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)

Reactive oxygen species (ROS) are implicated in the pathogenesis of several proliferative diseases, including atherosclerosis and cancer. Eukaryotic translation initiation factor 4E (eIF4E) plays an important role in cell proliferation and differentiation. To gain insight into molecular mechanisms by which ROS influence the pathogenesis of these diseases, I have studied the effect of H(2)O(2), a ROS, on eIF4E phosphorylation. H(2)O(2) induced eIF4E phosphorylation in a dose- and time-dependent manner in growth-arrested smooth muscle cells (SMC). H(2)O(2)-induced eIF4E phosphorylation occurred on serine residues. PD098059, a specific inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase inhibited ERK activities but had no significant effect on eIF4E phosphorylation induced by H(2)O(2). Similarly, SB203580, a specific inhibitor of p38 MAPK, although inhibiting H(2)O(2)-induced p38 MAPK activity, had no effect on H(2)O(2)-induced eIF4E phosphorylation. Calphostin C, a specific inhibitor of protein kinase C, also had no effect on H(2)O(2)-induced eIF4E phosphorylation. In contrast, trifluoperazine, an antagonist of calcium/calmodulin kinases, completely blocked H(2)O(2)-induced eIF4E phosphorylation. In addition, intracellular and extracellular Ca(2+) chelators significantly inhibited H(2)O(2)-induced eIF4E phosphorylation. Despite its ability to induce eIF4E phosphorylation, H(2)O(2) had no significant effect on protein levels and new protein synthesis as compared with control. In contrast, it induced the expression of c-Fos, c-Jun, and HSP70 in a time-dependent manner in SMC. Together, these results suggest that H(2)O(2), a ROS and a cellular oxidant, induces eIF4E phosphorylation in a manner that is dependent on Ca(2+) and Ca(2+)/calmodulin kinases and independent of ERKs, p38 MAPK, and protein kinase C. These results also suggest that enhanced eIF4E phosphorylation by H(2)O(2) appears to be an important event in SMC in response to oxidant stress and that eIF4E phosphorylation may be associated with the translation of a small subset of mRNAs such as c-fos, c-jun, and HSP70 gene mRNAs, whose products may have a critical role in cell survival.
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PMID:Oxidant stress stimulates phosphorylation of eIF4E without an effect on global protein synthesis in smooth muscle cells. Lack of evidence for a role of H202 in angiotensin II-induced hypertrophy. 1082 72

Increased oxidative stress has been reported in vivo in the diabetic state via the production of reactive oxygen species (ROS). Such stress is bound to play a key role on activation of circulating monocytes, leading to the accelerated atherosclerosis observed in diabetics. However the exact molecular mechanisms of monocyte activation by high glucose is currently unclear. Here, we demonstrate that chronic high glucose (CHG) causes a dramatic increase in the release of the inflammatory cytokine tumor necrosis factor alpha (TNFalpha), at least in part through enhanced TNFalpha mRNA transcription, mediated by ROS via activation of transcription factors nuclear factor kappaB (NF-kappaB) and activating protein-1 (AP-1). TNFalpha accumulation in the conditioned media was increased 10-fold and mRNA levels were increased 11.5-fold by CHG. The following observations supported that both NF-kappaB and AP-1 mediated enhanced TNFalpha transcription by CHG: 1) A 295-base pair fragment of the proximal TNFalpha promoter containing NF-kappaB and AP-1 sites reproduced the effects of CHG on TNFalpha transcription in a luciferase reporter assay, 2) mutational analyses of both NF-kappaB and the AP-1 sites abrogated 90% of the luciferase activity, 3) gel-shift analysis using the binding sites showed activation of NF-kappaB and AP-1 in CHG nuclear extracts, and 4) Western blot analyses demonstrated elevated nuclear levels of p65 and p50 and decreased cytosolic levels of IkappaBalpha in CHG-treated monocytes. That ROS acted as a key intermediate in the CHG pathway was supported by the following evidence: 1) increased superoxide levels similar to those observed with PMA or TNFalpha, 2) increased phosphorylation of stress-responsive mitogen-activated protein kinases p38 and JNK-1, 3) counteraction of the effects of CHG on TNFalpha production, the 295TNFluc reporter activity, activation of NF-kappaB, and repression of IkappaBalpha by antioxidants and p38 mitogen-activated protein kinase inhibitors. The study suggests that ROS function as key components in the regulatory pathway progressing from elevated glucose to monocyte activation.
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PMID:Molecular mechanisms of tumor necrosis factor alpha gene expression in monocytic cells via hyperglycemia-induced oxidant stress-dependent and -independent pathways. 1083 98

