Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upregulation of plasminogen activator inhibitor type 1 (PAI-1) expression is a critical mechanism through which transforming growth factor-beta1 (TGF-beta1) accelerates intimal growth. The aim of this study was to identify signaling pathways through which TGF-beta1 upregulates PAI-1 expression in endothelial cells (EC) and test interventions for blocking these pathways. We transduced cultured bovine EC with an adenoviral vector containing the PAI-1 promoter fused to a beta-galactosidase reporter gene. We used these cells, along with vectors expressing potential modifiers of TGF-beta1 signaling and pharmacologic antagonists of mitogen-activated protein kinase (MAPK) pathways to identify key mediators of basal and TGF-beta1-regulated PAI-1 expression. Basal activity of the PAI-1 promoter was directly correlated with Ras activation and was blocked by a dominant negative (DN) type I TGF-beta receptor. TGF-beta1-stimulated activity of the PAI-1 promoter did not require Ras activation, and was lessened or eliminated by expression of either DN type I or type II TGF-beta receptors and by inhibition of either of two MAPKs: MEK and p38. Our results suggest unanticipated pathways of TGF-beta1 signaling in EC and point to new strategies to limit TGF-beta1-induced vascular disease.
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PMID:Identification of intracellular pathways through which TGF-beta1 upregulates PAI-1 expression in endothelial cells. 1613 37

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.
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PMID:Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. 1617 Mar 53

Transforming growth factor-beta (TGF-beta) has been characterized as an injury-related factor, based on the observation that it is strongly up-regulated in many acute or chronic central nervous system disorders. TGF-beta is generally thought to be neuroprotective and several mechanisms have been proposed to explain this beneficial action. For instance, TGF-beta protects neurons against the potentiating effect of tissue-type plasminogen activator on NMDA receptor-mediated excitotoxicity, by up-regulating type-1 plasminogen activator inhibitor expression in astrocytes. TGF-beta has also anti-apoptotic properties, through a recruitment of a mitogen-activated protein kinase pathway and a concomitant activation of anti-apoptotic members of the Bcl-2 family. These multiple mechanisms might reflect the pleiotropic nature of TGF-beta, reinforcing the potential therapeutic value of this cytokine in several central nervous system disorders.
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PMID:Transforming growth factor-beta signalling in brain disorders. 1627

Net, Elk-1, and Sap-1 are members of the ternary complex factor (TCF) subfamily of Ets transcription factors. They form ternary complexes with serum response factor (SRF) on serum response elements of immediate early genes such as c-fos and egr-1 and mediate responses to growth factors and mitogen-activated protein kinase signaling. Although the TCFs have been extensively studied as intermediates in signaling cascades, surprisingly little is known about their different target genes and physiological functions. We report that Net homozygous mutant mouse embryonic fibroblasts have a defect in cell migration. This defect results at least in part from increased expression of plasminogen activator inhibitor type 1 (PAI-1), a serine protease inhibitor (serpin) that controls extracellular proteolysis and cell matrix adhesion. The defect in cell migration can be reverted by the addition of a PAI-1 blocking antibody. Net represses PAI-1 promoter activity and binds to a specific region of the promoter containing Ets binding sites in the absence of SRF. We conclude that Net is a negative regulator of PAI-1 expression and is thereby involved in cell migration.
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PMID:The ternary complex factor Net regulates cell migration through inhibition of PAI-1 expression. 1631 10

