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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We demonstrate here that growth hormone (GH) stimulates the activation of Rap1 and Rap2 in NIH-3T3 cells. Full activation of Rap1 and Rap2 by GH necessitated the combined activity of both JAK2 and c-Src kinases, although c-Src was predominantly required. GH-stimulated Rap1 and Rap2 activity was also demonstrated to be CrkII-C3G-dependent. GH stimulated the tyrosine phosphorylation of C3G, which again required the combined activity of JAK2 and c-Src. C3G tyrosine residue 504 was required for GH-stimulated Rap activation. Activated Rap1 inhibited GH-stimulated activation of RalA and subsequent GH-stimulated p44/42 MAP kinase activity and Elk-1-mediated transcription. In addition, we demonstrated that C3G-Rap1 mediated CrkII enhancement of GH-stimulated JNK/SAPK activity. We have therefore identified a linear JAK2-independent pathway switching GH-stimulated p44/42 MAP kinase and JNK/SAPK activities.
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PMID:Src-CrkII-C3G-dependent activation of Rap1 switches growth hormone-stimulated p44/42 MAP kinase and JNK/SAPK activities. 1273 87

Localization of transcription regulatory proteins in the nucleus is dynamically regulated, and may alter nucleoplasmic concentrations and/or assembly of multimolecular transcription regulatory complexes, which ultimately regulate gene expression. Since growth hormone (GH) regulates multiple transcription factors including C/EBP beta, the effect of GH on the subcellular localization of C/EBP beta was examined in 3T3-F442A preadipocytes. Indirect immunofluorescence shows that C/EBP beta is diffusely distributed in nuclei of quiescent cells. Within 5 min of GH treatment, the diffuse pattern dramatically becomes punctate. The relocalization of C/EBP beta coincides with DAPI staining of heterochromatin. Further, C/EBP beta and heterochromatin protein (HP)-1 alpha colocalize in the nucleus, consistent with localization of C/EBP beta to pericentromeric heterochromatin. In contrast, C/EBP delta exhibits a diffuse distribution in the nucleus that is not modified by GH treatment. C/EBP beta is rapidly and transiently phosphorylated on a conserved MAPK consensus site in response to GH (Piwien-Pilipuk, G., MacDougald, O. A., and Schwartz, J. (2002) J. Biol. Chem. 277, 44557-44565). Indirect immunofluorescence using antibodies specific for C/EBP beta phosphorylated on the conserved MAPK site shows that GH also rapidly induces a punctate pattern of staining for the phosphorylated C/EBP beta. In addition, phosphorylated C/EBP beta colocalizes to pericentromeric heterochromatin. The satellite DNA present in heterochromatin contains multiple C/EBP binding sites. DNA binding analysis shows that C/EBP beta, C/EBP delta, and C/EBP alpha (p42 and p30 forms) can bind to satellite DNA as homo- or heterocomplexes in vitro. Importantly, GH rapidly and transiently increases binding of endogenous C/EBP beta from 3T3-F442A cells to satellite DNA. Further, the GH-promoted nuclear relocalization of C/EBP beta to pericentromeric heterochromatin was prevented by the MEK inhibitor U0126. This observation suggests that GH-dependent MAPK activation plays a role in the regulation of nuclear relocalization of C/EBP beta. Nuclear redistribution introduces a new level of transcriptional regulation in GH action, since GH-mediated phosphorylation and nuclear redistribution of C/EBP beta may be coordinated to achieve spatial-temporal control of gene expression.
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PMID:Subnuclear localization of C/EBP beta is regulated by growth hormone and dependent on MAPK. 1282 55

