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)

The role of mitogen-activated protein (MAP) kinase cascades in platelet function remains to be determined. Several studies have suggested a role in the activation of phospholipase A2; however, other functions seem likely. The object of the present study was to determine the role of the MAP kinase cascade in platelet function. An inhibitor of the mitogen-activated protein kinase kinase MEK1, 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059), was used, at concentrations consistent with those reported to inhibit MEK1, to examine the role that this enzyme plays in platelet function. PD98059 inhibited aggregation in response to low-dose collagen and arachidonic acid, but not that in response to high-dose collagen, thrombin, thrombin receptor-activating peptide (TRAP), 9,11-dideoxy-11alpha, 9alpha-epoxymethano-prostaglandin F2alpha (U46619), or phorbol ester. Thrombin, thrombin receptor-activating peptide, U46619, collagen, and arachidonic acid each caused the release of [3H]serotonin from dense granules, but only that elicited by low-dose collagen and arachidonic acid was inhibited by PD98059. The release of [3H]arachidonic acid in response to thrombin or collagen was unaffected by PD98059 pretreatment. In contrast, collagen- and arachidonic acid-induced thromboxane formation was inhibited by PD98059. These data suggest that MEK1 is not involved in the platelet response to thrombin or U46619. Furthermore, the inhibitory effects of PD98059 on collagen- and arachidonic acid-induced responses suggest that PD98059 may inhibit the conversion of arachidonic acid to thromboxane, in addition to its reported effects on MEK1.
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PMID:Effects of the mitogen-activated protein (MAP) kinase kinase inhibitor 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059) on human platelet activation. 971 93

Ultraviolet radiation from the sun damages human skin, resulting in an old and wrinkled appearance. A substantial amount of circumstantial evidence indicates that photoaging results in part from alterations in the composition, organization, and structure of the collagenous extracellular matrix in the dermis. This paper reviews the authors' investigations into the molecular mechanisms by which ultraviolet irradiation damages the dermal extracellular matrix and provides evidence for prevention of this damage by all-trans retinoic acid in human skin in vivo. Based on experimental evidence a working model is proposed whereby ultraviolet irradiation activates growth factor and cytokine receptors on keratinocytes and dermal cells, resulting in downstream signal transduction through activation of MAP kinase pathways. These signaling pathways converge in the nucleus of cells to induce c-Jun, which heterodimerizes with constitutively expressed c-Fos to form activated complexes of the transcription factor AP-1. In the dermis and epidermis, AP-1 induces expression of matrix metalloproteinases collagenase, 92 kDa gelatinase, and stromelysin, which degrade collagen and other proteins that comprise the dermal extracellular matrix. It is hypothesized that dermal breakdown is followed by repair that, like all wound repair, is imperfect. Imperfect repair yields a deficit in the structural integrity of the dermis, a solar scar. Dermal degradation followed by imperfect repair is repeated with each intermittent exposure to ultraviolet irradiation, leading to accumulation of solar scarring, and ultimately visible photoaging. All-trans retinoic acid acts to inhibit induction of c-Jun protein by ultraviolet irradiation, thereby preventing increased matrix metalloproteinases and ensuing dermal damage.
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PMID:Molecular mechanisms of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo. 973 61

Epithelial cell differentiation is regulated by specific combinations of growth factors, hormones, and extracellular matrix (ECM). How these divergent signals are integrated is largely unknown. We used primary cultures of normal human bronchial epithelial cells (NHBEs) to investigate mechanisms of signal integration. In defined, serum-free media, NHBEs undergo mucosecretory differentiation only when grown in the presence of retinoids and on the appropriate substratum (collagen gels). We identified the retinoic acid receptor beta (RARbeta) gene as an early marker of NHBE differentiation. In contrast to immortalized cell lines, in NHBEs strong retinoid-induced RARbeta transcription occurs only when cells are grown on collagen gels, and it requires new protein synthesis and a cis-acting element that maps outside the known RARbeta promoter elements. NHBEs grown on collagen gels exhibit reduced epidermal growth factor (EGF)-induced Raf, MEK, and mitogen-activated protein kinase (MAPK) activity. This correlates with a specific inability to achieve high levels of p66(SHC) tyrosyl phosphorylation and association of p66(SHC) with GRB2, despite high levels of EGF receptor (EGFR) autophosphorylation. Notably, inhibition of EGFR or MEK/MAPK activation replaces the ECM requirement for RARbeta induction. Our results strongly suggest that a key mechanism by which specific ECMs facilitate retinoid-induced mucosecretory differentiation of NHBEs is by restricting the level of EGFR-dependent MEK/MAPK activation evoked by autocrine and/or paracrine EGFR ligands.
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PMID:Integration of growth factor, extracellular matrix, and retinoid signals during bronchial epithelial cell differentiation. 977 81

Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs during development, wound healing and cancer and involves stages that orchestrate a network of cooperative interactions. Peptide growth factors and extracellular matrix (ECM) components are two major groups of angiogenesis mediators. Among the different ECM proteins, collagens have been well-associated with in vivo angiogenesis. Using human umbilical vein endothelial cells (HUVEC) grown in 3-D collagen gels we show that: (1) HUVEC do not survive well in 3-D collagen gels due to rapid induction of apoptosis. (2) VEGF, a potent in vivo angiogenic factor, fails to induce tube formation. (3) PMA was effective in inducing tube formation and survival in HUVEC dispersed in 3-D collagen gels, activating MAP kinase, phosphoinositide 3-OH kinase (PI-3-kinase) and Akt/PKB (protein kinase B) pathways. (4) VEGF was effective in preventing PMA-induced tube-like structure regression after PMA-withdrawal by (5) activating the mitogen activated protein kinase (MAPK), rather than the Akt/PKB, signaling pathway.
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PMID:Distinct signal transduction pathways are utilized during the tube formation and survival phases of in vitro angiogenesis. 981 53

CD23, the low affinity IgE receptor, is up-regulated on the surface of IL-4-treated B cells and monocytes and is immediately proteolytically processed, releasing soluble fragments of CD23. Here, we report that inhibitors of the p38 mitogen-activated kinase (p38 MAPK), SK&F 86002 or the more selective inhibitor, SB 203580, reduce the levels of soluble CD23 formed by IL-4-stimulated human monocytes or the human monocytic cell line, U937. In contrast to compounds such as the metalloprotease inhibitor batimastat ([4-(N-hydroxyamino)-2-(R)-isobutyl-3-(S)-(2-thiophenethiomethyl)s uccinyl]-(S)-phenylalanine-N-methylamide, sodium salt), p38 MAPK inhibitors do not directly inhibit proteolytic processing of CD23. Further, evaluation of surface intact CD23 (iCD23) by flow cytometry demonstrated that SK&F 86002 and SB 203580 reduced the surface expression of iCD23 in a concentration-dependent fashion, while batimastat increased the surface expression of iCD23. The decrease in surface iCD23 was accompanied by a decrease in total cell-associated CD23 protein levels but not CD23 mRNA. IL-4 induced a late (>4-h) increase in p38 MAPK activity and corresponding activation of its substrate MAPKAPK-2. This activation was blocked by addition of SB 203580 before IL-4 induction, in parallel with the inhibition of CD23 expression. Modulation of CD23 by antibodies has been shown to alleviate the symptoms of murine collagen-induced arthritis, implicating CD23 as an important proinflammatory agent. These data show that in addition to the known cytokine inhibitory actions of SK&F 86002 and SB 203580, they also confer an additional potential anti-inflammatory activity through modulation of CD23 expression.
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PMID:Inhibitors of the p38 mitogen-activated kinase modulate IL-4 induction of low affinity IgE receptor (CD23) in human monocytes. 983 82

Overexpression of the epidermal growth factor receptors (EGFR) in polarized kidney epithelial cells caused them to appear in high numbers at both the basolateral and apical cell surfaces. We utilized these cells to look for differences in the regulation and signaling of apical vs. basolateral EGFR. Apical and basolateral EGFR were biologically active and mediated EGF-induced cell proliferation to similar degrees. Receptor downregulation and endocytosis were less efficient at the apical surface, resulting in prolonged EGF-induced tyrosine kinase activity at the apical cell membrane. Tyrosine phosphorylation of EGFR substrates known to mediate cell proliferation, Src-homologous and collagen protein (SHC), extracellularly regulated kinase 1 (ERK1), and ERK2 could be induced similarly by activation of apical or basolateral EGFR. Focal adhesion kinase was tyrosine phosphorylated more by basolateral than by apical EGFR; however, beta-catenin was tyrosine phosphorylated to a much greater degree following the activation of mislocalized apical EGFR. Thus EGFR regulation and EGFR-mediated phosphorylation of certain substrates differ at the apical and basolateral cell membrane domains. This suggests that EGFR mislocalization could result in abnormal signal transduction and aberrant cell behavior.
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PMID:Differential signaling and regulation of apical vs. basolateral EGFR in polarized epithelial cells. 984

