UNIPROT:P51812 - FACTA Search

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Query: UNIPROT:P51812 (mitogen-activated protein)
10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well known that external load plays a critical role in determining cardiac muscle mass and its phenotype, but little is known as to how mechanical load is transduced into intracellular signals regulating gene expression. To address this question we analyzed the 'mechano-transcription' coupling process using an in vitro model of load-induced cardiac hypertrophy, in which a stretch of rat cardiac myocytes, grown on a deformable substrate, causes a rapid induction of immediate-early genes followed by growth (hypertrophic) response. We report here that cell stretch rapidly activates a plethora of second messenger pathways, including tyrosine kinases, p21ras, mitogen-activated protein (MAP) kinases, S6 kinases (pp90RSK), protein kinase C, phospholipase C, phospholipase D, and probably the phospholipase A2 and P450 pathways. In contrast, the cAMP pathway is not activated significantly by stretch. The signals generated by these second messengers appear to converge into activation of the p67SRF-p62TCF complex via the serum response element, causing induction of c-fos. The stretch response may involve an autocrine or paracrine mechanism, because stretch-conditioned medium, when transferred to non-stretched myocytes, mimicked the effect of stretch. These results indicate that mechanical load causes rapid activation of multiple second messenger systems, which may in turn initiate a cascade of hypertrophic response of cardiac myocytes.
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PMID:Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. 838 10

Transforming growth factor beta 1 (TGF-beta 1) is a multifunctional cytokine that positively or negatively regulates the proliferation of various types of cells. In this study we have examined whether or not the activation of the mitogen-activated protein (MAP) kinases is involved in the transduction of cell growth modulation signals of TGF-beta 1, as MAP kinase activity is known to be closely associated with cell cycle progression. Although TGF-beta 1 stimulated the growth of quiescent Balb 3T3 and Swiss 3T3 cells, it failed to detectably stimulate the tyrosine phosphorylation and activation of the 41- and 43-kDa MAP kinases at any time point up to the reinitiation of DNA replication. TGF-beta 1 also failed to stimulate the expression of the c-fos gene. Furthermore, TGF-beta 1 synergistically enhanced the mitogenic action of epidermal growth factor (EGF) without affecting EGF-induced MAP kinase activation in these fibroblasts, and it inhibited the EGF-stimulated proliferation of mouse keratinocytes (PAM212) without inhibiting EGF-induced MAP kinase activation. Thus, the ability of TGF-beta 1 to modulate cell proliferation is apparently not associated with the activation of MAP kinases. In this respect, TGF-beta 1 is clearly distinct from the majority, if not all, of peptide growth factors, such as platelet-derived growth factor and EGF, whose ability to modulate cell proliferation is closely associated with the activation of MAP kinases. These results also suggest that the activation of MAP kinases is not an absolute requirement for growth factor-stimulated mitogenesis.
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PMID:Cell type-specific modulation of cell growth by transforming growth factor beta 1 does not correlate with mitogen-activated protein kinase activation. 853 May 7