C/EBP family members contribute to the induction of the interleukin-12 p40 gene and the genes encoding several other mediators of inflammation. Here, we show by chromatin immunoprecipitation that C/EBPbeta binds the p40 promoter following lipopolysaccharide stimulation of peritoneal macrophages. However, three modes of C/EBPbeta regulation reported in other cell types were not detected, including alternative translation initiation, nuclear translocation, and increased DNA binding following posttranslational modification. In contrast, C/EBPbeta concentrations greatly increased following stimulation via MAP kinase-dependent induction of C/EBPbeta gene transcription. Increased C/EBPbeta concentrations were unimportant for p40 induction, however, as transcription of the p40 gene initiated before C/EBPbeta concentrations increased. Furthermore, disruption of C/EBPbeta upregulation by a MAP kinase inhibitor only slightly diminished p40 induction. Phosphopeptide mapping revealed that endogenous C/EBPbeta in macrophages is phosphorylated on only a single tryptic peptide containing 14 potential phosphoacceptors. This peptide was constitutively phosphorylated in primary and transformed macrophages, in contrast to its inducible phosphorylation in other cell types in response to Ras and growth hormone signaling. Altered-specificity experiments supported the hypothesis that C/EBPbeta activity in macrophages does not require an inducible posttranslational modification. These findings suggest that, although C/EBPbeta contributes to the induction of numerous proinflammatory genes, it is fully active in unstimulated macrophages and poised to stimulate transcription in conjunction with other factors whose activities are induced.
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PMID:C/EBPbeta regulation in lipopolysaccharide-stimulated macrophages. 1283 71

Achondroplasia (ACH), the most common form of short-limbed dwarfism, and its related disorders are caused by constitutively activated point-mutated fibroblast growth factor receptor 3 (FGFR3). Recent studies have provided a large body of evidence to prove chondrocyte proliferation and differentiation in these disorders. However, little is known about the possible effects of the FGFR3 mutants on apoptosis of chondrocytes. In the present study, we analyzed apoptosis using a chondrogenic cell line, ATDC5, expressing the FGFR3 mutants causing ACH and thanatophoric dysplasia, which is a more severe neonatal lethal form comprising type I and type II. We found that the introduction of these mutated FGFR3s into ATDC5 cells decreased mRNA expression of parathyroid hormone-related peptide (PTHrP) and induced apoptosis. Importantly, replacement of PTHrP prevented the apoptotic changes in ATDC5 cells expressing ACH mutant. Insulin-like growth factor (IGF)-I, which is an important mediator of growth hormone (GH), also reduced apoptosis in ATDC5 cells expressing ACH mutant. IGF-I prevented apoptosis through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, indicating the mechanisms by which GH treatment improves disturbed bone growth in ACH.
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PMID:Molecular basis for the treatment of achondroplasia. 1467 99

The growth hormone receptor (GHR) is a cell surface receptor that mediates the somatogenic and metabolic effects of the growth hormone (GH). GHR signaling is transduced via the receptor-associated cytoplasmic tyrosine kinase called Janus protein kinase 2 (JAK2). The major intracellular signaling systems activated by JAK2 in response to GH include the signal transducer and activator of transcription (STAT) 5 and extracellular signal-regulated kinase (ERK)-1 and -2 pathways. In this report, we investigate the role of cholesterol-rich plasma membrane microdomains (caveolae and lipid rafts) in GH signaling. By subcellular fractionation of the GH-responsive 3T3-F442A murine preadipocyte, we found dramatic enrichment (6.7-fold) of plasma membrane GHR in the caveolae membranes (CM). JAK2 was also represented in the CM fraction, but was less enriched (2.5-fold) than GHR. ERK1/2 and the important ERK pathway upstream small adaptor protein, Grb2 (growth factor receptor-bound protein 2), were also enriched in caveolae (2.3- and 8.3-fold, respectively), but STAT5 was barely detected in the same fraction. Correspondingly, GH-induced tyrosine-phosphorylated GHR, JAK2, and ERK1/2 were highly represented in the CM fraction, whereas tyrosine-phosphorylated STAT5 was enriched in the non-membranous fraction of the post-nuclear supernatant. Additionally, GH induced further accumulation of GHR, Grb2, and SHC proteins in the CM fraction. Interestingly, treatment of the cells with the caveolae-disrupting agent, methyl-beta-cyclodextrin (mbetaCD), selectively inhibited GH-induced ERK1/2 activation but not STAT5 phosphorylation; repletion of cholesterol in mbetaCD-treated cells restored GH-induced ERK activation. Comparison of 3T3-F442A cells with the GHR-expressing human IM-9 lymphoblasts revealed similar enrichment of GHR in the lipid raft fraction of IM-9 as in the CM fraction of 3T3-F442A, but there were dramatic differences in the ERKs and Grb2. The IM-9 cell, in which ERKs are not activated by GH, displayed no enrichment of ERKs and Grb2 in the lipid raft fraction. Our results suggest that localization of GHRs in the CM fraction of the plasma membrane plays important roles in signaling.
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PMID:Caveolar and lipid raft localization of the growth hormone receptor and its signaling elements: impact on growth hormone signaling. 1501 Apr 56

