefore we investigated whether the c-myc IRES was active following DNA damage. As expected, in cells treated with either ethylmethane sulphonate or mitomycin C there was a large reduction in protein synthesis, although this was brought about by two different mechanisms. However, in each case the c-myc IRES was active and c-Myc protein expression was maintained. Finally we showed that the proteins required for this process are downstream of the p38 mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated protein kinase (ERK)/MEK(MAPK/ERK kinase) signalling pathways, since pre-treatment of cells with inhibitors of these pathways before DNA damage is initiated inhibits both c-myc IRES activity and expression of c-Myc protein.
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PMID:Internal ribosome entry segment-mediated initiation of c-Myc protein synthesis following genotoxic stress. 1156 82

Extracellular signals are transduced into cells through mitogen-activated protein kinases (MAPKs), which are activated by their upstream kinases. Recently, families of scaffolding proteins have been identified to tether specific combinations of these kinases along specific signaling pathways. Here we describe a protein, JLP (c-Jun NH2-terminal kinase-associated leucine zipper protein), which acts as a scaffolding protein to bring together Max and c-Myc along with JNK (c-Jun NH2-terminal kinase) and p38MAPK, as well as their upstream kinases MKK4 (MAPK kinase 4) and MEKK3 (MAPK kinase kinase 3). Thus, JLP defines a family of scaffolding proteins that bring MAPKs and their target transcription factors together for the execution of specific signaling pathways.
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PMID:JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors. 1239 7

Rel/NF-kappaB transcription factors regulate the division and survival of B lymphocytes. Here we show that B cells lacking NF-kappaB1 and c-Rel fail to increase in size upon mitogenic stimulation due to a reduction in induced c-myc expression. Mitogen-induced B cell growth, although not markedly impaired by FRAP/mTOR or MEK inhibitors, required phosphatidylinositol 3-kinase (PI3K) activity. Inhibition of PI3K-dependent growth coincided with a block in the nuclear import of NF-kappaB1/c-Rel dimers and a failure to upregulate c-myc. In addition, PI3K was shown to be necessary for a transcription-independent increase in c-Myc protein levels that accompanies mitogenic activation. Collectively, these findings establish a role for Rel/NF-kappaB signaling in the mitogen-induced growth of mammalian cells, which in B lymphocytes requires a PI3K/c-myc-dependent pathway.
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PMID:B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription. 1250 5

IL-16 is a ligand and chemotactic factor for CD4+ T cells. IL-16 inhibits the CD3 mediated lymphocyte activation and proliferation. The effects of IL-16 on the target cells are dependent on the cell type, the presence of co-activators etc. To understand the regulation function and mechanism of IL-16 on target cells, we used a 130 a.a. recombinant IL-16 to study its effects on the growth of Jurkat T leukemia cells in vitro. We found that the rIL-16 stimulated the proliferation of Jurkat cells at low dose (10(-9)M), but inhibited the growth of the cells at higher concentration (10(-5)M). Results showed that 10(-5) M of rIL-16 treatment induced an enhanced apoptosis in Jurkat cells. The treatment blocked the expression of FasL, but up-regulated the c-myc and Bid expression in the cells. Pre-treatment of PKC inhibitor or MEK1 inhibitor markedly increased or decreased the rIL-16 induced growth-inhibiting effects on Jurkat cells, respectively. The results suggested that the rIL-16 might be a regulator for the growth or apoptosis of Jurkat cells at a dose-dependent manner. The growth-inhibiting effects of rIL-16 might be Fas/FasL independent, but, associated with the activation of PKC, up-regulated expression of c-Myc and Bid, and the participation of the ERK signal pathway in Jurkat cells.
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PMID:The associated regulators and signal pathway in rIL-16/CD4 mediated growth regulation in Jurkat cells. 1252 94

