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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.
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PMID:Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. 748 20

EGF and related polypeptides are involved in the regulation of cell growth and differentiation of continuously regenerating tissues, in tissue repair processes and in placental and fetal development. Their initial mode of action generally constitutes binding to specific plasma membrane localized receptors, transduction of the signal across the plasma membrane, subsequent activation of signalling pathways in the cell, and the induction of early nuclear gene expression. EGF-induced signal transmission from the plasma membrane to the nucleus has been studied in microgravity in order to gain insight in the molecular mechanisms that constitute the effects of gravity on cell growth. Exposure of human A431 cells to microgravity strongly suppresses EGF- and PMA-induced c-fos and c-jun expression. In contrast, forskolin- and A23187-induced c-fos expression and constitutive beta-2 microglobulin expression remain unaffected. This suggests that microgravity differentially modulates EGF-induced signal transduction pathways. Since both EGF and PMA are known to be activators of PKC, which is not the case for forskolin and A23187, PKC-mediated signal transduction may be a cellular target for microgravity. Inhibition of EGF-induced c-fos expression by microgravity occurs downstream of the initiation of EGF-induced signal transduction, i.e., EGF binding and EGFR redistribution. In addition to PKC signaling, actin microfilament organization appears to be sensitive to microgravity. Therefore, the inhibition of signal transduction by microgravity may be related to alterations in actin microfilament organization. The fact that early gene expression is affected by agents that alter the organization of the actin microfilament system supports this hypothesis. The decrease in c-fos and c-jun expression in microgravity may result in the decreased formation of the FOS and JUN proteins. Consequently, a short-term reduction in gene expression in microgravity may have a more dramatic effect over the long term, since both the JUN and FOS protein families are required for normal cell cycle progression. However, since more than 20 years of manned spaceflight have shown that humans can survive in microgravity for prolonged periods, it appears that cells in the human body can partly or completely overcome gravitational stress. Although some insight in the molecular basis on human cells has been obtained, future studies will be needed for a better understanding of the grounds for alterations in the cellular biochemistry due to altered gravity conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of gravity on the cellular response to epidermal growth factor. 775 50

Amplifications of cellular oncogenes and growth factor genes have previously been reported in gliomas. Here we have evaluated 21 gliomas for amplification of tumor related genes including NMYC, EGFR, TGFalpha, MET, CMYC, SRC, HRAS, NRAS, SEC, ROS1, JUN, and WNT1. Five amplifications were observed. The epidermal growth factor receptor (EGFR) gene was amplified in 4 glioblastomas. The oncogene MET was amplified in a glioblastoma which showed no EGFR gene amplification. Importantly, both genes are located on chromosome 7 and belong to a family with tyrosine kinase activity. There was no amplification found for TGFalpha which was previously reported to be amplified in gliomas. The finding of MET and EGFR independently amplified in glioma lends further support to a crucial role of chromosome 7 in the development of gliomas.
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PMID:Two independent amplification events on chromosome 7 in glioma: amplification of the epidermal growth factor receptor gene and amplification of the oncogene MET. 801 63

The c-MET proto-oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), also known as scatter factor, a potent mitogen and motogen for epithelial cells. The level of the HGF receptor expressed by epithelial cells varies in different growth conditions, being lower in growth arrested confluent monolayers and higher in growing sparse cells. The amount of HGF receptor mRNA increases from 3- to 5-fold after stimulation of confluent monolayers by serum and up to 10-fold after stimulation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (TPA). An increased level of the receptor mRNA was also observed after cell stimulation with nanomolar concentration of HGF itself. The effect was transient, dose, and time-dependent. Transcription of a reporter gene under control of the cloned 297 base pair c-MET promoter was also stimulated by serum, TPA, or HGF. The accumulation of specific mRNA is followed by appearance of the HGF receptor precursor protein, which is further processed to the receptor mature form. After HGF stimulation, HGF receptor expression follows c-FOS and c-JUN induction with a peak approximately 4 h. Pretreatment with the protein synthesis inhibitor puromycin strongly reduced the response to HGF, while cycloheximide alone increased the level of the receptor mRNA. These data show that c-MET behaves as a delayed early-response gene and suggest that the HGF response is autoamplified by inducing the specific receptor.
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PMID:Hepatocyte growth factor (HGF) receptor expression is inducible and is part of the delayed-early response to HGF. 817 99