Hyperlipidemia alters gene expression of arterial endothelial and smooth muscle cells (SMCs) and induces atherosclerotic lesions, in which cell proliferation and apoptosis co-exist. The signal transduction pathways that mediate these responses in the vessel wall in vivo have yet to be identified. Stress-activated protein kinases (SAPKs) or c-Jun NH(2)-terminal protein kinases (JNKs) are thought to be crucial in transmitting transmembrane signals required for cell differentiation and apoptosis in vitro. In the present study, we investigated the localization and activity of SAPK/JNK in atherosclerotic lesions of cholesterol-fed rabbits. Immunofluorescence analysis revealed abundant and heterogeneous distribution of pan-SAPK/JNK and phosphorylated SAPK/JNK, which were mainly localized in cell nuclei of the lesional cap and basal regions. Double staining of the lesions demonstrated that a portion of alpha-actin(+) SMCs and RAM11(+) macrophages contained abundant phosphorylated SAPK/JNK proteins. SAPK/JNK protein levels in protein extracts from atherosclerotic lesions were two- to threefold higher than the vessels of chow-fed rabbits. SAPK/JNK activities were elevated three- to fivefold higher than the normal vessels. Interestingly, increased SAPK/JNK in lesions was co-localized or coincided with high levels of transcription factor p53 as identified by double labeling and immunoprecipitation. Abundant pro-apoptotic protein BAX and BCL-X(S) were also observed. Furthermore, low-density lipoprotein (LDL) and oxidized LDL stimulated SAPK/JNK activation in cultured SMCs in a time- and dose-dependent manner. LDL also induced SAPK/JNK activation in vascular SMCs derived from LDL-receptor-deficient Watanabe rabbits, indicating a LDL-receptor-independent process. Thus, SAPK/JNK persistently hyperexpressed and activated in lesions may play a key role in mediating cell differentiation and apoptosis during the development of atherosclerosis via activation of transcription factor p53.
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PMID:Increased expression and activation of stress-activated protein kinases/c-Jun NH(2)-terminal protein kinases in atherosclerotic lesions coincide with p53. 1085 11

Extracellular matrix proteins such as fibronectin (FN) and laminin (LM) are known to help control the growth and phenotype of vascular smooth muscle cells (VSMCs). Here we have analyzed the relationship between growth factor and integrin signaling pathways in VSMCs. Culturing porcine coronary artery smooth muscle cells (PCASMCs) on FN and LM leads to distinct effects on cell proliferation and contractile protein expression. PCASMCs cultured on FN proliferate at a higher rate than cells cultured on LM, regardless of the growth factor used to support proliferation. Moreover, cells cultured on LM show higher levels of expression of smooth muscle myosin heavy chain (a marker of smooth muscle cell differentiation) than cells cultured on FN. In contrast to the effects on proliferation and contractile protein expression, both FN and LM supported cell migration in response to PDGF. Also, both FN and LM supported activation of ERK1 and ERK2 in response to PDGF and bFGF. However, FN and LM did show a difference in their ability to support signaling through the focal adhesion kinase (FAK). PCASMCs cultured on FN show robust activation of FAK in response to either PDGF or bFGF, however, cells cultured on LM show little-to-no activation of FAK in response to the growth factors. The results show that integrin signaling pathways have a profound effect on VSMC proliferation and phenotype, and that FAK is an important intermediate in these signaling pathways. The implications of our findings on the mechanisms controlling VSMC proliferation and phenotype in pathological states such as atherosclerosis and restenosis are discussed.
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PMID:Control of smooth muscle cell proliferation and phenotype by integrin signaling through focal adhesion kinase. 1087 43

