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)

The mechanisms controlling the proliferation of astrocytes are of great interest but are not well defined. We have previously shown that the endogenous neuropeptides, endothelin-3 (ET-3), and atrial natriuretic peptide (ANP), modulate the proliferation of astrocytes through positively and negatively regulating the transcription of the immediate-early gene egr-1 which transactivates basic fibroblast growth factor (bFGF) by unknown mechanisms. In these studies, we determined the involvement of MAP kinase (Erk) activation by ET-3 in the transcription of egr-1, and the molecular determinants by which Egr-1 transactivates bFGF. Transfection of astrocytes with a mitogen-activated protein (MAP) kinase (MAPK) expression vector increased the transcription of a cotransfected egr-chloramphenicol acetyltransferase (CAT) construct 3-fold. This induction was totally abolished by a dominant negative MAPK mutant. A 3-fold induction of egr-CAT expression by ET-3 was significantly reduced by treatment with ANP, or a cotransfected dominant negative MAPK plasmid. Using mobility shift assays, we showed that ET-3 induced the expression of Egr-1 protein which bound specifically to several early growth-related protein (Egr-1) binding sites on the bFGF promoter, and that this effect was significantly reversed by treatment with ANP. We also found that the Sp1 transcriptional factor was bound at these same sites, but was not stimulated by ET-3. Deletion experiments indicated that only the site at -160 bp of the bFGF promoter was significant for bFGF transactivation by Egr-1. We conclude that the astrocyte mitogen, ET-3, stimulates egr-1 transcription through a MAP kinase (Erk) related mechanism, and that Egr-1 transactivates bFGF through a specific noncanonical, Egr-1 site on the promoter. ANP inhibits each of these steps, providing a pathway for its anti-proliferative action.
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PMID:Egr-1 activates basic fibroblast growth factor transcription. Mechanistic implications for astrocyte proliferation. 870 7

The cardiac genes for the A- and B-type natriuretic peptides (ANP and BNP) are coordinately induced by growth promoters, such as alpha1-adrenergic receptor agonists (e.g. phenylephrine (PE)). Although inducible elements in the ANP gene have been identified, responsible elements in the BNP gene are unknown. In this study, reporter constructs transfected into neonatal rat ventricular myocytes showed that in the context of 2.5 kilobase pairs of native BNP 5'-flanking sequences, a 2-base pair mutation in a promoter-proximal M-CAT site (CATTCT) disrupted basal and PE-inducible transcription by more than 98%. Expression of constitutively active forms of Ras, Raf-1 kinase, and protein kinase C, all of which are activated by PE in cardiac myocytes, strongly stimulated BNP reporter expression. Isolated M-CAT elements conferred PE, protein kinase C, and Ras inducibility to a minimal BNP promoter, however, they did not confer Raf-1 inducibility. These results show that M-CAT elements can serve as targets for Ras-dependent, Raf-1-independent pathways, implying the involvement of c-Jun N-terminal kinase and/or p38 mitogen-activated protein kinases, but not extracellular signal-regulated protein kinase/mitogen-activated protein kinase. Moreover, the essential M-CAT element distinguishes the BNP gene from the ANP gene, which utilizes serum response elements and an Sp1-like sequence.
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PMID:Differential effects of protein kinase C, Ras, and Raf-1 kinase on the induction of the cardiac B-type natriuretic peptide gene through a critical promoter-proximal M-CAT element. 905 48

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

Vascular Endothelial Growth Factor (VEGF) is a potent mitogen for vascular endothelial cells that has been implicated in tumor neovascularization. We show that, in hamster fibroblasts (CCL39 cells), VEGF mRNAs are expressed at low levels in serum-deprived or exponentially growing cells, whereas it is rapidly induced after stimulation of quiescent cells with serum. CCL39 derivatives, transformed with Polyoma virus or with active members of the p42/p44 mitogen-activated protein (MAP) kinase pathway, Gly/Val point mutant of Ras at position 12 (Ras-Val12), MKK1 in which Ser218 and Ser222 were mutated to Asp (MKK1-SS/DD)), express very high levels of VEGF mRNA. To analyze the contribution of the p42/p44MAP kinase in this induction, we used the CCL39-derived cell line (Raf-1:ER) expressing an estradiol-activable Raf-1. We show a time and an estradiol dose-dependent up-regulation of VEGF mRNA clearly detectable after 2 h of stimulation. The induction of VEGF mRNA in response to conditioned activation of Raf-1 is reverted by an inhibitor of MKK1, PD 098059, highlighting a specific role for the p42/p44 MAP kinase pathway in VEGF expression. Interestingly, hypoxia has an additive effect on VEGF induction in CCL39 cells stimulated by serum or in Raf-1:ER cells stimulated by estradiol. In contrast to VEGF, the isoforms VEGF-B and VEGF-C are poorly regulated by growth and oncogenic factors. We have identified a GC-rich region of the VEGF promoter between -88 and -66 base pairs which contains all the elements responsible of its up-regulation by constitutive active Ras or MKK1-SS/DD. By mutation of the putative binding sites and electrophoretic mobility supershift experiments, we showed that the GC-rich region constitutively binds Sp1 and AP-2 transcription factors. Furthermore, following activation of the p42/p44 MAP kinase module, the binding of Sp1 and AP-2 is increased in the complexes formed in this region of the promoter. Altogether, these data suggest that hypoxia and p42/p44 MAP kinase independently play a key role in the regulation of the VEGF expression.
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PMID:p42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts. 966 Jul 76