Connexin 43 (Cx43) is essential for survival and is tightly regulated at the transcriptional and post-transcriptional levels. A number of previous studies have demonstrated altered expression in malignant tissues, and in the presence of carcinogenic factors. We examined the effect of protooncogenes of Cx43 expression, and found no effect on Cx43 promoter activity in cells transformed with Src or erbB2. On the other hand, we identified and characterized a novel sequence that mediates Cx43 promoter regulation in cell lines engineered to overexpress H-Ras. Compared with wild-type NIH3T3 cells, both Cx43 mRNA and protein levels are increased in NIH3T3-Ras cells. The H-Ras+ cells also have enhanced Cx43 promoter activation, which is inhibited by the MEK1 inhibitor 2'-amino-3'-methoxyflavone (PD98059), suggesting that Ras-mediated Cx43 overexpression is via the mitogen activated protein kinase kinase/extracellular signal-regulated pathway. Deletion analysis of the Cx43 promoter revealed a 200-bp region downstream of the Cx43 transcription start site as the minimal sequence essential for the Ras-mediated Cx43 up-regulation. Using this 200-base pair fragment in electrophoretic mobility shift assays, we identified one main protein complex that binds efficiently and is more abundant in nuclear extracts from NIH3T3-Ras and MCF7-Ras cells compared with their matched controls. This complex selectively recognizes a consensus sequence, AGTTCAATCA, located at positions +149 to +158 of the Cx43 promoter. Supershift assays identified the 90-kDa heat shock protein (HSP90) and c-Myc as constituents of this DNA-binding complex. Treatment of cells with the HSP90 inhibitor geldanamycin resulted in repression of the Cx43 promoter activity, and inhibits binding of the complex to the Cx43 promoter. Coimmunoprecipitation studies confirmed the interaction between endogenous HSP90 and c-Myc. This study provides evidence that the transcriptional up-regulation of Cx43 by Ras-Raf-MAPK is mediated via the interaction of a novel Cx43 promoter element with a protein complex that contains both HSP90 and c-Myc.
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PMID:Unexpected induction of the human connexin 43 promoter by the ras signaling pathway is mediated by a novel putative promoter sequence. 1264 83

Cell transformation by growth-promoting oncoproteins renders cells extremely sensitive to apoptosis through an unknown mechanism affecting the mitochondrial pathway of apoptosis. We have shown previously that sensitization to apoptosis also correlated with the activation of the stress-activated protein kinase p38. In the present study, we investigated the role of p38 in c-Myc-dependent apoptosis induced by the anticancer agent cisplatin. Cisplatin treatment of Rat1 cells with deregulated expression of c-Myc resulted in nuclear fragmentation that was accompanied in all cells by the activation of Bax and the translocation of cytochrome c from the mitochondria to the cytoplasm. None of these features of apoptosis was induced in control Rat-1 cells. p38 was also activated by cisplatin only in cells with deregulated expression of c-Myc, but, in contrast with all features of apoptosis, this activation was not affected by Bcl-2. Remarkably, overexpression of an interfering mutant of the p38alpha isoform, but not p38beta, blocked cisplatin-induced Bax activation or cytochrome c release and nuclear fragmentation. Analysis of the kinase cascade upstream of p38 revealed a c-Myc-dependent activation by cisplatin of mitogen-activated protein kinase kinase (MKK) 3/6 and apoptosis signal-regulating kinase 1 (Ask1). Inhibition of Ask1 blocked p38 activation by cisplatin and all features of apoptosis. Several of these data were confirmed using other DNA-damaging agents. The findings indicated that c-Myc potentiation of the mitochondrial pathway of apoptosis results, at least in part, from a sensitization of Ask1 activation, allowing DNA-damaging agents to induce in cascade Ask1, p38alpha and Bax.
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PMID:c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade. 1264 44

In earlier studies, we and others have established that activation of EGFR can promote survival in association with upregulation of Bcl-x(L). However, the mechanism responsible for upregulation of Bcl-x(L) is unknown. For the current studies we have chosen pro-apoptotic, c-Myc-overexpressing murine mammary epithelial cells (MMECs) derived from MMTV-c-Myc transgenic mouse tumors. We now demonstrate that EGFR activation promotes survival through Akt and Erk1/2. Blockade of EGFR kinase activity and the PI3-K/Akt and MEK/Erk pathways with pharmacological inhibitors resulted in a significant induction of cellular apoptosis, paralleled by a downregulation of both Akt and Erk1/2 proteins. Consistent with a survival-promoting role of Akt, we observed that constitutively activated Akt (Myr-Akt) inhibited apoptosis of pro-apoptotic, c-Myc-overexpressing cells following the inhibition of EGFR tyrosine kinase activity. In addressing possible downstream effectors of EGFR through activated Akt, we detected significant upregulation of Bcl-x(L) protein, suggesting this pro-survival protein is a target of Akt in MMECs. By using pharmacological inhibitors of PI3-K/Akt and MEK/Erk together with dominant-negative Akt and Erk1 we observed the decrease in Bcl-x(L) protein. Our findings may be of importance for understanding the emerging role of Bcl-x(L) as a potential marker of poor prognosis in breast cancer.
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PMID:Epidermal growth factor inhibition of c-Myc-mediated apoptosis through Akt and Erk involves Bcl-xL upregulation in mammary epithelial cells. 1283 94