Angiotensin II (Ang II) stimulates the activation of extracellular signal-regulated kinase (ERK), a subgroup of the mitogen-activated protein kinase (MAPK) family, in cultured vascular smooth muscle cells (VSMC). This ERK activation was recently shown to be a critical regulatory factor for Ang II-mediated migration and growth. It has been demonstrated that the thiazolidinedione troglitazone (TRO) blocked Ang II-induced DNA synthesis and migration in VSMC. Here we provide evidence for TRO to inhibit Ang II-induced ERK activation which was suggested to constitute the mechanism by which this agent blocks Ang II-induced VSMC growth and migration. We have found that pretreatment with PD98059, which selectively blocks the activity of ERK pathway at the level of MAPK kinase, decreased Ang II-induced AP-1 activation and that TRO is capable of inhibiting Ang II-induced AP-1 activation. On the other hand, the other thiazolidinediones pioglitazone (PIO) and rosiglitazone (ROSI) had little effect on Ang II-induced activation of ERK or AP-1, suggesting the inhibitory effects of TRO on VSMC activation by Ang II be independent of the peroxisome proliferator-activated receptor-gamma (PPARgamma) for which thiazolidinediones are ligands. Ang II-induced ERK activation was inhibited by protein kinase C (PKC)-specific inhibitor GF109203X, while TRO was also able to block PKC activator phorbol 12 myristate 13-acetate (PMA)-induced ERK activation. Accordingly, TRO may inhibit Ang II-induced MAPK activation at least partly by an inhibition of PKC. These results support the assumption that by targeting MAPK activation, TRO may inhibits the critical signaling steps leading to restenosis and atherosclerosis that may result in part from dysregulated VSMC growth and migration induced by Ang II.
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PMID:The effects of thiazolidinediones on vascular smooth muscle cell activation by angiotensin II. 1089 86

Hypercholesterolemia (HC) is associated with coronary endothelial dysfunction and increased circulating levels of endothelin-1. We show that pre-treatment of intact rat aortic rings with cholesterol synergistically enhances the vasoconstriction induced by endothelin-1 suggesting that elevated levels of cholesterol may predispose to hypertension by modulating the vascular reactivity to endogenous vasoconstrictors. Moreover, we report that SB202190, a selective inhibitor of p38 MAPK, and PD98059 an inhibitor of MEK1/2 are able to abolish the vasoactive properties of cholesterol. MK-886, an inhibitor of 5-lipoxygenase is inefficient at blocking the vasoactive properties of cholesterol whereas NS-398, a selective inhibitor of cyclooxygenase-2 (COX-2) completely abolishes cholesterol-induced vasoconstriction. In intact rat aortae, cholesterol stimulates prostaglandin E(2) and prostaglandin F(2 alpha) production, an effect that can be completely prevented by inhibiting p38 MAPK, or COX-2. In vitro, cholesterol appears to stimulate a similar pro-inflammatory pathway in human cerebrovascular smooth muscle cells. Disruption of the MAPK/COX-2 pathway may represent a valuable therapy to block the hypertension associated with HC, as well as the development of atherosclerosis.
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PMID:Cholesterol modulates vascular reactivity to endothelin-1 by stimulating a pro-inflammatory pathway. 1091 76