During the last 10 years, various adipocytokines have been described which influence insulin sensitivity profoundly and might, therefore, potentially link obesity and insulin resistance. Recently, monocyte chemoattractant protein (MCP)-1 was characterized as a novel adipose-secreted factor upregulated in obesity and insulin resistance that impairs insulin signaling in fat cells in vitro and can be found in atherosclerotic lesions. To clarify expression and regulation of this adipocytokine, MCP-1 mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance. Interestingly, MCP-1 synthesis was significantly downregulated between 43% and 68% during differentiation of 3T3-L1 preadipocytes. Furthermore, 10 ng/ml tumor necrosis factor alpha, 100 nM insulin, 500 ng/ml growth hormone (GH), and 30 ng/ml interleukin (IL)-6-induced MCP-1 mRNA by up to 124-, 23-, 8-, and 2.5-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 0.5 ng/ml GH and 30 ng/ml IL-6. In contrast, the glucocorticoid dexamethasone potently downregulated MCP-1 with significant suppression detectable at concentrations as low as 3 nM and as early as 2h after effector addition. Studies using pharmacological inhibitors suggested that the positive effects of GH and IL-6 on MCP-1 synthesis are at least in part mediated by janus kinase 2 and p44/42 mitogen-activated protein kinase. Taken together, our results show a differential regulation of MCP-1 mRNA by insulin resistance-inducing hormones and support the view that this adipocytokine might be an interesting novel candidate linking insulin resistance, obesity, and atherosclerosis. This adipocytokine could thus be a potential pharmacological target for the treatment of impaired insulin sensitivity.
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PMID:Monocyte chemoattractant protein 1 expression is stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes. 1506 99

We demonstrate here that growth hormone (GH) stimulates the activation of RhoA and its substrate Rho kinase (ROCK) in NIH-3T3 cells. GH-stimulated formation of GTP-bound RhoA requires JAK2-dependent dissociation of RhoA from its negative regulator p190 RhoGAP. Inactivation of RhoA does not affect GH-stimulated JAK2 tyrosine phosphorylation nor p44/42 MAPK activity. However, RhoA and ROCK activities are required for GH-stimulated, Stat5-mediated transcription. RhoA-dependent enhancement of GH-stimulated, Stat5-mediated transcription is due to repression of histone deacetylase 6 activity recruited by transcription cofactor p300 that negatively regulates GH-stimulated, Stat5-mediated transcription. We also demonstrate that RhoA is the pivot for cAMP-dependent protein kinase inhibition of GH-stimulated, Stat5-mediated transcription as a consequence of cAMP-dependent protein kinase inactivation of RhoA through serine residue 188 of RhoA. We have therefore provided a novel mechanism by which a Ras-like small GTPase, RhoA, can regulate Stat5-mediated transcription.
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PMID:RhoA/ROCK activation by growth hormone abrogates p300/histone deacetylase 6 repression of Stat5-mediated transcription. 1510 57