Non-small cell lung carcinoma specimens of 173 previously untreated patients were analyzed for the expression of proteins encoded by the oncogenes c-myc, c-fos, c-jun, c-erbB-1, c-erbB-2, c-H-ras, c-K-ras and c-N-ras. Forty-six per cent of the tumors were positive for the c-MYC protein, 60% for c-FOS, 50% for c-JUN, 80% for c-ERBB-1, 55% for c-ERBB-2, 12% for c-H-RAS, 5% for c-K-RAS and 71% for c-N-RAS. Proteins encoded by c-fos and c-jun are overexpressed more frequently in carcinomas of smokers (c-fos: P < 0.005; c-jun: P < 0.01). When we grouped the patients according to their tumor histology the results became more evident. Squamous cell lung carcinomas of smokers showed a higher incidence of c-FOS (P = 0.01), c-JUN (P < 0.01) and c-ERBB-1 (P = 0.01) proteins than squamous cell lung carcinomas of non-smokers. The expression rate and the intensity of staining proved not to be influenced either by the number of cigarettes smoked daily or by cessation of smoking. In adenocarcinomas, however, we only found a trend for a more frequent overexpression of c-fos (P = 0.07) and c-jun (P = 0.14) encoded proteins in carcinomas of smokers and no correlation between the expression of c-erbB-1 products and smoking. No correlation was found between the expression of c-MYC, c-ERBB-2, c-H-RAS, c-K-RAS and c-N-RAS proteins and the smoking habits of the patients, neither in squamous cell carcinomas nor in adenocarcinomas of the lung.
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PMID:Overexpression of oncoproteins in non-small cell lung carcinomas of smokers. 838 72

We report a case of chronic myelomonocytic leukemia in which cytogenetic analysis revealed a 47,XY, +1, +der(7)del(7)(q32q36)ins(7;1)(q32;p36.3p22) chromosomal constitution. This abnormal karyotype, which as a whole is new to any myeloid malignancy, points to a possible pathogenetic role for the oncogenes MET and FGR on the derivative chromosome 7, and for the CSF1 and JUN genes flanking the breakpoint on chromosome 1.
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PMID:An unusual cytogenetic abnormality involving chromosomes 1 and 7 in a case of chronic myelomonocytic leukemia. 853 43

We have studied the contribution of the individual kinases of the MAP (mitogen-activated protein) kinase family, including ERK (extracellular-signal regulated kinase), JNK/SAPK (c-JUN NH2-terminal kinase/stress-activated protein kinase) and p38, to activation of the HSP27 (heat shock protein 27) kinase MAPKAP kinase-2/3 and to HSP27 phosphorylation in Chinese hamster CCL39 cells stimulated by either growth factors, cytokines or stressing agents. In vitro assays using fractionated cell extracts or immunoprecipitates indicated that only fractions containing ERK or p38, and not those containing JNK/SAPK, had the capacity to activate MAPKAP kinase-2/3. In vivo, however, it appeared that only p38 is an upstream activator of HSP27 phosphorylation after both stress or growth factor stimulation: expression of an interfering mutant of ras, which blocked the activation of ERK by both types of inducers, had no effect on HSP27 phosphorylation and p38 activation; and the cell-permeant specific inhibitor of 038, SB203580, blocked MAPKAP-kinase2/3 activation and HSP27 phosphorylation. HSP27 has been suggested to have a phosphorylation-activated homeostatic function at the actin cytoskeleton level. This raises the possibility that p38 might be directly involved in mediating actin responses to external stimuli. Accordingly, we observed that a prior activation of p38 increased the stability of the actin microfilaments in cells exposed to cytochalasin D. The effect was dependent on the expression of HSP27 and was totally annihilated by blocking the p38 activity with SB203580. The results provide strong support to the idea that activation of p38 during adverse environmental conditions serves a homeostatic function aimed at regulating actin dynamics that would otherwise be destabilized during stress. Its activation during normal agonist stimulation may constitute an additional actin signaling pathway, the importance of which depends on the level of expression of HSP27.
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PMID:Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. 905 88