Injury of endothelial cells induced by reactive oxygen species plays an important role in the development of early stages of vascular diseases such as hypertension and atherosclerosis. Exposure of human umbilical vein endothelial cells to hydrogen peroxide (H(2)O(2)), a common form of reaction oxygen species, triggers a series of intracellular events, including actin cytoskeletal reorganization, cytoplasm shrinkage, membrane blebbing and protein-tyrosine phosphorylation. The effect of H(2)O(2) on endothelial cells is dramatically enhanced when a survival pathway involving extracellular signal-regulated kinase is blocked by PD098059. In contrast, the injury of endothelial cells mediated by H(2)O(2) is inhibited by PP2, a selective specific inhibitor for protein-tyrosine kinase Src. Cortactin, a filamentous actin (F-actin)-associated protein, becomes phosphorylated at tyrosine residues upon stimulation by H(2)O(2) in a manner dependent on the activity of Src. The level of tyrosine phosphorylation of cortactin is correlated with the formation of membrane blebs. Overexpression of wild-type cortactin tagged with green fluorescent protein in endothelial cells via a retroviral vector substantiates the H(2)O(2)-induced morphological changes, whereas overexpression of a green fluorescent protein-cortactin mutant deficient in tyrosine phosphorylation renders endothelial cells resistant to H(2)O(2). The functional role of cortactin in H(2)O(2)-mediated shape changes was also evaluated in NIH 3T3 cells. Stable 3T3 transfectants expressing wild-type cortactin in the presence of either H(2)O(2)/PD098059 or H(2)O(2) alone at 200 microm exhibited a dramatic shape change characterized by rounding up or aggregation. However, the similar changes were not detected with cells overexpressing a cortactin mutant deficient in tyrosine phosphorylation. These data demonstrate an important role of the Src/cortactin-dependent actin reorganization in the injury of endothelial cells mediated by reactive oxygen species.
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PMID:Tyrosine phosphorylation of cortactin is required for H2O2-mediated injury of human endothelial cells. 1095 84

Occlusive accelerated atherosclerosis of coronary grafts is the predominant factor that limits longevity of heart transplant recipients. This form of vascular disease affects both the large epicardial and the smaller intramyocardial vessels, leading to characteristic clinical presentation that necessitates the use of sophisticated techniques for their accurate detection. Accelerated atherosclerosis after transplantation is a multifactorial disease with many events contributing to its progression. The initial vascular injury associated with ischemia-reperfusion appears to aggravate preexisting conditions in the donor vasculature in addition to activation of new immunological and nonimmunological mechanisms. Throughout these events, the endothelium remains a primary target of cell- and humoral-mediated injury. Changes in the vascular intima leads to alterations in vascular smooth muscle cell (VSMC) physiology, resulting in VSMC phenotypic modulation with the orchestration of a broad spectrum of growth and inflammatory reactions, which might be a healing response to vascular injury. Endogenous nitric oxide (NO) pathways regulate a multiplicity of cellular mechanisms that play a major role in determining the structure and function of the vessel wall during normal conditions and during remodeling associated with accelerated atherosclerosis. Recently identified signaling pathways, including mitogen-activated protein kinase, cGMP-dependent protein kinase, phosphatidylinositol 3-kinase, and transcriptional events in which nuclear factor kappa B and activator protein 1 take part, can be associated with NO modulation of cell cycle perturbations and phenotypic alteration of VSMC during accelerated atherosclerosis. This article reviews recent progress covering the aforementioned matters. We start by summarizing the clincal aspects and pathogenesis of accelerated atherosclerosis associated with transplantation, including clinical presentation and detection. This summary is followed by a discussion of the multiple factors of the disease process, including immunological and nonimmunolgical contributions. The next section focuses on cellular responses of the VSMCs relevant to lesion formation, with special emphasis on classical and recent paradigms of phenotypic modulation of these cells. To examine the influence of NO on VSMC phenotypic modulation and consequent lesion development, we briefly overview characteristics of NO production in the normal coronary vascular bed and the changes in endogenous NO release and activity during atherosclerosis. This overview is followed by a section covering molecular mechanisms whereby NO regulates a range of signaling pathways, transcriptional events underlying cell cycle perturbation, and phenotypic alteration of VSMC in accelerated atherosclerosis.
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PMID:Transplant atherosclerosis: role of phenotypic modulation of vascular smooth muscle by nitric oxide. 1097 14

