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)

Cell-cycle progression is mediated by a co-ordinated interaction between cyclin-dependent kinases and their target proteins including the pRB and E2F/DP-1 complexes. Immunoneutralization and antisense experiments have established that the abundance of cyclin D1, a regulatory subunit of the cyclin-dependent kinases, may be rate-limiting for G1 phase progression of the cell cycle. Simian virus 40 (SV40) small tumor (t) antigen is capable of promoting G1 phase progression and augments substantially the efficiency of SV40 transformation through several distinct domains. In these studies, small t antigen stimulated cyclin D1 promoter activity 7-fold, primarily through an AP-1 binding site at -954 with additional contributions from a CRE site at -57. The cyclin D1 AP-1 and CRE sites were sufficient for activation by small t antigen when linked to an heterologous promoter. Point mutations of small t antigen between residues 97-103 that reduced PP2A binding were partially defective in the induction of the cyclin D1 promoter. These mutations also reduced activation of MEK1 and two distinct members of the mitogen-activated protein kinase family, the ERKs (extracellular signal regulated kinases) and the SAPKs (stress-activated protein kinases), in transfected cells. Dominant negative mutants of either MEK1, ERK or SEK1, reduced small t-dependent induction of the cyclin D1 promoter. SV40 small t induction of the cyclin D1 promoter involves both the ERK and SAPK pathways that together may contribute to the proliferative and transformation enhancing activity of small t antigen.
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PMID:Induction of cyclin D1 by simian virus 40 small tumor antigen. 891 10

Trivalent arsenic (As3+) is highly carcinogenic, but devoid of known mutagenic activity. Therefore, it is likely to act as a tumor promoter. To understand the molecular basis for the tumor-promoting activity of As3+, we examined its effect on transcription factor AP-1, whose activity is stimulated by several other tumor promoters. We found that As3+, but not As5+, which is toxic but not carcinogenic, is a potent stimulator of AP-1 transcriptional activity and an efficient inducer of c-fos and c-jun gene expression. Induction of c-jun and c-fos transcription by As3+ correlates with activation of Jun kinases (JNKs) and p38/Mpk2, which phosphorylate transcription factors that activate these immediate early genes. No effect on ERK activity was observed. As5+, on the other hand, had a negligible effect on JNK or p38/Mpk2 activity. Biochemical analysis and co-transfection experiments strongly suggest that the primary mechanism by which As3+ stimulates JNK activity involves the inhibition of a constitutive dual-specificity JNK phosphatase. This phosphatase activity appears to be responsible for maintaining low basal JNK activity in non-stimulated cells and its inhibition may lead to tumor promotion through induction of proto-oncogenes such as c-jun and c-fos, and stimulation of AP-1 activity. The same phosphatase may also regulate p38/Mpk2 activity.
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PMID:The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase. 894 50

A variety of injuries, such as bacterial infection or ischemic tissue necrosis, induce systemic acute phase reaction expressed as fever, leukocytosis, release of several hormones, activation of clotting, complement and kinin forming pathways, and drastic increase of synthesis of certain plasma proteins. The reaction is triggered by 'alarm molecules', including free radicals, which activate several stress-sensitive protein kinases (ERK, p38, JNK) in macrophages and other responsive cells. These kinases phosphorylate, usually in a multi-step cascade, transcription factors belonging primarily to C/EBP, NF-kappa B and AP-1 families. Active transcription factors after translocation to nucleus interact with responsive elements in the gene promoters of acute-phase cytokines: tumor necrosis factor-alpha, interleukin-1 and interleukin-6. Enhanced transcription of these genes is usually followed by rapid translation and precursor protein processing leading to the release of biologically active cytokines. Fine tuning of the acute phase response appears to be regulated at all stages: primary signals, kinase cascades, transcription factors, mRNA stability and translation, cytokine precursor processing, secretion and bioavailability. This makes possible designing of specific inhibitors of cytokine synthesis as potential therapeutic drugs.
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PMID:Initiation of acute phase response and synthesis of cytokines. 895 Jan 92

Urokinase-type plasminogen activator (uPA) expression is induced upon cytoskeletal reorganization (CSR) by a mechanism independent of protein kinase C and cAMP protein kinase in nontransformed renal epithelial (LLC-PK1) cells. This CSR-dependent uPA gene activation is mediated by an AP-1-recognizing element located 2 kilobases upstream of the transcription initiation site. The phosphorylation of c-Jun, a component of AP-1, is induced by CSR, which seems to increase both the activity and stability of c-Jun (Lee, J. S., von der Ahe, D., Kiefer, B., and Nagamine, Y. (1993) Nucleic Acids Res. 21, 3365-3372). It has been shown that c-Jun is phosphorylated by members of the mitogen-activated protein kinase family, i.e. ERKs and JNKs. ERKs are activated through a growth factor-coupled Ras/Raf-dependent signaling pathway, while JNKs are activated through a stress-induced signaling pathway. Although CSR induces both ERK-2 and JNK activity, JNK does not seem to be involved in the uPA gene induction because UV irradiation, which activates JNK as efficiently as CSR, does not activate the uPA promoter. Further analysis showed the involvement of SOS, Ras, and Raf-1 in the pathway induced by CSR. Our results suggest that cells sense changes in cell morphology using the cytoskeleton as a sensor and respond by activating the ERK-involving signaling pathway from within the cell.
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PMID:Cytoskeleton reorganization induces the urokinase-type plasminogen activator gene via the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. 899 79