Hepatic stellate cells (HSCs) become activated into myofibroblast-like cells during the early stages of hepatic injury associated with fibrogenesis. The subsequent dysregulation of alphaI(I) collagen gene expression is a central pathogenetic step during the development of cirrhosis. Our recent study in rat HSCs (Davis, B. H., Chen, A., and Beno, D. (1996) J. Biol. Chem. 271, 11039-11042) found that ERK1,2 activation might be required for maximal alphaI(I) collagen gene expression. However, the role of the parallel JNK cascade in regulating alphaI(I) collagen gene expression was unknown. In this study, we initially found that UV irradiation of HSCs activated JNK but not ERK1,2. Furthermore, UV irradiation increased endogenous alpha I(I) collagen mRNA abundance and stimulated alpha I(I) collagen gene transcription in HSCs. The effect of the activation of JNK and Jun on alpha I(I) collagen gene expression was further evaluated via transfection of chloramphenicol acetyltransferase reporter plasmids with various sizes of truncated 5' upstream promoter sequence (UPS) of the alphaI(I) collagen gene. This revealed that dominant negative transcription factor JUN suppressed alpha I(I) collagen gene transcription in HSCs maintained in media with 20% serum and constitutively activated JUN increased alphaI(I) collagen gene transcription in HSCs cultured in media with 0.4% serum. UV activated JNK utilized a distal GC box in the 5'-UPS of the collagen gene to regulate gene transcription. This observation was confirmed by site-directed mutagenesis. In co-transfection experiments, the col-chloramphenicol acetyltransferase reporter with a mutagenized GC box was not suppressed by dn-JUN and was not stimulated by activated JUN or by UV irradiation. Southwestern blotting analyses and gel shift assays with basic transcription element-binding protein antiserum suggested that the GC box was bound by basic transcription element-binding protein, a recently described DNA-binding protein. In conclusion, the current study combined with our previous report suggests that ERK1,2 and JNK cascades regulate alphaI(I) collagen expression in HSCs through different regions of the 5'-UPS of the gene. The distal GC box in the 5'-UPS of the alphaI(I) collagen gene may play a central role in receiving extracellular signals through the JNK pathway.
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PMID:UV irradiation activates JNK and increases alphaI(I) collagen gene expression in rat hepatic stellate cells. 986 24

Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with an exceptionally wide substrate specificity and restricted tissue-specific expression. Here we show that MMP-13 expression is induced in normal human skin fibroblasts cultured within three-dimensional collagen gel resulting in production and proteolytic activation of MMP-13. Induction of MMP-13 mRNAs by collagen gel was potently inhibited by blocking antibodies against alpha1 and alpha2 integrin subunits and augmented by activating antibody against beta1 integrin subunit, indicating that both alpha1 beta1 and alpha2 beta1 integrins mediate the MMP-13-inducing cellular signal generated by three-dimensional collagen. Collagen-related induction of MMP-13 expression was dependent on tyrosine kinase activity, as it was abolished by treatment of fibroblasts with tyrosine kinase inhibitors genistein and herbimycin A. Contact of fibroblasts to three-dimensional collagen resulted in simultaneous activation of mitogen-activated protein kinases (MAPKs) in three distinct subgroups: extracellular signal-regulated kinase (ERK)1 and ERK2, Jun N-terminal kinase/stress-activated protein kinase, and p38. Induction of MMP-13 expression was inhibited by treatment of fibroblasts with a specific p38 inhibitor, SB 203580, whereas blocking the ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by PD 98059, a selective inhibitor of MEK1,2 activation potently augmented MMP-13 expression. Furthermore, specific activation of ERK1,2 pathway by 12-O-tetradecanoylphorbol-13-acetate markedly suppressed MMP-13 expression in dermal fibroblasts in collagen gel. These results show that collagen-dependent induction of MMP-13 in dermal fibroblasts requires p38 activity, and is inhibited by activation of ERK1,2. Therefore, the balance between the activity of ERK1,2 and p38 MAPK pathways appears to be crucial in regulation of MMP-13 expression in dermal fibroblasts, suggesting that p38 MAPK may serve as a target for selective inhibition of collagen degradation, e.g. in chronic dermal ulcers.
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PMID:Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. 989 Oct 15