Epidermal growth factor (EGF) plays a major role in non-small cell lung cancer cell autocrine growth and has been reported to activate the JUN kinase/stress-activated protein kinase (JNK/SAPK) pathway in model cells. Activation of JNK/SAPK leads to the phosphorylation of c-JUN protooncogene on serines 63 and 73. This mechanism is required for and cooperates in the transformation of rat embryo fibroblasts by Ha-RAS. However, the function of JNK/SAPK in human tumor growth is unknown. We have tested several lung carcinoma cell lines. All exhibited UV-C-inducible JNK/SAPK activity; two exhibited constitutive activity in low serum, and two (M103 and A549) exhibited EGF-inducible JNK/SAPK activity. In A549 cells, EGF induced a rapid and prolonged (up to 24 h) activation of the JNK/SAPK pathway that correlated with a 150-190% growth stimulation. Stably transfected clones of A549 cells expressing c-JUN(S63A,S73A), a transdominant inhibitor of c-JUN, completely blocked the EGF-stimulated proliferation effect but did not alter the basal proliferation rate. Consistent with these results JNK antisense oligonucleotides targeted to JNK1 and JNK2 entirely eliminated the EGF-stimulated JNK/SAPK activity and blocked EGF-stimulated growth but not basal growth. In contrast, specific inhibition of the RAF/ERK pathway by PD98059 (MEK1 inhibitor) completely blocked ERK activation by EGF and basal cell growth but not EGF-stimulated growth, thereby dissociating the growth-promoting roles of each pathway. Our observations indicate, for the first time, that JNK/SAPK may be a preferential effector pathway for the growth properties of EGF in A549 cells.
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PMID:The JUN kinase/stress-activated protein kinase pathway is required for epidermal growth factor stimulation of growth of human A549 lung carcinoma cells. 940 38

Gene alterations in the ret proto-oncogene, which encodes a receptor tyrosine kinase, have been found to associate with several human diseases. In this study, we showed that induction of the vgf promoter activity is a good molecular indicator for RET activation in PC12 cells, a rat pheochromocytoma cell line. We demonstrated that all forms of RET oncoprotein, including RET chimeric oncoproteins found in human papillary thyroid carcinomas (RET/PTC) as well as RET oncoproteins found in patients with multiple endocrine neoplasia type 2A and 2B (2A/RET and 2B/RET) can induce vgf promoter activity in PC12 cells. In contrast, a RET mutant found in a patient with Hirschsprung's disease, as well as a RET/PTC1 mutant with deletion of the dimerization domain, failed to induce vgf promoter activity in PC12 cells. We further determined that the signaling events mediated by phosphorylated Tyr294 and phosphorylated Tyr451 binding sites are essential for RET/PTC1 to induce vgf promoter activity in PC12 cells. We also showed that RET/PTC1, 2A/RET, and 2B/RET induce ELK-, cAMP-responsive element binding protein (CREB), or JUN-mediated gene expression in PC12 cells, and these three signaling events are mediated by phosphorylated Tyr294 and phosphorylated Tyr451 binding sites in RET/PTC1.
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PMID:Signal transduction pathways activated by RET oncoproteins in PC12 pheochromocytoma cells. 947 34

Patients with previously untreated squamous cell lung carcinomas were evaluated to see if combining the expression of molecular and cellular factors with the most important clinical prognostic factors could improve the diagnostic ability to predict prognosis. For this reason, immunohistochemistry was used to examine the squamous cell lung carcinomas from 121 patients for their expression of ERBB-1, vascular endothelial growth factor (VEGF), cyclin A, FOS, JUN and MYC. Median survival was shorter for patients with ERBB-1-, VEGF-, cyclin A-, FOS-, or JUN-positive tumours. For those patients with positive lymph node involvement, the survival times were also shorter in the VEGF-positive, cyclin A-positive and FOS-positive groups. Multivariate analysis independently demonstrated a significant prognostic value for lymph node involvement, VEGF and FOS.
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PMID:Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas. 948 27


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