The activation of transcriptional factor c-Fos/c-Jun AP-1 is essential for normal T cell responsiveness and is often impaired in T cells during aging. In the present study, we investigated whether aberrancies in the regulation of c-fos/c-jun at the mRNA or protein level might underlie the age-associated impairments of AP-1 in human T cells. Whereas T cells from young subjects stimulated with cross-linked anti-CD3epsilon mAb OKT3 plus PMA or with the lectin PHA plus PMA demonstrated considerable increases in c-Fos protein expression, the expression of c-Fos but not c-Jun was markedly reduced in stimulated T cells from certain elderly subjects. In addition, RNase protection assays revealed that anti-CD3/PMA-stimulated T cells from a substantial proportion of elderly subjects exhibited decreased levels of c-fos and/or c-jun mRNA compared to T cells from young subjects. Using electrophoretic mobility shift assays, the levels of nuclear regulatory proteins recognizing the AP-1 consensus TRE motif, the proximal c-jun TRE-like promoter element, and the c-fos serum response element (SRE) were determined in resting and stimulated T cells. Although the stimulation of T cells from young subjects resulted in coordinated increases of nuclear protein complexes binding the AP-1 TRE, c-jun TRE, and c-fos SRE DNA sequence motifs, age-related reductions in the activation of AP-1 were accompanied by decreased levels of c-jun TRE and c-fos SRE binding complexes. Furthermore, the nuclear protein complexes binding the SRE motif induced in activated T cells of young and elderly subjects contained serum response factor and Elk-1 pointing toward age-related defects in the activation of transcriptional regulatory proteins distinct from c-jun/AP-1. These results suggest that underlying aberrancies in the induction of c-fos/c-jun as well as their nuclear regulatory proteins may contribute to the age-related impairments of AP-1 activation in human T cells.
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PMID:Impaired induction of c-fos/c-jun genes and of transcriptional regulatory proteins binding distinct c-fos/c-jun promoter elements in activated human T cells during aging. 901 87

Intracellular reactive oxygen intermediate (ROI) levels play an important role in numerous physiological and pathophysiological conditions. Apart from causing oxidative stress and damage, ROI changes differentially activate gene expression. However the proto-oncogene encoding the AP-1 transcription factor subunit c-Fos is induced by both prooxidants and antioxidants. Here, the transcription factor Elk-1 is identified as being responsible for c-fos serum response element (SRE) induction in response to changes in the cellular redox status induced by treatment with either the oxidant H2O2 or various structurally unrelated antioxidants. A temporal correlation is observed between changes in the phosphorylation status of Elk-1 and the activation of the mitogen-activated protein kinase 2 (ERK2) in response to cellular redox changes. Correspondingly, the transcriptional response of the SRE to redox fluctuations is attenuated upon mutation of critical ERK2 target residues within the Elk-1 transactivation domain to alanine. Signals elicited by antagonistic intracellular redox changes converge at or above the level of Ras or an effector of Ras, leading to similar activation of c-fos transcription, since an [N17]Ras mutant interfered with redox signaling. Hence components of signaling pathways are revealed to be shared by mitogenic and redox-dependent stimuli.
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PMID:Antioxidants as well as oxidants activate c-fos via Ras-dependent activation of extracellular-signal-regulated kinase 2 and Elk-1. 906 44

After insulin receptor activation, many cytoplasmic enzymes, including mitogen-activated protein (MAP) kinase, MAP kinase kinase (MEK) and casein kinase II (CKII) are activated, but exactly how insulin signalling progresses to the nucleus remains poorly understood. In Chinese hamster ovary cells overexpressing human insulin receptors [CHO(Hirc)], MEK, CKII and the MAP kinases ERK I and ERK II can be detected by immunoblotting in the nucleus, as well as in the cytoplasm, in the unstimulated state. Nuclear localization of MAP kinase is also observed in 3T3-F442A adipocytes, NIH-3T3 cells and Fao hepatoma cells, whereas MEK is found in the nucleus only in Fao and CHO cells. Insulin treatment for 5-30 min induces a translocation of MEK from the cytoplasm to the nucleus, whereas the MAP kinases and CKII are not translocated into the nucleus in response to insulin during this period. However, nuclear MAP kinase and CKII activities increase by 2-3-fold within 1-10 min after stimulation with insulin. By using gel-shift assays, it has been shown that insulin also stimulates nuclear protein binding to an AP-1 site with kinetics similar to MEK translocation and MAP kinase and CKII activation. Treatment of the extracts in vitro with protein phosphatase 2A or treatment of the intact cells with 5, 6-dichloro-1-beta-d-ribofuranosylbenzimidazole, a cell-permeable inhibitor of CKII, almost completely blocks the insulin-induced DNA-binding activity, whereas incubation of cells with a MEK inhibitor produces only a slight decrease. These results suggest that insulin signalling results in the activation of serine kinases in the nucleus via two pathways: (1) insulin stimulates the nuclear translocation of some kinases, such as MEK, which might directly phosphorylate nuclear protein substrates or activate other nuclear kinases, and (2) insulin activates nuclear kinases without translocation. The latter is true of CKII, which seems to regulate the binding of nuclear proteins to the AP-1 site, possibly by phosphorylation of AP-1 transcription factors.
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PMID:Insulin regulation of mitogen-activated protein kinase kinase (MEK), mitogen-activated protein kinase and casein kinase in the cell nucleus: a possible role in the regulation of gene expression. 916 93