Expression of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting step in hepatic gluconeogenesis, is primarily regulated at the level of gene transcription. Insulin and phorbol esters inhibit basal PEPCK transcription and antagonize the induction of PEPCK gene expression by glucocorticoids and glucagon (or its second messenger cAMP). Insulin activates a signaling cascade involving Ras --> Raf --> p42/p44 mitogen-activated protein (MAP) kinase kinase (MEK) --> p42/p44 MAP kinase (ERK 1 and 2). Recent reports suggest that activation of this Ras/MAP kinase pathway is critical for the effects of insulin on mitogenesis and c-fos transcription but is not required for insulin action on metabolic processes such as glycogen synthesis, lipogenesis, and Glut-4-mediated glucose transport. We have used three distinct approaches to examine the role of the Ras/MAP kinase pathway in the regulation of PEPCK transcription by insulin in H4IIE-derived liver cells: (i) chemical inhibition of Ras farnesylation, (ii) infection of cells with an adenovirus vector encoding a dominant-negative mutant of Ras, and (iii) use of a chemical inhibitor of MEK. Although each of these methods blocks insulin activation of MAP kinase, none alters insulin antagonism of cAMP- and glucocorticoid-stimulated PEPCK transcription. Although phorbol esters activate MAP kinase and mimic the effects of insulin on PEPCK gene transcription, inhibition of MEK has no effect on phorbol ester inhibition of PEPCK gene transcription. Using the structurally and mechanistically distinct phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors, wortmannin and LY 294002, we provide further evidence supporting a role for PI 3-kinase activation in the regulation of PEPCK gene transcription by insulin. We conclude that neither insulin nor phorbol ester regulation of PEPCK gene transcription requires activation of the Ras/MAP kinase pathway and that insulin signaling to the PEPCK promoter is dependent on PI 3-kinase activation.
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PMID:Insulin regulation of phosphoenolpyruvate carboxykinase gene expression does not require activation of the Ras/mitogen-activated protein kinase signaling pathway. 856 35

Previously, our laboratory has shown that lactosylceramide (LacCer) can serve as a mitogenic agent in the proliferation of aortic smooth muscle cells "a hallmark in the pathogenesis of atherosclerosis" (Chatterjee, S. (1991) Biochem. Biophys. Res. Commun. 181, 554-561). Here we report a novel aspect of LacCer-mediated signal transduction. We demonstrate that LacCer (10 microM) can stimulate the phosphorylation of mitogen-activated protein (MAP) kinase p44MAPK to phosphorylated p44MAPK in aortic smooth muscle cells from rabbit or human origin. Western immunoblot assays and direct measurement of activity in immunoprecipitated MAP kinase revealed that within 5 min of incubation of cells with LacCer there was a 3.5-fold increase in the activity of p44MAPK. This continued up to 10 min of incubation; thereafter, the MAP kinase activity decreased in these cells. Phosphoamino acid analysis revealed that the tyrosine and threonine moieties of p44MAPK was phosphorylated by LacCer. Incubation of cells with ceramide and glucosylceramide did not significantly stimulate p44MAPK activity. Preincubation with tyrphostin (20 microM; a potent and specific inhibitor of tyrosine kinase) markedly inhibited the LacCer mediated stimulation in p44MAPK activity. Next we investigated the upstream and downstream parameters in MAP kinase signaling pathways. We found that lactosylceramide stimulated (7-fold) the loading of GTP on Ras. Concomitantly, LacCer stimulated the phosphorylation of MAP kinase kinases (MEK) and Raf within 2.5 min. Lactosylceramide specifically induced c-fos mRNA expression (3-fold) in these cells as compared to control. In summary, one of the biochemical mechanisms in LacCer mediated induction in the proliferation of aortic smooth muscle cells may involve Ras-GTP loading, activation of the kinase cascade (MEK, Raf, p44MAPK), and c-fos expression.
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PMID:Lactosylceramide stimulates Ras-GTP loading, kinases (MEK, Raf), p44 mitogen-activated protein kinase, and c-fos expression in human aortic smooth muscle cells. 863 72

A number of studies have demonstrated that the proliferative capacity of cells declines with aging. In particular, epidermal growth factor (EGF)-stimulated DNA synthesis is reduced in hepatocytes from aged rats relative to young rats. Growth factor stimulation activates a genetic program in large part regulated by a family of mitogen-activated protein kinases (MAPK) that phosphorylate and thereby activate transcription factors involved in controlling the expression of proliferation-associated genes. In the present study, we compared the activation of the extracellular signal-regulated kinase 2 (ERK2) and c-Jun N-terminal kinase 1 (JNK1) MAPK in EGF-stimulated hepatocytes derived from young (6-month) and aged (24-month) rats. JNK activity was not appreciably altered by EGF treatment of cells from either age group. In contrast, ERK2 was highly activated by EGF treatment, but the magnitude of activation was significantly lower in hepatocytes of aged animals compared to those of young animals (7-fold versus 20-fold, respectively). The reduced ERK2 activity in response to EGF was associated with decreased c-fos and c-jun mRNA expression and lower levels of AP-1 transcription factor DNA binding activity in the aged hepatocytes. Finally, the basal expression of MAPK phosphatase 1, a MAPK-regulated gene involved in regulating MAPK activity, was higher in aged hepatocytes. Taken together, these findings suggest that an alteration in the balance between MAP kinase-phosphatase activities could contribute to the age-related decline in proliferative capacity.
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PMID:Age-related decline in mitogen-activated protein kinase activity in epidermal growth factor-stimulated rat hepatocytes. 863 68