In this report we have studied insulin regulation of malic enzyme (ME) gene transcription in rat H-35 hepatoma cells and localized the insulin-responsive region of the ME promoter between positions -177 and -102. This region contains a putative insulin response element (IRE-II). When nuclear extracts from untreated or insulin-treated H-35 cells were incubated with IRE-II, transcription factors Sp1 and Sp3 were observed to bind constitutively to this element, whereas insulin induces the quick and transient binding of an insulin response factor. This induction requires de novo protein synthesis. Competition and supershift assays demonstrated that the insulin response factor is the immediate-early gene Egr-1. In vitro assays revealed that Egr-1 displaces Sp1 from its binding site in IRE-II. Insulin induces Egr-1 mRNA, with a time course pattern that corresponds perfectly to the Egr-1 binding to IRE-II. This induction depends on the activation of mitogen-activated protein (MAP) kinase, and it is phosphatidylinositol 3-kinase-independent, as demonstrated with specific inhibitors for both pathways. By cotransfecting the wild-type or a dominant negative Ras, an upstream regulator of MAP kinase, we show that Ras inhibits ME promoter activity. Furthermore, overexpression of Egr-1 in H-35 cells represses the ME gene promoter in a dose-dependent manner. These results suggest that insulin induces a quick, transient, and Ras/MAP kinase-dependent activation of Egr-1 which leads to a transient repression of ME gene transcription. On a late phase, insulin would activate a different, Egr-1-independent pathway, which would result in activation of the ME gene.
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PMID:Insulin-induced early growth response gene (Egr-1) mediates a short term repression of rat malic enzyme gene transcription. 1036 49

Heme oxygenase (HO) is responsible for the physiological breakdown of heme into equimolar amounts of biliverdin, carbon monoxide, and iron. Three isoforms (HO-1, HO-2, and HO-3) have been identified. HO-1 is ubiquitous and its mRNA and activity can be increased several-fold by heme, other metalloporphyrins, transition metals, and stimuli that induce cellular stress. HO-1 is recognized as a major heat shock/stress response protein. Recent work from our laboratory has demonstrated several potential consensus regulatory elements in the 5'-untranslated region (UTR) of HO-1, including activator protein 1 (AP-1), metal responsive element (MRE), oncogene c-myc/max heterodimer binding site (Myc/Max), antioxidant response element (ARE), and GC box binding (Sp1) sites. Using deletion-reporter gene constructs, we have mapped sites that mediate the arsenite-dependent induction of HO-1, and we have shown that components of the extracellular signal-regulated kinase (ERK) and p38 (a homologue of the yeast HOG1 kinase), but not c-jun N-terminal kinase (JNK), mitogen-activated protein (MAP) kinase pathways are involved in arsenite-dependent upregulation. In contrast, HO-2 is present chiefly in the brain and testes and is virtually uninducible. HO-3 has very low activity; its physiological function probably involves heme binding. Products of the HO reaction have important effects: carbon monoxide is a potent vasodilator, which is thought to play a key role in the modulation of vascular tone, especially in the liver under physiological conditions, and in many organs under "stressful" conditions associated with HO-1 induction. Biliverdin and its product bilirubin, formed in most mammals, are potent antioxidants. In contrast, "free" iron increases oxidative stress and regulates the expression of many mRNAs (e.g., DCT-1, ferritin, and transferrin receptor) by affecting the conformation of iron regulatory protein (IRP)-1 and its binding to iron regulatory elements (IREs) in the 5'- or 3'-UTRs of the mRNAs.
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PMID:Heme oxygenase: recent advances in understanding its regulation and role. 1051 65

Angiogenesis is associated with a number of pathological situations. In this study, we have focused our attention on the role of p42/p44 MAP (mitogen-activated protein) kinases and hypoxia in the control of angiogenesis. We demonstrate that p42/p44 MAP kinases play a pivotal role in angiogenesis by exerting a determinant action at three levels: i) persistent activation of p42/p44 MAP kinases abrogates apoptosis; ii) p42/p44 MAP kinase activity is critical for controlling proliferation and growth arrest of confluent endothelial cells; and iii) p42/p44 MAP kinases promote VEGF (vascular endothelial growth factor) expression by activating its transcription via recruitment of the AP-2/Sp1 (activator protein-2) complex on the proximal region (-88/-66) of the VEGF promoter and by direct phosphorylation of hypoxia-inducible factor 1 alpha (HIF-1 alpha). HIF-1 alpha plays a crucial role in the control of HIF-1 activity, which mediates hypoxia-induced VEGF expression. We show that oxygen-regulated HIF-1 alpha protein levels are not affected by intracellular localization (nucleus versus cytoplasm). Finally, we propose a model which suggests an autoregulatory feedback mechanism controlling HIF-1 alpha and therefore HIF-1-dependent gene expression.
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PMID:Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. 1100 55

