Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transfected Jurkat cells overexpressing extracellular signal-regulated kinase (ERK1), also referred to as mitogen-activated protein (MAP) kinase, were selected by Western blotting assay using anti-ERK1 and antiphosphotyrosine antibodies in combination with a functional MAP kinase assay. We then asked whether enhanced ERK1 expression had any effect on induction of T-cell cytokine genes. The results show that overexpression of ERK1 enhances expression of T-cell interleukin-2 (IL-2), IL-3, and granulocyte-macrophage colony-stimulating factor mRNA; no change was seen in expression of the alpha-actin gene. DNA-binding activities of the transcription factors AP1, NF-AT, and NF-kB were specifically increased twofold to fourfold in ERK1-overexpressing clones relative to nontransformed or vector-transformed cells, whereas no enhancement of CK1-CK2 protein DNA binding activity was detected after ERK1 overexpression. Additionally, increased NF-AT DNA binding activity was associated with functional enhancement of NF-AT transactivating activity in ERK1-overexpressing cells. These results provide direct evidence for the role of MAP kinase in the regulation of cytokine gene expression and indicate that such regulation is likely mediated through the enhanced DNA binding activity of specific nuclear transcription factors.
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PMID:Overexpression of mitogen-activated protein kinase (ERK1) enhances T-cell cytokine gene expression: role of AP1, NF-AT, and NF-KB. 840 Feb 95

Signaling via the Ras pathway involves sequential activation of Ras, Raf-1, mitogen-activated protein kinase kinase (MKK), and the extracellular signal-regulated (ERK) group of mitogen-activated protein (MAP) kinases. Expression from the c-Fos, atrial natriuretic factor (ANF), and myosin light chain-2 (MLC-2) promoters during phenylephrine-induced cardiac muscle cell hypertrophy requires activation of this pathway. Furthermore, constitutively active Ras or Raf-1 can mimic the action of phenylephrine in inducing expression from these promoters. In this study, we tested whether constitutively active MKK, the molecule immediately downstream of Raf, was sufficient to induce expression. Expression of constitutively active MKK induce ERK2 kinase activity and caused expression from the c-Fos promoter, but did not significantly activate expression of reporter genes under the control of either the ANF or MLC-2 promoters. Expression of CL100, a phosphatase that inactivates ERKs, prevented expression from all of the promoters. Taken together, these data suggest that ERK activation is required for expression from the Fos, ANF, and MLC-2 promoters but MKK and ERK activation is sufficient for expression only from the Fos promoter. Constitutively active MKK synergized with phenylephrine to increase expression from a c-Fos- or an AP1-driven reporter. However, active MKK inhibited phenylephrine- and Raf-1-induced expression from the ANF and MLC-2 promoters. A DNA sequence in the MLC-2 promoter that is a target for inhibition by active MKK, but not CL100, was mapped to a previously characterized DNA element (HF1) that is responsible for cardiac specificity. Thus, activation of cardiac gene expression during phenylephrine-induced hypertrophy requires ERK activation but constitutive activation by MKK can inhibit expression by targeting a DNA element that controls the cardiac specificity of gene expression.
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PMID:Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase. 858 50

Activation of several GTPases stimulates Na+-H+ exchange, resulting in an increased efflux of intracellular H+. These GTPases include alpha subunits of the heterotrimeric G proteins Gq and G13, as well as the low molecular weight GTP-binding proteins Ras, Cdc42, and Rho (Hooley, R., Yu, C.-Y., Simon, M., and Barber, D. L. (1996) J. Biol. Chem. 271, 6152-6158). GTPases coupled to the inhibition of Na+-H+ exchange, however, have not been identified. Several neurotransmitters, including somatostatin and dopamine, inhibit Na+-H+ exchange through a guanine-nucleotide-dependent mechanism, suggesting the involvement of a GTPase. In this study we determined that mutational activation of the alpha subunit of G12 inhibits the ubiquitously expressed Na+-H+ exchanger isoform, NHE1. Transient expression of mutationally activated Galpha12 inhibited serum- and Galpha13-stimulated NHE1 activity in HEK293 cells and CCL39 fibroblasts. In addition, in NHE-deficient AP1 cells stably expressing specific NHE isoforms, mutationally activated Galpha12 inhibited NHE1 activity but stimulated activities of the Na+-H+ exchanger (NHE) isoforms NHE2 and NHE3. In contrast, mutationally activated Galpha13, another member of the Galpha12/13 family, stimulated all three NHE isoforms. Although previous studies have identified a parallel action of Galpha12 and Galpha13 in regulating MAP (mitogen-activated protein) kinases and cell growth, these GTPases have opposing effects on NHE1 activity.
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PMID:Galpha12 differentially regulates Na+-H+ exchanger isoforms. 879 30