The c-fos proto-oncogene is activated by a plethora of signals via the transcription factors Sap-1a and CREB. Recently, the coactivator CBP has been demonstrated to act in concert with CREB when CREB is phosphorylated by protein kinase A. We show that CBP also binds directly to Sap-1a. While phosphorylation of Sap-1a by mitogen-activated protein kinases is not necessary for CBP/Sap-1a interaction, functional cooperation between these two proteins requires Sap-1a to become phosphorylated. CBP-antagonists impair Sap-1a-mediated transactivation. Similarly, the CBP antagonist E1A suppresses c-fos upregulation by phosphorylated CREB, indicating that CBP is a central component of c-fos regulation. Furthermore, CBP is phosphorylated by protein kinase A in vitro and the transactivation potential of the carboxy-terminal region of CBP is enhanced in the presence of active protein kinase A in vivo. Thus, CBP, in addition to CREB, is a target for cAMP-dependent signaling. However, combined phosphorylation of CBP by protein kinase A and mitogen-activated protein kinases appears to be non-cooperative, suggesting that CBP serves the function of a dampening integrator of two different signaling pathways.
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PMID:Regulation of the c-fos promoter by the ternary complex factor Sap-1a and its coactivator CBP. 864 57

Rat pheochromocytoma PC12 cells are shown to express a single class of high affinity binding sites for bone morphogenetic protein (BMP)-2 (1,300 receptors/cell, Kd = 31.3 pM). Affinity cross-linking using radiolabeled BMP-2 demonstrated the presence of six components with apparent molecular masses of 170, 155, 105, 90, 80, and 70 kDa. BMP-2 induced morphological changes in PC12 cells with the concomitant expression of three neurofilament proteins. Thus, BMP-2 would appear to be another neurotrophic factor that, like nerve growth factor or basic fibroblast growth factor, stimulates the neuronal differentiation of PC12 cells. Unlike nerve growth factor and basic fibroblast growth factor, however, BMP-2 failed to induce the activation of either 41- and 43-kDa mitogen-activated protein (MAP) kinases or the MAP kinase/extracellular signal-regulated kinase kinase (MEK). Also, BMP-2 did not induce the expression of the c-fos gene in PC12 cells. Activin A was also capable of inducing the neuronal differentiation of PC12 cells without activating MAP kinases and MEK. These findings show a clear dissociation between the requirement for the activation of the MAP kinase cascade and the ability of BMP-2 and activin A to induce PC12 cell neuronal differentiation. In addition, these results suggest that the activation of MAP kinases and MEK is not an absolute requirement for PC12 cell differentiation.
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PMID:Characterization of the bone morphogenetic protein-2 as a neurotrophic factor. Induction of neuronal differentiation of PC12 cells in the absence of mitogen-activated protein kinase activation. 866 61

