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)

Heme oxygenase-1 (HO), the heat shock/stress cognate of the heat shock protein 32 (HSP32) family of proteins, is postulated to be a component of cellular defense mechanisms against oxidative stress-mediated injury. Nitric oxide (NO) is among the extensive array of stimuli that induce HO-1. The cellular signaling mechanisms that regulate the induction of HO-1 by NO are not understood. In the present study, we have demonstrated that exposure of HeLa cells to the NO donor, sodium nitroprusside (SNP), results in concentration and time-dependent increase in HO-1 mRNA and activation of MAPKs: ERK (ERK1 and ERK2) and p38 pathways, but not SAPK/JNK pathway. Pre-treatment of the cells with PD98059, a selective ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, blocked the induction of HO-1 by the NO donor in a dose-dependent manner. In addition, an increase in HO-1 mRNA level that was detected as early as 2 hrs.following SNP treatment preceded c-jun and c-fos induction. These transcription factors are downstream of SAPK/JNK pathway, and their increased expression was detected at 3hr. and 6hr. after SNP treatment. Similarly, AP-1 DNA binding activity was not increased when measured 6 hrs. after SNP treatment. ERK and p38 inhibitors also suppressed induction of HO-1 by SNAP and GSNO. The increase in HO-1 mRNA was inhibited by actinomycin D and cycloheximide, but not by NAC, and was not mimicked by the lipophilic cGMP analogue, 8-bromo-cGMP, suggesting that NO-mediated induction required de novo RNA and protein synthesis and was unrelated to cGMP and redox signaling. Collectively, the findings suggest that MAP kinase ERK and p38 pathways are involved in the NO-mediated induction of HO-1 and that SAPK/JNK pathway and increased DNA binding of AP-1 transcription factor are not involved in HO-1 gene activation by NO. A plausible mechanism by which the NO donors cause HO-1 induction may involve HO-1 gene regulation by its substrate, heme.
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PMID:Nitric oxide induces heme oxygenase-1 via mitogen-activated protein kinases ERK and p38. 1087 47

Through insights into the molecular genetics of neuroendocrine tumors (NETs), the genes predisposing to multiple endocrine neoplasia (MEN) syndromes were identified. In MEN1, tumors occur in the parathyroids, endocrine pancreas, anterior pituitary, adrenal glands and thymic neuroendocrine tissues. The MEN1 gene encodes a putative growth-suppressor protein, menin, binding JunD, a transcriptional factor belonging to the AP-1 complex. However, new partners binding menin remain to be found. The MEN1 gene might be involved in 1-50% of sporadic NETs. Another critical mechanism involved in NETs is the deregulation of the RET-signalling pathways by oncogenic point mutations responsible for MEN2 syndromes. MEN2 refers to the inherited forms of medullary thyroid carcinoma. The RET proto-oncogene, a tyrosine-kinase receptor, is activated by missense mutations occurring either in the extracellular dimerization domain or intracellular tyrosine kinase catalytic regions. In both cases the receptor is constitutionally activated in the absence of natural ligands. Endocrine tumors also belong to the clinical pattern of Recklinghausen (NF1) and von Hippel-Lindau (VHL) diseases. The genes for both syndromes have been characterized and provide new pathways for endocrine tumorigenesis related to G-protein physiology (NF1) and transcriptional regulation and/or endothelial cell proliferation (VHL), respectively. Here, we propose a basic overview of recent data on genetic events leading a normal endocrine cell towards a fully malignant phenotype.
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PMID:Molecular genetics of neuroendocrine tumors. 1094 Jun 82