Angiotensin II (Ang II) stimulates expression of tyrosine hydroxylase and norepinephrine transporter genes in brain neurons; however, the signal-transduction mechanism is not clearly defined. This study was conducted to determine the involvement of the mitogen-activated protein (MAP) kinase signaling pathway in Ang II stimulation of these genes. MAP kinase was localized in the perinuclear region of the neuronal soma. Ang II caused activation of MAP kinase and its subsequent translocation from the cytoplasmic to nuclear compartment, both effects being mediated by AT1 receptor subtype. Ang II also stimulated SRE- and AP1-binding activities and fos gene expression and its translocation in a MAP kinase-dependent process. These observations are the first demonstration of a downstream signaling pathway involving MAP kinase in Ang II-mediated neuromodulation in noradrenergic neurons.
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PMID:Angiotensin II regulation of neuromodulation: downstream signaling mechanism from activation of mitogen-activated protein kinase. 897 26

The activation status of the ras pathway was studied in eight ovarian tumor cell lines. Three biochemical parameters indicative of ras activation were tested: (a) the ratio of the ras-GTP:ras-GDP complex; (b) the activity of mitogen-activated protein kinases p42/p44; and (c) ets-2 phosphorylation at position threonine 72, a mitogen-activated protein kinase phosphorylation site in vivo. Four of the ovarian tumor cell lines had an activated ras pathway by these three parameters, whereas only one of these contained a mutated ras gene. In addition, ras/ets-2 responsive genes such as the urokinase plasminogen activator (uPA) were activated in these four cell lines. Transient transfection assays indicated that the compound ets-AP1 oncogene responsive enhancer present in the uPA gene was the target of ras signaling in ovarian tumor cells and that the combination of activated ras and ets-2 could superactivate the uPA enhancer element. Coexpression of the dominant-negative ras-Asn17 cDNA gene abrogated activity of this uPA element in ovarian tumor cells. These data indicate that ets-2 is a nuclear target of ras action in ovarian tumor cell lines and that ras signaling pathways may be activated in ovarian cancer by mechanisms independent of direct genetic damage to ras genes.
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PMID:Activation of the ras-mitogen-activated protein kinase pathway and phosphorylation of ets-2 at position threonine 72 in human ovarian cancer cell lines. 960 74

Interleukin 1 (IL1) is a primary regulator of inflammatory and immune responses. Via its type I receptor it activates specific protein kinases, including the NF kappa B inducing kinase (NIK) and three distinct mitogen-activated protein (MAP) kinase cascades. These modulate a number of transcription factors including NF kappa B, AP1 and CREB each of which regulate a plethora of immediate early genes central to the inflammatory response. Phase I clinical trials of the soluble type I receptor and IRAP indicate that these have potential anti-inflammatory effects.
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PMID:Interleukin-1. 978 72

Interleukin 1 (IL-1) activates p42/p44 and p38 mitogen-activated protein kinases (MAP kinases) in target cells. Here we have used two specific inhibitors, PD98059 which inhibits MAP kinase kinase (MEK), and SB203580 which inhibits p38 MAP kinase to explore the involvement of these kinases in the induction of IL-2 by IL-1 in the murine thymoma cell line EL4.NOB-1. Both kinase inhibitors suppressed IL-1-stimulated IL-2 production. PD98059 blocked IL-2 mRNA accumulation and the induction of a reporter gene linked to the IL-2 promoter. In contrast, SB203580 only marginally inhibited IL-2 promoter-linked reporter gene expression and had no inhibitory effect on IL-2 mRNA levels. Neither PD98059 nor SB203580 had an inhibitory effect on NFkappaB-driven reporter gene expression in response to IL-1. Surprisingly, higher concentrations of SB203580 (30 microM) potentiated the IL-1 responses. PD98059 also inhibited induction of IL-2 by phorbol 12-myristate 13-acetate (PMA), and AP1-linked reporter gene expression in response to PMA but not IL-1. These results indicate that p42/p44 MAP kinase is involved in the regulation of IL-2 gene transcription by IL-1, whilst p38 MAP kinase has a post-transcriptional target. Additional IL-1 signalling pathways can clearly compensate for the lack of p38 MAP kinase which result in potentiation of the IL-1 responses observed at high-dose SB203580.
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PMID:Distinct roles for p42/p44 and p38 mitogen-activated protein kinases in the induction of IL-2 by IL-1. 1047

The monofunctional alkylating agent N-methyl-N-nitro-N-nitrosoguanidine (MNNG) is a widespread environmental carcinogen that causes DNA lesions, leading to cell death. However, MNNG can also trigger a cell-protective response by inducing the expression of DNA repair/transcription-related genes. We demonstrate that the urokinase-type plasminogen activator (uPA) gene product, a broad spectrum extracellular protease to which no DNA repair function has been assigned, is transcriptionally induced by MNNG in C2C12 and NIH3T3 cells. This induction required an AP1-enhancer element located at -2.4 kilobase (kb), because it was abrogated by deletion of this site. MNNG was found to induce the activation of JNK/SAPK and p38 mitogen-activated protein kinases (MAPKs). Accordingly, we attempted to assess the contribution of each of these MNNG-inducible MAPKs to uPA gene induction by this alkylating agent. Coexpression of dominant negative versions of kinases of the JNK pathway, such as catalytically inactive forms of MEKK1, MKK7, and JNKK, and of cytoplasmic JNK-inhibitor JIP-1, as well as treatment of cells with curcumin (which blocks JNK activation by MNNG), inhibited MNNG-induced uPA transcriptional activity. In contrast, neither dominant negative MKK6 nor SB203580, which specifically inhibit p38 MAP kinase activation, abrogated the MNNG-induced effect. Taken together, our results show that the JNK signaling pathway links external MNNG stimulation and AP1-dependent uPA gene expression, providing the first functional dissection of a transcription-coupled signal transduction pathway for MNNG. (Blood. 2000;96:1415-1424)
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PMID:The cJun N-terminal kinase (JNK) signaling pathway mediates induction of urokinase-type plasminogen activator (uPA) by the alkylating agent MNNG. 1094 86