13-Deoxytedanolide is a structurally unique macrolide with strong antitumor activity isolated from a marine sponge. Recently, we showed that 13-deoxytedanolide bound to the large subunit of the yeast ribosome and inhibited polypeptide elongation in vitro, but the mechanism by which it exerts antitumor activity is still unknown. Here we show that 13-deoxytedanolide strongly induces plasminogen activator inhibitor 1 (PAI-1) promoter-derived gene expression. 13-Deoxytedanolide, unlike TGF-beta, did not cause apparent nuclear translocation of Smad2/3, but it relocalized the temperature-sensitive mutant of mouse p53 (p53Val153) from the cytoplasm to the nucleus at a nonpermissive temperature, suggesting that 13-deoxytedanolide inhibits protein synthesis. Indeed, the drug inhibited in vivo protein synthesis at low nanomolar concentrations and strongly activated stress-activated protein kinases such as p38 mitogen-activated protein kinase and Jun NH2-terminal protein kinase (JNK). Anisomycin, a well-known inducer of ribotoxic stress that activates both p38 and JNK, also activated PAI-1 gene expression, while other protein synthesis inhibitors that do not activate the kinases failed to do so. PAI-1 gene expression by 13-deoxytedanolide and anisomycin was blocked by SB202190, a specific inhibitor of p38, and SP600125, an inhibitor of both p38 and JNK. 13-Deoxytedanolide and anisomycin caused activation of apoptosis signal-regulating kinase 1, MKK3/MKK6, and SEK1/MKK4, the regulatory kinases upstream of p38 and JNK. These results suggest that 13-deoxytedanolide, like anisomycin, triggers a ribotoxic stress response that activates stress-activated protein kinase cascades, thereby inducing PAI-1 gene expression and apoptosis.
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PMID:Induction of a ribotoxic stress response that stimulates stress-activated protein kinases by 13-deoxytedanolide, an antitumor marine macrolide. 1642 34

Various adipocytokines have been described which influence insulin sensitivity and vascular function profoundly and might, therefore, potentially link obesity, insulin resistance, and atherosclerosis. Among those, plasminogen activator inhibitor (PAI)-1 is an adipose-secreted factor upregulated in obesity and insulin resistance that inhibits fibrinolysis. Furthermore, recent studies in knockout mice suggest that PAI-1 directly impairs insulin sensitivity. In the current study, the impact of growth hormone (GH) and interleukin (IL)-6 on PAI-1 mRNA synthesis and secretion was determined in 3T3-L1 adipocytes. Interestingly, 500 ng/ml GH and 30 ng/ml IL-6 increased PAI-1 secretion five-fold and 3.6-fold, respectively. Furthermore, GH and IL-6 induced PAI-1 mRNA by up to 7.3-fold, and 3.6-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 5 ng/ml GH and 10 ng/ml IL-6. Other insulin resistance-inducing hormones which stimulated PAI-1 synthesis included insulin, TNFalpha, and dexamethasone. Studies using pharmacological inhibitors suggested that basal and GH-induced PAI-1 synthesis were at least in part mediated by p44/42 mitogen-activated protein kinase but not janus kinase 2 and phosphatidylinositol 3-kinase. Taken together, our results show a differential regulation of PAI-1 mRNA by insulin resistance-inducing hormones including GH and IL-6.
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PMID:Plasminogen activator inhibitor-1 expression and secretion are stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes. 1671 70

It was shown previously that Ea4-peptide of trout pro-IGF-I exerted mitogenic activity in non-transformed cells and inhibited colony formation in a soft agar medium of established human cancer cells. Here we report that the same peptide inhibits the invasion of human breast cancer cells (MDA-MB-231) through a matrigel membrane in a dose-dependent manner. The expression of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI1) genes in MDA-MB-231 cells were downregulated by treatment with rtEa4-peptide. The inhibition of expression of these genes in response to rtEa4-peptide treatment was reduced to the control level when inhibitors for c-Jun N-terminal kinase 1/2 (JNK1/2), mitogen activated protein kinase kinase 1/2 (Mek1/2), p38 mitogen activated protein kinase (p38 MAPK), phosphatidylinositol 3-kinase (PI3K), and phosphokinase C (PKC) were used. These results suggest that inhibition of invasion of MDA-MB-231 cells by rtEa4-peptide may be mediated via the suppression of uPA, tPA, and PAI1 gene activities through signal transduction pathways.
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PMID:Inhibition of human breast cancer cell (MBA-MD-231) invasion by the Ea4-peptide of rainbow trout pro-IGF-I. 1679 42

