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)

This study was performed to examine effects of the overexpression of protein kinase C (PKC) isoforms (i.e., beta I, beta II, gamma, delta, eta, and zeta) on mitogen-activated protein (MAP) kinase (Erk-1 and -2) signaling and growth characteristics of NIH3T3 cells. Phorbol ester (PMA) activated endogenous and ectopically expressed PKC alpha, beta I, beta II, gamma, delta, epsilon, and eta. Overexpression of the examined PKC isoforms enhanced PMA-induced MAP kinase activation. Potentiation of MAP kinase activation was also observed upon stimulation of cells with platelet-derived growth factor (PDGF) although there was no indication for the activation PKC isoforms by PDGF. Inhibition of PKC blocked PMA- but not PDGF-induced MAP kinase activation. Thus, potentiation of PDGF-induced MAP kinase activation appears to be independent to PKC activity, while PMA-induced MAP kinase activation requires PKC activity. The ability of PKC isoforms to potentiate MAP kinase activation is not related to the growth characteristics of cells because individual PKC isoforms differentially regulated maximum density and proliferation of cells.
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PMID:Modulation of MAP kinase signaling and growth characteristics by the overexpression of protein kinase C in NIH3T3 cells. 976 12

Under conventional culture conditions, smooth muscle cells display their phenotypic modulation from a differentiated to a dedifferentiated state. Here, we established a primary culture system of smooth muscle cells maintaining a differentiated phenotype, as characterized by expression of smooth muscle-specific marker genes such as h-caldesmon and calponin, cell morphology, and ligand-induced contractility. Laminin retarded the progression of dedifferentiation of smooth muscle cells. Insulin-like growth factors (IGF-I and IGF-II) and insulin markedly prolonged the differentiated phenotype, with IGF-I being the more potent. In contrast, serum, epidermal growth factor, transforming growth factors, and platelet-derived growth factors potently induced dedifferentiation compared with angiotensin II, arginine-vasopressin, and basic fibroblast growth factor. Using the present culture system, we investigated signaling pathways regulating a phenotype of smooth muscle cells. In cultured cells, IGF-I specifically activated phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, protein kinase B, but not mitogen-activated protein kinases. Specific inhibitors of PI3-kinase (wortmannin and LY294002) induced dedifferentiation of smooth muscle cells even when they were cultured on laminin under IGF-I-stimulated conditions. The sole effect of laminin to retard the dedifferentiation was completely blocked by anti-IGF-I antibody, and laminin promoted the endogenous expression of IGF-I in cultured cells. The reduced promoter activity of the caldesmon gene induced by platelet-derived growth factor BB was overcome by the forced expression of the constitutive active form of PI3-kinase p110alpha catalytic subunit. These findings suggest that an IGF-I signaling pathway through PI3-kinase plays a critical role in maintaining a differentiated phenotype of smooth muscle cells.
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PMID:Differentiated phenotype of smooth muscle cells depends on signaling pathways through insulin-like growth factors and phosphatidylinositol 3-kinase. 978 87

Angiotensin II acts on the cardiac fibroblast to produce a mitogenic response. Nitric oxide and N-acetylcysteine have been used to determine if oxidative stress influenced the effects of angiotensin II on the cardiac fibroblast. Angiotensin II activated the mitogen-activated protein kinases designated extracellular signal-regulated kinases within 5 min by interacting with the AT1 receptor. This activation was completely independent of protein kinase C and was inhibited when farnesylation was blocked, implicating Ras involvement. Pretreatment of cardiac fibroblasts with either N-acetylcysteine for 8 h or nitric oxide for 10 min suppressed this activation by angiotensin II in a dose-dependent manner. However, when both agents were added, inhibition was essentially complete. This combined effect of N-acetylcysteine and nitric oxide to block ERKs activation also was found if the activity was stimulated by either another growth factor (platelet-derived growth factor) or by the addition of phorbol ester, suggesting the effect was not limited to the receptor site alone. The results are consistent with the hypothesis that hormonal activation of mitogenic steps such as ERKs is influenced by increased oxidative stress, which is reduced by the combined effects of N-acetylcysteine and nitric oxide.
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PMID:Nitric oxide and N-acetylcysteine inhibit the activation of mitogen-activated protein kinases by angiotensin II in rat cardiac fibroblasts. 983 56