Insulin induces apolipoprotein A-I, apoA-I gene transcription via a membrane receptor with intrinsic tyrosine kinase activity. This finding prompted us to ask whether the gene is stimulated by epidermal growth factor (EGF), EGF a peptide hormone that binds to another member of the receptor superfamily with tyrosine kinase activity. Our data showed that like insulin, EGF increased abundance of apoA-I protein and transcription of the gene in human hepatoma, Hep G2 cells. The effects of both hormones appeared direct because their induction of apoA-I gene transcription was not affected by the protein synthesis inhibitor, cycloheximide. Although both insulin and EGF stimulate apoA-I expression, each hormone binds to a distinct membrane receptor thus suggesting differential intracellular signaling. Therefore, we used a panel of inhibitors to define the pathway(s) that mediate the actions of these hormones. Whereas, the actions of EGF required only the Ras-mitogen-activated protein, MAP kinase, those of insulin were mediated by equal participation of both the Ras-MAP kinase and protein kinase C, PKC cascades. Despite differences in signaling pathways triggered by each hormone receptor, the activation of apoA-I transcription required the participation of a single transcription factor, Sp1. Furthermore, EGF induction of transcription was attenuated by mutating the MAP kinase site at amino acid, Thr(266) rendering Sp1 phosphorylation deficient. In summary, EGF stimulation of apoA-I expression is mediated solely by the Ras-MAP kinase cascade and enhanced activity of this pathway requires Sp1 with an intact phosphorylation site at Thr(266). However, insulin induction of this gene is different and requires both Ras-MAP kinase and PKC pathways but their actions are also mediated by Sp1.
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PMID:Epidermal growth factor induction of apolipoprotein A-I is mediated by the Ras-MAP kinase cascade and Sp1. 1127 17

Interleukin-10 (IL-10), a pleiotropic cytokine that inhibits inflammatory and cell-mediated immune responses, is produced by a wide variety of cell types including T and B cells and monocytes/macrophages. Regulation of pro- and anti-inflammatory cytokines has been suggested to involve distinct signaling pathways. In this study, we investigated the regulation of the human IL-10 (hIL-10) promoter in the human monocytic cell line THP-1 following activation with lipopolysaccharide (LPS). Analysis of hIL-10 promoter sequences revealed that DNA sequences located between base pairs -652 and -571 are necessary for IL-10 transcription. A computer analysis of the promoter sequence between base pairs -652 and -571 revealed the existence of consensus sequences for Sp1, PEA1, YY1, and Epstein-Barr virus-specific nuclear antigen-2 (EBNA-2)-like transcription factors. THP-1 cells transfected with a plasmid containing mutant Sp1 abrogated the promoter activity, whereas plasmids containing the sequences for PEA1, YY1, and EBNA-2-like transcription factors did not influence hIL-10 promoter activity. To understand the events upstream of Sp1 activation, we investigated the role of p38 and extracellular signal-regulated kinase mitogen-activated protein kinases by using their specific inhibitors. SB202190 and SB203580, the p38-specific inhibitors, inhibited LPS-induced IL-10 production. In contrast, PD98059, a specific inhibitor of extracellular signal-regulated kinase kinases, failed to modulate IL-10 production. Furthermore, SB203580 inhibited LPS-induced activation of Sp1, as well as the promoter activity in cells transfected with a plasmid containing the Sp1 consensus sequence. These results suggest that p38 mitogen-activated protein kinase regulates LPS-induced activation of Sp1, which in turn regulates transcription of the hIL-10 gene.
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PMID:The p38 mitogen-activated kinase pathway regulates the human interleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccharide-stimulated human macrophages. 1127 48

Metastatic diseases of prostate cancer reveal high expression of alpha6 integrin and the activation of mitogen-activated protein kinases (MAP kinase). Therefore, the present study was conducted to examine whether MAP kinase pathway is involved in the alpha6 integrin gene expression in androgen-independent prostate cancer cell lines. alpha6 integrin mRNA expression, the alpha6 integrin promoter-induced luciferase activities and MAP kinase enzyme activities in androgen-independent LNCaP and PC-3 cell lines were higher than those in androgen-dependent LNCaP. Deletion and mutation analysis showed that Sp1 consensus sequence at -48 to -43 bp from the transcription start site was necessary for basal promoter activity. Binding of Sp1 to its consensus sequence in three cell lines was confirmed by electrophoretic mobility shift assays. Sp1 binding to its consensus sequence, as well as promoter activity and mRNA expression, were found to be inhibited by an inhibitor of MAP kinase kinase 1 and 2, U0126, in the androgen-independent cell lines. Our results indicate that the proximal Sp1 is necessary for basal promoter activity of the alpha6 integrin, suggesting that signal transduction from MAP kinases to activation of Sp1 might be involved in alpha6 integrin gene expression in androgen-independent prostate cancer cell lines.
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PMID:Mitogen-activated protein kinase pathway is involved in alpha6 integrin gene expression in androgen-independent prostate cancer cells: role of proximal Sp1 consensus sequence. 1133 92


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