The aims of this study were to elucidate the molecular mechanism by which growth hormone (GH) excess is anti-fibrotic in vitro and in vivo model. The in vivo model GH excess showed a significant increase of relative wall thickness with no concomitant disturbance of cardiac diastolic function. Western blot for extracellular matrix (ECM) structural proteins showed minimal change in the GH treatment group, compared to an Angiotensin II (Ang II) subpressor dose group. In cultured cardiac fibroblasts, we investigated the abundance of ECM proteins, phosphorylation of p38 mitogen-activated protein kinase (MAPK), and transforming growth factor-beta (TGF-beta)-specific transcriptional activity. GH down-regulated the expression of PAI-1 and fibronectin proteins activated by TGF-beta. In reporter assays, GH, but not insulin-like growth factor-1 (IGF-1), reduced TGF-beta-specific transcriptional activity. Moreover, GH markedly down-regulated TGF-beta-induced phosphorylation of p38 MAPK. These results demonstrated that a chronic excess of GH have an anti-fibrotic effect on cardiac remodeling, probably through a down-regulation of TGF-beta signaling via de-phosphorylation of p38 MAPK.
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PMID:GH suppresses TGF-beta-mediated fibrosis and retains cardiac diastolic function. 1513 May 18

Various hormones and growth factors have been implicated in progression of prostate cancer, but their role and the underlying molecular mechanism(s) involved remain poorly understood. In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer. We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines. GHR mRNA levels were 80% higher and GHR(tr) only 25% higher, in the carcinoma tissues than in BPH. Both isoforms were also expressed in LNCaP and PC3 cell lines and somewhat less so in DU145 cells. The LNCaP cell GHR protein was further characterized, on the basis of its M(r) of 120kDa, its binding to two different GHR monoclonal antibodies, its high affinity and purely somatogenic binding to (125)I-hGH and its ability to secrete GH binding protein, all characteristic of a functional GHR. Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB. No effect of GH (72h) could be shown on basal or androgen-induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH caused a rapid (2-12h) though transient striking increase in immunoreactive androgen receptor (AR) levels (< or =5-fold), followed by a slower (24-48h) reduction (< or = 80%), with only modest parallel changes in serine-phosphorylated AR. In conclusion, the GH-induced activation of signaling pathways, its effects on AR protein in LNCaP cells and the isoform-specific regulation of GHR in prostate cancer patient tissues, suggest that GH, most likely in concert with other hormones and growth factors, may play an important role in progression of human prostate cancer.
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PMID:Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells. 1519 5

We investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone and in combination with bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC-3940-II on the growth of H-69 human small cell lung carcinoma (SCLC) xenografted into nude mice. Since the activation of the signaling pathways involving protein kinase C (PKC) and the subsequent steps involving mitogen-activated protein kinase (MAPK) and c-fos and c-jun oncogenes are known to be important mechanisms implicated in cellular growth, we investigated how the blockade of tumoral GHRH receptor splice variants and BN/GRP receptors by these antagonists could interfere with these intracellular signaling pathways. Treatment with GHRH antagonists JV-1-65 or MZ-J-7-110 for 4 weeks significantly (p<0.05) decreased the tumor volume by 22.7+/-3.0% and 36.7 +/- 3.6%, respectively, as compared to controls. A larger decrease in tumor volume of 73.0 +/- 9.5% (p<0.01) was produced by BN/GRP antagonist RC-3940-II and its combination with JV-I-65 caused the greatest tumor reduction of 91.0 +/- 9.8% (p<0.01) vs. controls. H-69 SCLC tumors expressed alpha-, betaII-, delta- and eta-PKC isoforms. Antagonists of GHRH and BN/GRP decreased significantly (p<0.05) the expression of betaII- and delta-, but not of alpha- and eta-PKC isoforms. They also inhibited MAPK levels, the effects being significant (p<0.05) in the groups that received BN/GRP antagonist. In addition, expression of c-fos and c-jun mRNA was reduced after combined treatment with JV-1-65 and RC-3940-II. The proliferation of H-69 SCLC cells "in vitro" was also significantly inhibited after incubation of cells with GHRH antagonist, PKC inhibitors or MAPK inhibitor. These findings suggest that the anti-proliferative effects of antagonists of GHRH and BN/GRP on H69-SCLC involve an inhibition of the signaling pathways of specific PKC isoforms, MAPK and c-fos and c-jun oncogenes.
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PMID:Suppression of growth of H-69 small cell lung carcinoma by antagonists of growth hormone releasing hormone and bombesin is associated with an inhibition of protein kinase C signaling. 1538 37


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