Plasminogen activator inhibitor 1 (PAI-1) is an important mediator of atherosclerosis and liver fibrosis in insulin resistance. Circulating levels of PAI-1 are elevated in obese individuals, and PAI-1 messenger RNA is significantly higher in the livers of obese type 2 diabetic individuals than in nonobese type 2 diabetic individuals. To address the mechanism underlying the up-regulation of hepatic PAI-1 in obesity, we tested the effects of tumor necrosis factor alpha (TNF-alpha), an important link between obesity and insulin resistance, on PAI-1 production in the nonmalignant human hepatocyte cell line, THLE-5b. Incubation of THLE-5b cells with TNF-alpha stimulated PAI-1 production via protein kinase C-, mitogen-activated protein kinase-, protein tyrosine kinase-, and nuclear factor-kappaB-dependent pathways. A thiazolidinedione, pioglitazone, reduced TNF-alpha-induced PAI-1 production by 32%, via protein kinase C- and nuclear factor-kappaB-dependent pathways. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin inhibited TNF-alpha-induced PAI-1 production by 59%, which was reversed by coincubation with mevalonic acid. In conclusion, obesity and TNF-alpha up-regulation of PAI-1 expression in human hepatocytes may contribute to the impairment of the fibrinolytic system, leading to the development of atherosclerosis and liver fibrosis in insulin-resistant individuals. A thiazolidinedione and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor may thus be candidate drugs to inhibit obesity-associated hepatic PAI-1 production.
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PMID:Tumor necrosis factor-alpha-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line. 1704 48

In cancer, Transforming Growth Factor beta (TGFbeta) increases proliferation and promotes invasion via selective loss of signalling pathways. Oesophageal adenocarcinoma arises from Barrett's oesophagus, progresses rapidly and is usually fatal. The contribution of perturbed TGFbeta signalling in the promotion of metastasis in this disease has not been elucidated. We therefore investigated the role of TGFbeta in Barrett's associated oesophageal adenocarcinoma using a panel of cell lines (OE33, TE7, SEG, BIC, FLO). 4/5 adenocarcinoma cell lines failed to cell cycle arrest, down-regulate c-Myc or induce p21 in response to TGFbeta, and modulation of a Smad3/4 specific promoter was inhibited. These hyperproliferative adenocarcinoma cell lines displayed a TGFbeta induced increase in the expression of the extracellular matrix degrading proteinases, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1), which correlated with an invasive cell phenotype as measured by in vitro migration, invasion and cell scattering assays. Inhibiting ERK and JNK pathways significantly reduced PAI and uPA induction and inhibited the invasive cell phenotype. These results suggest that TGFbeta Smad-dependent signalling is perturbed in Barrett's carcinogenesis, resulting in failure of growth-arrest. However, TGFbeta can promote PAI and uPA expression and invasion through MAPK pathways. These data would support a dual role for TGFbeta in oesophageal adenocarcinoma.
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PMID:Selective loss of TGFbeta Smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines. 1726 80

The role of transforming growth factor-beta (TGF-beta) receptor complex in the pathogenesis of crescentic glomerulonephritis (GN) is not clear. To test the hypothesis that TGF-beta signaling plays a crucial role in the development and progression of crescentic GN by inducing the activation of extracellular signal-regulated kinase (ERK) and expression of its target genes, anti-glomerular basement membrane (GBM) GN was induced in TGF-beta type II receptor (TGF-betaIIR) gene heterozygous (TGF-betaIIR(+/-)) C57BL/6J mice and wild-type animals. GN was initiated in preimmunized mice by administration of rabbit anti-mouse GBM serum. TGF-betaIIR deficiency was significantly associated with decreased renal damage at days 14, 21, and 28 after induction of GN: renal function impairment, proteinuria, proportion of crescents, glomerular accumulation of periodic acid-Schiff-positive material, relative cortical interstitial volume, as well as renal cortical phosphorylation of ERK and plasminogen activator inhibitor type I (PAI-1) and alpha2(I) collagen mRNA levels were significantly decreased in TGF-betaIIR(+/-) mice compared with wild-type animals. These results provide the first direct evidence that TGF-betaIIR deficiency protects against renal injury in crescentic GN, possibly by inhibiting the sustained activation of ERK and PAI-1 and alpha2(I) collagen gene expression. Thus, TGF-beta signaling appears to play an important role in the development and progression of crescentic GN by inducing the ERK activity, and PAI-1 and alpha2(I) mRNA expression.
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PMID:TGF-beta type II receptor deficiency prevents renal injury via decrease in ERK activity in crescentic glomerulonephritis. 1729 19


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