Although there is no current evidence for ras gene mutation in choroidal melanoma, there is an increasing body of evidence indicating that deregulated intracellular signalling pathways are involved in choroidal melanoma pathogenesis. The various components of the linear Raf/MEK/ERK signalling pathway have been implicated in various tumours. We therefore investigated the role of Raf-1 and the MEK/ERK module in the proliferation of human normal choroidal melanocytes (NCM) and cells from the ocular choroidal melanoma (OCM-1) cell line. OCM-1 cells proliferated four times faster than NCM. High basal activation of the MEK/ERK module was observed in unstimulated OCM-1 cells, whereas rapid and persistent activation was detected after serum stimulation, throughout the 24-h period of culture. In contrast, the activation of MEK/ERK was barely detectable in unstimulated NCM and occurred late (6 h) after the stimulation of cell proliferation. Inhibition of Raf-1 and MEK1/2 activation by pharmacological approaches and of the production of Raf-1 and ERK1/2 by antisense oligonucleotide approaches demonstrated that Raf-1 and the MEK/ERK module controlled proliferation in OCM-1 cells, but not in NCM. OCM-1 cells produced very low levels of p27Kip1, whereas NCM produced constant, high levels of p27Kip1. The inhibition of Raf-1 or MEK1/2 induced a large increase in p27Kip1 in OCM-1 cells, associated with an arrest of cell proliferation. Levels of c-Myc production were high and constant in OCM-1 cells and low in NCM, in contrast to what was observed for p27Kip1. The inhibition of both Raf-1 and MEK1/2 induced a decrease in c-Myc production and downregulated c-Myc activity by preventing c-Myc phosphorylation in OCM-1 cells. We conclude that Raf-1 and the MEK/ERK module control the production of both p27Kip1 and c-Myc, and the activation of c-Myc for OCM-1 cell proliferation.
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PMID:Opposite long-term regulation of c-Myc and p27Kip1 through overactivation of Raf-1 and the MEK/ERK module in proliferating human choroidal melanoma cells. 1465 78

MAPK (mitogen-activated protein kinase) pathways constitute major regulators of cellular transcriptional programmes. We analysed the ERK1,2 (extracellular-signal-regulated kinase 1,2) transcriptome in a non-transformed MEC (mammary epithelial cell) line, MCF-12A, utilizing rAd MEK1EE, a recombinant adenovirus encoding constitutively active MEK1 (MAPK/ERK kinase 1). rAd MEK1EE infection induced morphological changes and DNA synthesis which were inhibited by the MEK1,2 inhibitor PD184352. Hierarchical clustering of data derived from seven time points over 24 h identified 430 and 305 co-ordinately up-regulated and down-regulated genes respectively. c-Myc binding sites were identified in the promoters of most of these up-regulated genes. A total of 46 candidate effectors of the Raf/MEK/ERK1,2 pathway in MECs were identified by comparing our dataset with previously reported Raf-1-regulated genes. These analyses led to the identification of a suite of growth factors co-ordinately induced by MEK1EE, including multiple ErbB ligands, vascular endothelial growth factor and PHRP (parathyroid hormone-related protein). PHRP is the primary mediator of humoral hypercalcaemia of malignancy, and has been implicated in metastasis to bone. We demonstrate that PHRP is secreted by MEK1EE-expressing cells. This secretion is inhibited by PD184352, but not by ErbB inhibitors. Our results suggest that, in addition to anti-proliferative properties, MEK1,2 inhibitors may be anti-angiogenic and possess therapeutic utility in the treatment of PHRP-positive tumours.
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PMID:Analysis of the ERK1,2 transcriptome in mammary epithelial cells. 1510 7


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