Cell cycle progression is regulated by cAMP in several cell types. Cellular cAMP levels depend on the activity of different adenylyl cyclases (ACs), which have varied signal-receiving capabilities. The role of individual ACs in regulating proliferative responses was investigated. Native NIH 3T3 cells contain AC6, an isoform that is inhibited by a variety of signals. Proliferation of exogenous AC6-expressing cells was the same as in control cells. In contrast, expression of AC2, an isoform stimulated by protein kinase C (PKC), resulted in inhibition of cell cycle progression and increased doubling time. In AC2-expressing cells, platelet-derived growth factor (PDGF) elevated cAMP levels in a PKC-dependent manner. PDGF stimulation of mitogen-activated protein kinases 1 and 2 (MAPK 1,2), DNA synthesis, and cyclin D1 expression was reduced in AC2-expressing cells as compared with control cells. Dominant negative protein kinase A relieved the AC2 inhibition of PDGF-induced DNA synthesis. Expression of AC2 also blocked H-ras-induced transformation of NIH 3T3 cells. These observations indicate that, because AC2 is stimulated by PKC, it can be activated by PDGF concurrently with the stimulation of MAPK 1,2. The elevation in cAMP results in inhibition of signal flow from the PDGF receptor to MAPK 1,2 and a significant reduction in the proliferative response to PDGF. Thus, the molecular identity and signal receiving capability of the AC isoforms in a cell could be important for proliferative homeostasis.
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PMID:Identity of adenylyl cyclase isoform determines the rate of cell cycle progression in NIH 3T3 cells. 984 19

SHP-2 is a widely distributed Src homology 2 (SH2) domain-containing tyrosine phosphatase that is recruited to growth factor receptors on stimulation. We have transiently co-expressed several catalytically active and inactive forms of the enzyme with the platelet-derived growth factor (PDGF) receptor in human embryonic kidney 293 cells. The catalytically active forms of SHP-2 decreased the tyrosine phosphorylation of the receptor, whereas the catalytically inactive forms increased the phosphorylation. However, PDGF-induced activation of the mitogen-activated protein (MAP) kinase pathway was enhanced by the active forms of SHP-2 but decreased by the inactive forms. The results suggest that the PDGF receptor is a physiological substrate of SHP-2 and that SHP-2 has a positive role in the PDGF-stimulated activation of MAP kinase. The dissociation of the receptor phosphorylation from the activation of MAP kinase suggests that signalling through growth factor receptors does not depend merely on their tyrosine phosphorylation.
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PMID:Tyrosine phosphatase SHP-2 dephosphorylates the platelet-derived growth factor receptor but enhances its downstream signalling. 993 Dec 95

To understand the role of redox-sensitive mechanisms in vascular smooth muscle cell (VSMC) growth, we have studied the effect of N-acetylcysteine (NAC), a thiol antioxidant, and diphenyleneiodonium (DPI), a potent NADH/NADPH oxidase inhibitor, on serum-, platelet-derived growth factor BB-, and thrombin-induced ERK2, JNK1, and p38 mitogen-activated protein (MAP) kinase activation; c-Fos, c-Jun, and JunB expression; and DNA synthesis. Both NAC and DPI completely inhibited agonist-induced AP-1 activity and DNA synthesis in VSMC. On the contrary, these compounds had differential effects on agonist-induced ERK2, JNK1, and p38 MAP kinase activation and c-Fos, c-Jun, and JunB expression. NAC inhibited agonist-induced ERK2, JNK1, and p38 MAP kinase activation and c-Fos, c-Jun, and JunB expression except for platelet-derived growth factor BB-induced ERK2 activation. In contrast, DPI only inhibited agonist-induced p38 MAP kinase activation and c-Fos and JunB expression. Antibody supershift assays indicated the presence of c-Fos and JunB in the AP-1 complex formed in response to all three agonists. In addition, cotransfection of VSMC with expression plasmids for c-Fos and members of the Jun family along with the AP-1-dependent reporter gene revealed that AP-1 with c-Fos and JunB composition exhibited a higher transactivating activity than AP-1 with other compositions tested. All three agonists significantly stimulated reactive oxygen species production, and this effect was inhibited by both NAC and DPI. Together, these results strongly suggest a role for redox-sensitive mechanisms in agonist-induced ERK2, JNK1, and p38 MAP kinase activation; c-Fos, c-Jun, and JunB expression; AP-1 activity; and DNA synthesis in VSMC. These results also suggest a role for NADH/NADPH oxidase activity in some subset of early signaling events such as p38 MAP kinase activation and c-Fos and JunB induction, which appear to be important in agonist-induced AP-1 activity and DNA synthesis in VSMC.
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PMID:JunB forms the majority of the AP-1 complex and is a target for redox regulation by receptor tyrosine kinase and G protein-coupled receptor agonists in smooth muscle cells. 1002 27

This study examines the possible involvement of endogenous platelet-derived growth factor (PDGF) in the angiotensin II-induced growth of rat aortic smooth muscle cells. In quiescent confluent cells, anti-PDGF-AB neutralizing antibody inhibited angiotensin II-induced DNA synthesis and protein synthesis. PDGF-AA, -AB, and -BB produced concentration-dependent increases in DNA synthesis and protein synthesis. Genistein did not inhibit PDGF-AB-induced [3H]thymidine incorporation and [3H]leucine incorporation. PDGF-AB stimulated mitogen-activated protein (MAP) kinases, and PDGF-induced MAP kinase activation was inhibited by genistein. Angiotensin II induced PDGF-A chain messenger RNA expression, and genistein inhibited angiotensin-induced PDGF gene expression. These findings suggest that endogenous PDGF is, at least in part, involved in angiotensin II-induced cell growth in rat vascular smooth muscle cells. It appears that genistein inhibits angiotensin II-induced DNA synthesis partly by inhibiting PDGF-A gene expression.
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PMID:Evidence for the involvement of platelet-derived growth factor in the angiotensin II-induced growth of rat vascular smooth muscle cells. 1007 31