P2Y(2) receptors, which mediate contractile and mitogenic effects of extracellular nucleotides in vascular smooth muscle cells (VSMCs), are upregulated in the synthetic phenotype of VSMCs and in the neointima after balloon angioplasty, suggesting a role in the development of atherosclerosis. Because released cytokines in atherosclerotic lesions mediate multiple effects on gene transcription in VSMCs, we speculated that cytokines could be involved in the regulation of P2Y(2) receptor expression. Using a competitive reverse transcription-polymerase chain reaction, we detected that interleukin (IL)-1beta induced a time- and dose-dependent upregulation of P2Y(2) receptor mRNA, which was dramatically enhanced when combined with interferon-gamma or tumor necrosis factor-alpha. Lipopolysaccharide also significantly increased the expression of P2Y(2) receptor mRNA. The upregulation of P2Y(2) receptor mRNA was paralleled at the functional level because IL-1beta significantly increased the UTP-stimulated DNA synthesis and the release of intracellular Ca(2+). Actinomycin D completely blocked the upregulation of P2Y(2) receptor mRNA expression by IL-1beta, indicating de novo mRNA synthesis. There was no cAMP accumulation in the cells stimulated with IL-1beta. The cyclooxygenase inhibitor indomethacin and the protein kinase C inhibitor RO-31-8220 inhibited IL-1beta-induced upregulation of P2Y(2) receptor mRNA expression, whereas rapamycin and PD098059 had no effects. Furthermore, neither P38 mitogen-activated protein kinase inhibitor SB20358 alone nor its combination with PD098059 blocked the effect of IL-1beta on the expression of P2Y(2) receptor mRNA. Our results demonstrate that inflammatory mediators upregulate vascular P2Y(2) receptors at the transcriptional and at the functional level through protein kinase C and cyclooxygenase but not cAMP, extracellular signal-regulated kinases 1 and 2, or P38-dependent pathways. This may result in increased growth-stimulatory or contractile effects of extracellular UTP and ATP, which may be of importance in the development of vascular disease.
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PMID:Cytokines induce upregulation of vascular P2Y(2) receptors and increased mitogenic responses to UTP and ATP. 1097 50

Mechanical force is an important modulator of cellular morphology and function in a variety of tissues, and is particularly important in cardiovascular systems. Vascular smooth muscle cell (VSMC) hypertrophy and proliferation contribute to the development of atherosclerosis, hypertension, and restenosis, where mechanical forces are largely disturbed. How VSMCs sense and transduce the extracellular mechanical signals into the cell nucleus resulting in quantitative and qualitative changes in gene expression is an interesting and important research field. Recently, it has been demonstrated that mechanical stress rapidly induced phosphorylation of platelet-derived growth factor (PDGF) receptor, activation of integrin receptor, stretch-activated cation channels, and G proteins, which might serve as mechanosensors. Once mechanical force is sensed, protein kinase C and mitogen-activated protein kinases (MAPKs) were activated, leading to increased c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. Interestingly, physical forces also rapidly resulted in expression of MAPK phosphatase-1 (MKP-1), which inactivates MAPKs. Thus, mechanical stresses can directly stretch the cell membrane and alter receptor or G protein conformation, thereby initiating signalling pathways, usually used by growth factors. These findings have significantly enhanced our knowledge of the pathogenesis of arteriosclerosis and provided promising information for therapeutic interventions for vascular diseases.
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PMID:Mechanical stress-initiated signal transductions in vascular smooth muscle cells. 1098 77


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