The v-Src oncoprotein induces mitogenesis and transformation of cells through multiple effects on diverse signalling pathways that are influenced by the cellular context in which v-Src is expressed. Here we have examined the effects of a temperature-sensitive (ts) v-Src on transcription of the c-fos proto-oncogene, in serum-deprived and growing Rat-1 fibroblasts. We have also considered the role of mitogen-activated protein (MAP) kinase, a known mediator of ternary complex formation at the c-fos serum response element (SRE), which results in transcriptional enhancement in response to growth factors. In cells exponentially growing in the presence of serum, activation of v-Src stimulated MAP kinase and c-fos transcription. In cells made quiescent by serum deprivation, however, v-Src did not induce a c-fos transcriptional response, nor was there stimulation of ternary complex formation, despite normal activation of MAP kinase. Thus, activation of MAP kinase and stimulation of c-fos transcription and ternary complex formation are uncoupled in the absence of serum growth factors. Stimulation of c-fos by v-Src in growing cells, however, coincided with formation of a complex with an oligonucleotide spanning the c-Sis-inducible element (SIE) upstream from the SRE, suggesting that the signal transduction and activator of transcription (STAT) family of transcription factors, which bind here, may function in response to the v-Src oncoprotein. During these studies, we also observed that addition of fresh serum growth factors to growing Rat-1 fibroblasts expressing ts v-Src at the restrictive temperature resulted in substantially impaired activation of MAP kinase. This interference with normal growth factor signalling implies that catalytically inactive Src acts in a dominant negative manner by blocking normal activation of MAP kinase, although not at the expense of c-fos transcription. Thus, serum-induced c-fos transcription can also occur in an MAP kinase-independent manner.
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PMID:Uncoupling of the pathways which link MAP kinase to c-fos transcription and AP-1 in response to growth stimuli. 873 May 15

Angiotensin II (ANG II), a potent growth-promoting factor of vascular smooth muscle cells (VSMC), induces activation of mitogen-activated protein (MAP) kinases and subsequent expression of the c-fos protooncogene in VSMC. However, it remains obscure whether ANG II induces activation of the ras protooncogene product (Ras), and if it does, whether Ras is involved in signaling from the ANG II receptor to the MAP kinase pathway in VSMC. In cultured VSMC, ANG II activated Ras comparably to epidermal growth factor. ANG II-induced Ras activation was detectable within 1 min and maximal at 2-5 min. The ANG II type 1 (AT1) receptor antagonist, CV-11974, completely inhibited this reaction. Pertussis toxin treatment of VSMC inhibited ANG II-induced Ras activation by approximately 70% but had no effect on ANG II-induced MAP kinase activation and c-fos expression. These results indicate that ANG II activates Ras via AT1 receptors, which are predominantly linked to a G protein of the Gi subfamily in VSMC1 and suggest that Ras activation may not be a prerequisite for ANG II-induced MAP kinase activation and c-fos expression in this cell type.
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PMID:Angiotensin II type 1 receptor-mediated activation of Ras in cultured rat vascular smooth muscle cells. 877 Jan 1

To understand the molecular mechanism by which the angiotensin II (AII) type 1 receptor (AT1 receptor) transduces its biological signal, we examined the role of various signaling molecules involved in AT1 receptor signaling in Chinese hamster ovary cells stably transfected with the AT1 receptor. AT1 receptor-transfected cells responded to AII treatment by inhibiting adenylyl cyclase, increasing the intracellular Ca2+ concentration, and activating protein kinase C (PKC) alpha and PKC epsilon. AII also activated the c-fos gene and mitogen-activated protein (MAP) kinases. The activation of PKC, the c-fos gene, and MAP kinases was blocked by inhibition of PKC induced by pretreatment with 12-O-tetradecanoylphorbol-13-acetate but not by pretreatment with pertussis toxin, suggesting that PKC couples to the activation of the the c-fos gene and MAP kinases. In addition, AII activated Raf-1 and MAP kinase kinase in a PKC-dependent manner. A dominant negative mutant of Ras had no effect on AII-induced MAP kinase or c-fos gene activation. Thus, the AT1 receptor signals through Raf-1 and its downstream signaling molecules by a PKC-dependent mechanism that does not involve Ras activation.
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PMID:Angiotensin II type 1 receptor signals through Raf-1 by a protein kinase C-dependent, Ras-independent mechanism. 879 90

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