Tenascin-C is an extracellular matrix glycoprotein, the expression of which is upregulated in remodeling arteries. In previous studies we showed that the presence of tenascin-C alters vascular smooth muscle cell shape and amplifies their proliferative response by promoting growth factor receptor clustering and phosphorylation. Moreover, we demonstrated that denatured type I collagen induces smooth muscle cell tenascin-C protein production via beta3 integrins. In the present study, we examine the pathway by which beta3 integrins stimulate expression of tenascin-C, and define a promoter sequence that is critical for its induction. On native collagen, A10 smooth muscle cells adopt a stellate morphology and produce low levels of tenascin-C mRNA and protein, whereas on denatured collagen they spread extensively and produce high levels of tenascin-C mRNA and protein, which is incorporated into an elaborate extracellular matrix. Increased tenascin-C synthesis on denatured collagen is associated with elevated protein tyrosine phosphorylation, including activation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). beta3 integrin function-blocking antibodies attenuate ERK1/2 activation and tenascin-C protein synthesis. Consistent with these findings, treatment with the specific MEK inhibitor, PD 98059, results in suppression of tenascin-C protein synthesis. To investigate whether beta3 integrin-dependent activation of ERK1/2 regulates the tenascin-C promoter, we transfected A10 cells with a full-length (approx. 4 kb) mouse tenascin-C gene promoter-chloramphenicol acetyltransferse reporter construct and showed that, relative to native collagen, its activity is increased on denatured collagen. Next, to identify regions of the promoter involved, we examined a series of tenascin-C promoter constructs with 5' deletions and showed that denatured collagen-dependent promoter activity was retained by a 122-base pair element, located -43 to -165 bp upstream of the RNA start site. Activation of this element was suppressed either by blocking beta3 integrins, or by preventing ERK1/2 activation. These observations demonstrate that smooth muscle cell binding to beta3 integrins activates the mitogen activated protein kinase pathway, which is required for the induction of tenascin-C gene expression via a potential extracellular matrix response element in the tenascin-C gene promoter. Our data suggest a mechanism by which remodeling of type I collagen modulates tenascin-C gene expression via a beta3 integrin-mediated signaling pathway, and as such represents a paradigm for vascular development and disease whereby smooth muscle cells respond to perturbations in extracellular matrix composition by altering their phenotype and patterns of gene expression.
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PMID:Induction of vascular smooth muscle cell tenascin-C gene expression by denatured type I collagen is dependent upon a beta3 integrin-mediated mitogen-activated protein kinase pathway and a 122-base pair promoter element. 991 56

-Estrogens are known to induce cardioprotective effects by inhibiting smooth muscle cell (SMC) growth and neointima formation. However, the use of estrogens as cardioprotective agents is limited by carcinogenic effects in women and feminizing effects in men. If noncarcinogenic and nonfeminizing estrogenlike compounds, such as natural phytoestrogens, afford cardioprotection, this would provide a safe method for prevention of cardiovascular disease in both men and women. Therefore, we evaluated and compared in human aortic SMCs the effects of phytoestrogens (formononetin, genistein, biochanin A, daidzein, and equol) on 2.5% fetal calf serum-induced proliferation (3H-thymidine incorporation and cell number), collagen synthesis (3H-proline incorporation), and total protein synthesis (3H-leucine incorporation) and on PDGF-BB (25 ng/mL)-induced migration (modified Boydens chambers). Moreover, the effects of phytoestrogens on PDGF-BB (25 ng/mL)-induced mitogen-activated protein kinase (MAP kinase) activity in SMCs was also studied. Phytoestrogens inhibited proliferation, collagen and total protein synthesis, migration, and MAP kinase activity in a concentration-dependent manner and in the following order of potency: biochanin A>genistein>equol>daidzein>formononetin. In conclusion, our studies provide the first evidence that in human aortic SMCs phytoestrogens inhibit mitogen-induced proliferation, migration and extracellular matrix synthesis and inhibit/downregulate MAP kinase activity. Thus, phytoestrogens may confer protective effects on the cardiovascular system by inhibiting vascular remodeling and neointima formation and may be clinically useful as a safer substitute for feminizing estrogens in preventing cardiovascular disease in both women and men.
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PMID:Phytoestrogens inhibit growth and MAP kinase activity in human aortic smooth muscle cells. 993 Nov 1


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