Intraarticular injection of dexamethasone (DEX) accelerates cartilage degradation due to the suppression of chondrocyte proliferation and extracellular matrix formation. The present study first demonstrated the interaction between DEX and TGF beta, a potent growth factor for cultured rat articular chondrocytes (CRAC), and then investigated the molecular mechanism by which DEX counteracts TGF beta-induced chondrocyte proliferation and differentiation through the regulation of AP-1 activity. DEX reduced serum-deprived and TGF beta-stimulated cell growth and [(3)H]-thymidine incorporation of CRAC. DEX also inhibited the expression of (alpha)1 type II collagen with concomitant suppression of the promoter activity. Transfection studies using a reporter vector with AP-1 responsive elements showed that DEX reduced TGF beta-activated but not basal luciferase activities. Activation of 3TP-luc, another AP-1 responsive element containing reporter was also blocked by DEX. GAL4-Elk1 studies revealed that DEX suppressed TGF beta-induced ERK activation which led to c-fos gene expression followed by increase in AP-1 complex formation, whereas the Smad pathway was not involved in DEX-dependent negative regulation of AP-1 in a reporter assay that requires FAST1-Smad2 for the activation. DEX also eliminated TGF beta-induced c-fos mRNA expression and ERK activation in Northern analysis and in vitro kinase assay, respectively. Further, DNA synthesis and transactivation of type II collagen by TGF beta were inhibited by PD98059, an inhibitor of MEK. Our results indicate that DEX suppressed TGF beta-induced chondrocyte proliferation and type II collagen expression, probably through selective inhibition of ERK integrated AP-1 activation.
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PMID:Dexamethasone inhibition of TGF beta-induced cell growth and type II collagen mRNA expression through ERK-integrated AP-1 activity in cultured rat articular chondrocytes. 1096 45

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal vascular fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolalpha(2)(I) activity in freshly isolated aortas and renal cortical slices (P:<0. 01) followed by similar increase in procolalpha(2)(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFkappaB (PDTC) did not have any effect in the Ang II-induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-fos proto-oncogene. This increase of c-fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-beta (TGF-beta), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-beta-induced activation of procolalpha(2)(I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-beta signaling pathways.
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PMID:Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. 1098 60

We have previously shown that protein kinase C (PKC)-epsilon, nuclear factor (NF)-kappaB, and mitogen-activated protein kinases (MAPKs) are essential signaling elements in ischemic preconditioning. In the present study, we examined whether activation of PKCepsilon affects the activation of NF-kappaB in cardiac myocytes and whether MAPKs are mediators of this signaling event. Activation of PKCepsilon (+108% above control) in adult rabbit cardiomyocytes to a degree that has been previously shown to protect myocytes against hypoxic injury increased the DNA-binding activity of NF-kappaB (+164%) and activator protein (AP)-1 (+127%) but not that of Elk-1. Activation of PKCeta did not have an effect on these transcription factors. Activation of PKCepsilon also enhanced the phosphorylation activities of the p44/p42 MAPKs and the p54/p46 c-Jun NH(2)-terminal kinases (JNKs). PKCepsilon-induced activation of NF-kappaB and AP-1 was completely abolished by inhibition of the p44/p42 MAPK pathway with PD98059 and by inhibition of the p54/p46 JNK pathway with a dominant negative mutant of MAPK kinase-4, indicating that both signaling pathways are necessary. Taken together, these data identify NF-kappaB and AP-1 as downstream targets of PKCepsilon, thereby establishing a molecular link between activation of PKCepsilon and activation of NF-kappaB and AP-1 in cardiomyocytes. The results further demonstrate that both the p44/p42 MAPK and the p54/p46 JNK signaling pathways are essential mediators of this event.
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PMID:PKCepsilon modulates NF-kappaB and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes. 1100 55