The M(r) 78,000 glucose-regulated protein (GRP78) can be induced by physiological stresses such as glucose deprivation and hypoxia. In solid tumors, hypoxia can promote malignant progression and confer resistance to irradiation and chemotherapy by altering gene expression. Here, we investigated the molecular mechanisms and signaling pathway involved in the late and prolonged induction of the GRP78 gene by hypoxia in a human gastric cancer cell line, MKN28. Nuclear run-on assays and mRNA stability measurements revealed that transcriptional activation, not stabilization of mRNA, contributed to the dramatic induction of GRP78 gene under hypoxia. Induction of GRP78 by chronic hypoxia was completely abolished by pretreatment with PD98059 [a specific inhibitor of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK1)] or by overexpression of a dominant-negative MEK1 mutant, demonstrating a direct involvement of ERK in the induction of transcription at the GRP78 promoter under these conditions. Furthermore, hypoxia increased the transcriptional activity of a 12-O-tetradecanoylphorbol-13-acetate response element-like motif on the GRP78 promoter and increased the abundance and DNA binding activity of AP-1 complex composed of c-Jun and c-Fos. A selective protein kinase C (PKC) inhibitor, GF109203X, inhibited the induction of GRP78 gene expression as well as the activities of both ERK and Raf-1. Among six PKC isoforms expressed in MKN28 cells, PKC-epsilon expression level and kinase activity were increased by hypoxia. Transfection of MKN28 cells with a dominant-negative PKC-epsilon blocked the induction of GRP78 through ERK by hypoxia, indicating that PKC-epsilon directly participated in GRP78 induction under hypoxia. Taken together, this study shows that a PKC-epsilon-Raf-1-MEK-ERK-AP1 signaling cascade acts on a 12-O-tetradecanoylphorbol-13-acetate response element-like element to mediate hypoxia-induced GRP78 expression in human gastric cancer cells. We also confirmed in vivo the overexpression of GRP78 in surgical specimens of human primary gastric tumors.
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PMID:Induction of glucose-regulated protein 78 by chronic hypoxia in human gastric tumor cells through a protein kinase C-epsilon/ERK/AP-1 signaling cascade. 1171 66

The negative-regulatory feedback loop between p53 and hdm2 forms part of a finely balanced regulatory network of proteins that controls cell cycle progression and commitment to apoptosis. Expression of hdm2, and its mouse orthologue mdm2, is known to be induced by p53, but recent evidence has demonstrated mdm2 expression can also be regulated via p53-independent pathways. However the p53 independent mechanisms that control transcription of the human hdm2 gene have not been studied. Differential levels of hdm2 mRNA and protein expression have been reported in several types of human malignancy, including breast cancers in which hdm2 expression correlates with positive estrogen receptor alpha (ERalpha) status. Experimental models have demonstrated that hdm2 overexpression can promote breast cancer development. Here, we show that the elevated level of hdm2 protein in ERalpha(+ve) breast cancer cell lines such as MCF-7 and T47D is because of transcription from the p53-inducible P2 promoter of hdm2. The P2 promoter is inactive in ERalpha(-ve) cell lines such as SKBr3. Hdm2-P2 promoter activity in T47D cells is independent of p53, as well as of known regulators of the mouse mdm2-P2 promoter, including ERalpha and ras-raf-mitogen-activated protein/extracellular signal-regulated kinase (MEK) mitogen-activated protein kinase (MAPK) signaling. We show that hdm2-P2 activity in T47D cells is dependent on the integrity of both an evolutionarily conserved composite binding site for AP1 and ETS family transcription factors (AP1-ETS) and a nonconserved upstream (nnGGGGC)(5) repeat sequence. Lack of hdm2-P2 activity in ERalpha(-ve) cells is shown to be a consequence of reduced transcriptional activation through the AP1-ETS element. Overexpression of ETS2 in SKBr3 cells reconstitutes AP1-ETS element-dependent hdm2-P2 promoter activity, resulting in increased levels of hdm2 protein in the cells. Our findings support the hypothesis that the elevated levels of hdm2 expression reported in cancers such as ERalpha(+ve) breast tumors play an important role in the development of these tumors.
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PMID:p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. 1275 Feb 88


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