We hypothesized that in bovine tracheal myocytes, growth factor treatment induces transcription from the cyclin D1 promoter that is dependent on the activation of both Ras and extracellular signal-related kinase (ERK). We found that platelet-derived growth factor (PDGF) treatment induced substantial activation of ERK2 that was blocked by expression of a dominant-negative Ha-Ras. Further, expression of a constitutively active Ha-Ras induced substantial ERK2 activity, consistent with the notion that Ras is required and sufficient for ERK activation. PDGF treatment induced only modest activation of the Jun amino terminal kinase-1 (JNK1) and p38 mitogen-activated protein kinases (MAPKs). Active Ras induced similar responses, implying that complete activation of the JNK and p38 pathways requires additional or alternative upstream signaling intermediates besides Ras. In contrast, expression of a constitutively active Rac1, an alternative guanosine triphosphatase involved in intracellular signaling, produced a high level of JNK1 activation, suggesting that Rac1 is an important upstream activator of JNK in this system. Active Ras and MAPK/ ERK kinase-1 (MEK1) (the upstream activator of ERK) each induced cyclin D1 promoter activity, whereas active stress-activated protein kinase/ERK kinase-1 (SEK1), an upstream activator of JNK, did not. Finally, the synthetic MEK inhibitor PD98059 blocked Ras-induced cyclin D1 promoter activity. Together, these data suggest that in bovine tracheal myocytes: (1) activation of MAPK by PDGF is dependent on Ras; (2) active Ras is sufficient for ERK activation but is insufficient for maximal activation of JNK or p38; (3) activation of Rac1 is sufficient for maximal JNK activation; and (4) Ras, MEK, and ERK constitute a distinct pathway to cyclin D1 transcriptional activation.
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PMID:Platelet-derived growth factor stimulation of mitogen-activated protein kinases and cyclin D1 promoter activity in cultured airway smooth-muscle cells. Role of Ras. 1034 Sep 49

The expression and activity of factors influencing early neuronal development are altered by ethanol. Such factors include growth factors, for example, platelet-derived growth factor and basic fibroblast growth factor (for cell proliferation), and cell adhesion molecules (for neuronal migration). One agent, transforming growth factor beta1 (TGFbeta1), may affect both events. We tested the hypothesis that ethanol alters myriad TGFbeta1-mediated activities [i.e., cell proliferation and neural cell adhesion molecule (N-CAM) expression] using B104 neuroblastoma cells. TGFbeta1 inhibited the proliferation of B104 cells as evidenced by decreases in cell number and [3H]thymidine ([3H]dT) incorporation. TGFbeta1 induced sustained activation of extracellular signal-regulated kinases (ERKs), which are part of the family of mitogen-activated protein kinases (MAPKs). Treatment with PD98059 (a MAPK kinase blocker) abolished TGFbeta1-regulated inhibition of [3H]dT incorporation. TGFbeta1-mediated growth inhibition was potentiated by ethanol exposure. Ethanol also produced prolonged activation of ERK, an effect that was partially eliminated by treatment with PD98059. On the other hand, TGFbeta1 up-regulated N-CAM expression, and this up-regulation was not affected by treatment with PD98059. Ethanol inhibited the TGFbeta1-induced up-regulation of N-CAM expression in a concentration-dependent manner. Thus, TGFbeta1 affects ERK-dependent cell proliferation and ERK-independent N-CAM expression in B104 cells. Both activities are sensitive to ethanol and may underlie the ethanol-induced alterations in the proliferation and migration of CNS neurons.
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PMID:Transforming growth factor beta1-regulated cell proliferation and expression of neural cell adhesion molecule in B104 neuroblastoma cells: differential effects of ethanol. 1034 37

In this study we show that platelet-derived growth factor (PDGF)-induced DNA binding as well as transcriptional activation of Stat5b are markedly increased by inhibition of the MAP (mitogen-activated protein) kinase kinase MEK. In addition to the previously demonstrated tyrosine phosphorylation, we show that serine and threonine phosphorylation of Stat5b is increased in response to PDGF stimulation. However, inhibition of MEK had no effect on the phosphorylation level of Stat5b or on the nuclear translocation of Stat5b. These observations indicate that MEK is a negative modulator of PDGF-induced Stat5b activation through a mechanism not involving direct phosphorylation of Stat5b.
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PMID:MEK is a negative regulator of Stat5b in PDGF-stimulated cells. 1035 46


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