While monocyte/macrophage (Mphi) adherence to a matrix is necessary for differentiation and prolonged survival, the effect of adherence on the signaling mechanisms responsible for Mphi activation is unknown. Lipopolysaccharide (LPS) activates Mphi by signaling through members of the mitogen activated protein kinase (MAPK) family thereby inducing transcription of proinflammatory cytokines, such as TNF-alpha. Since adherence has been shown to affect different activities of various myeloid phagocytes, we investigated whether adherence affects intracellular signaling and modulates activation of the Mphi proinflammatory phenotype. We assessed the effect of adherence on activation of rabbit alveolar Mphi by measuring LPS-induced TNF-alpha mRNA and TNF-alpha secreted product in adherent versus nonadherent cells, in vitro. The effect of adherence on LPS-induced activation of MAPK was assessed by western analysis using a dual phosphospecific antibody against p38MAPK, p42,44ERK, and p54SAPK. LPS is known to induce activation of NF-kappaB and AP-1. Modulation of these two transcription factors by LPS under adherent versus nonadherent conditions was evaluated by gel-shift analyses. The results were that adherent cells treated with LPS, 10 ng/mL or 1 microg/ml, elicited a 26- and 132-fold increase, respectively, in TNF-alpha production. Nonadherent cells did not elicit significant TNF-alpha in response to LPS. Adherence alone induced significant ERK and AP-1 activation, but did not stimulate a significant TNF-alpha response and no further activation of ERK and AP-1 was observed with LPS stimulation. Adherence alone did not activate p38MAPK or NF-kappaB, but primed Mphi for an augmented response to LPS in activation of p38, NF-kappaB and in production of TNF-alpha. We conclude that adherence primes Mphi for activation and regulates MAPK signal transduction pathways.
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PMID:Adherence regulates macrophage signal transduction and primes tumor necrosis factor production. 1104 6

In a previous study, we demonstrated that the length of glass fibers was a critical determinant of fiber potency in induction of tumor necrosis factor (TNF)-alpha and that activation of NF-kappaB was an important factor in this response. In the present study, we analyzed the role of mitogen-activated protein (MAP) kinases in the induction of TNF-alpha by glass fibers. Glass fibers induced phosphorylation of MAP kinases, p38, and ERK in primary rat alveolar macrophages, and this phosphorylation was associated with TNF-alpha gene expression. Long fibers were more potent than short fibers in activation of MAP kinases. Results from mechanistic analysis support that MAP kinases activate transcription factor c-Jun. The activated c-Jun acts on the TNF-alpha gene promoter through two binding sites, the cyclic AMP response element and the activator protein 1-binding site. These results suggest that in addition to the NF-kappaB pathway for TNF-alpha production, glass fibers are able to activate c-Jun through MAP kinase pathways that lead to induction of TNF-alpha expression.
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PMID:Activation of mitogen-activated protein kinase p38 and extracellular signal-regulated kinase is involved in glass fiber-induced tumor necrosis factor-alpha production in macrophages. 1108 51

Receptor activator of nuclear factor kappaB (RANK), a lately identified member of the tumor necrosis factor receptor superfamily, plays important roles both in osteoclastogenesis and in lymph node development. Previously, we and others showed that RANK could stimulate the activity of c-Jun N-terminal kinase (JNK). In this study, we investigated the mechanism by which RANK activates JNK. We found that N-terminal deletion mutants of tumor necrosis factor receptor-associated factor 2 and 6 were inhibitory to RANK activation of JNK. The JNK activation by RANK was also reduced by cotransfection of kinase-inactive mutants of apoptosis signal-regulating kinase 1, MAPK/ERK kinase kinase 1, and nuclear factor kappaB-inducing kinase. In addition, dominant negative mutants of Rac and Ras decreased the RANK stimulation of JNK activity. Furthermore, we determined whether the RANK engagement of JNK signaling pathways could lead to the activation of the activator protein 1 (AP-1) transcription factor, one of the potential downstream targets of activated JNK. RANK was found to activate AP-1 in a manner dependent on the signaling molecules involved in the JNK activation by this receptor. Furthermore, the activation of JNK and ERK, but not that of p38, appeared to be involved in the AP-1 activation by RANK. Thus, RANK may use both JNK and ERK pathways to signal to the AP-1 transcription factor.
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PMID:Activation of c-Jun N-terminal kinase and activator protein 1 by receptor activator of nuclear factor kappaB. 1109 94