Recent experiments have elucidated two molecular mechanisms that may account for the failure of anergic T cell clones to initiate IL-2 gene transcription following TCR stimulation. First, a block has been identified in the ERK and JNK mitogen-activated protein kinase pathways; the block results from a failure to activate p21ras. It leads to reduced induction of c-Fos and JunB proteins and to a failure to form and phosphorylate the activator protein (AP)-1 heterodimers required for IL-2 gene transcriptional activation. Second, repressor molecules (Nil-2-a and a molecule related to AP-1) have been characterized that dominantly inhibit IL-2 gene transcription.
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PMID:T cell clonal anergy. 920 8

More than 60% of anaplastic large-cell lymphomas (Ki-1 lymphoma) are associated with a t(2;5)(p23;q35) translocation that produces an 80 kDa hyperphosphorylated chimeric protein (p80) derived from the fusion of the anaplastic lymphoma kinase (ALK) with nucleophosmin (NPM). The NPM-ALK chimeric gene is an activated tyrosine kinase that has been shown to be a potent oncogene. We have developed a cellular model for the study of p80 action in rat 1a fibroblasts. Expression of cDNA's encoding NPM-ALK (p80) in rat 1a fibroblasts induces anchorage-independent growth in soft agar and promotes foci formation in culture. Cells expressing exogenous p80 showed significantly increased proliferation characterized by accelerated cell cycle entry into S-phase. Consistent with increased G0/G1 to S-phase transition, there is also marked up-regulation of cyclin A and cyclin D1 expression. In addition, p80 transformed cells showed elevated expression of several immediate early genes involved in cellular proliferation, including fos, jun, and c-myc. DNA binding analysis of nuclear extracts prepared from p80 transformed cells reveal marked up-regulation of AP-1 DNA binding activity. Functional AP-1-specific transfection assays also show up-regulation of AP-1-dependent transcriptional activation. These finding demonstrate that p80 transformed rat 1a fibroblast can be a highly useful model system for the molecular and biochemical characterization of the mechanisms of action of this interesting new oncogene.
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PMID:The activated anaplastic lymphoma kinase increases cellular proliferation and oncogene up-regulation in rat 1a fibroblasts. 933 49

The small GTPase RhoB is immediate-early inducible by DNA damaging treatments and thus part of the early response of eukaryotic cells to genotoxic stress. To investigate the regulation of this cellular response, we isolated the gene for rhoB from a mouse genomic library. Sequence analysis of the rhoB gene showed that its coding region does not contain introns. The promoter region of rhoB harbors regulatory elements such as TATA, CAAT, and Sp1 boxes but not consensus sequences for AP-1, Elk-1, or c-Jun/ATF-2. The rhoB promoter was activated by UV irradiation, but not by 12-O-tetradecanoylphorbol-13-acetate treatment. rhoB promoter deletion constructs revealed a fragment of 0.17 kilobases in size which was sufficient in eliciting the UV response. This minimal promoter fragment contains TATA and CAAT boxes but no other known regulatory elements. Neither MEK inhibitor PD98059 nor p38 kinase inhibitor SB203580 blocked stimulation of rhoB by UVC (UV light, 254 nm) which indicates that ERK or p38 mitogen-activated protein (MAP) kinase are not involved in the UV induction of rhoB. Also, phosphatidylinositol 3-kinase inhibitor wortmannin, which blocks UV stimulation of both JNK and p38 MAP kinase, did not inhibit rhoB activation. Furthermore, activation of JNK by interleukin-1beta did not affect rhoB expression. These data indicate that JNK is not involved in the regulation of rhoB. Overexpression of wild-type Rac as well as the Rho guanine-dissociation inhibitor caused activation of rhoB. Wild-type RhoB inhibited both basal and UV-stimulated rhoB promoter activity, indicating a negative regulatory feedback by RhoB itself. The data provide evidence both for a signal transduction pathway independent of JNK, ERK, and p38 MAP kinase to be involved in the induction of rhoB by genotoxic stress, and furthermore, indicate autoregulation of rhoB.
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PMID:rhoB encoding a UV-inducible Ras-related small GTP-binding protein is regulated by GTPases of the Rho family and independent of JNK, ERK, and p38 MAP kinase. 938 98


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