In pheochromocytoma (PC12) cells nerve growth factor (NGF) and epidermal growth factor (EGF) activate similar receptor tyrosine kinase signaling pathways but evoke strikingly different biological outcomes: NGF induces differentiation and EGF acts as a mitogen. A novel approach was developed for identifying transcription factor activities associated with NGF-activated, but not EGF-activated, signaling, using random oligonucleotide clones from a DNA recognition library to isolate specific DNA binding proteins from PC12 nuclear extracts. A protein complex from NGF-treated, but not EGF-treated, cells was identified that exhibits increased mobility and DNA binding activity in gel mobility shift assays. The binding complex was identified in supershift assays as Fra-2/JunD. The clones used as probes contain either AP-1 or cAMP response element binding (CREB) recognition elements. Time course experiments revealed further differences in NGF and EGF signaling in PC12 cells. NGF elicits a more delayed and sustained ERK phosphorylation than EGF, consistent with previous reports. Both growth factors transiently induce c-fos, but NGF evokes a greater response than EGF. NGF specifically increases Fra-1 and Fra-2 levels at 4 and 24 hr. The latter is represented in Western blots by bands in the 40-46 kDa range. NGF, but not EGF, enhances the upper bands, corresponding to phosphorylated Fra-2. These findings suggest that prolonged alterations in Fra-2 and subsequent increases in Fra-2/JunD binding to AP-1 and CREB response elements common among many gene promoters could serve to trigger broadly an NGF-specific program of gene expression.
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PMID:Nerve growth factor, but not epidermal growth factor, increases Fra-2 expression and alters Fra-2/JunD binding to AP-1 and CREB binding elements in pheochromocytoma (PC12) cells. 1115 Mar 15

The mitochondrial antioxidant enzyme manganese-containing superoxide dismutase (MnSOD) functions as a tumor suppressor gene. Reconstitution of MnSOD expression in several human cancer cell lines leads to reversion of malignancy and induces a resistant phenotype to the cytotoxic effects of TNF and hyperthermia. The signaling pathways that underlie these phenotypic changes in MnSOD-overexpressing cells are unknown, although alterations in the activity of several redox-sensitive transcription factors, including AP-1 and NF-kappaB, have been observed. To determine the downstream signaling molecules involved in MnSOD-induced cell resistant phenotype, in the present study we analyzed the expression profile of several groups of genes related to stress response, DNA repair, and apoptosis, in a human breast cancer MCF-7 cell line overexpressing MnSOD (MCF+SOD). Of 588 genes examined, 5 (0.85%) were up-regulated (2-42-fold), and 11 (1.9%) were down-regulated (2-33-fold) in the MCF+SOD cells compared to the parental MCF-7 cells. The five up-regulated genes were MET, GADD153, CD9, alpha-catenin and plakoglobin. The genes with the most significant down-regulation included: vascular endothelial growth factor receptor 1, TNF-alpha converting enzyme, and interleukin-1beta. GADD153 (involved in the repair of DNA double strand breaks) showed a 33-fold increase in microarray analysis and these results were confirmed by RT-PCR. To further determine the specificity in MnSOD-induced gene regulation, MCF+SOD cells were stably transfected with an antisense MnSOD sequence whose expression was controlled by a tetracycline-inducible regulator. Expression of three up-regulated genes was measured after induction of antisense MnSOD expression. Interestingly, expression level of GADD153 but not MET or CD9 was reduced 24 h after antisense MnSOD induction. Together, these results suggest that reconstitution of MnSOD in tumor cells can specifically modulate the expression of down-stream effector genes. GADD153 and other elements observed in the MCF+SOD cells may play a key role in signaling the MnSOD-induced cell phenotypic change.
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PMID:Genes regulated in human breast cancer cells overexpressing manganese-containing superoxide dismutase. 1116 72


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