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)

Recent evidences have demonstrated an important role for glomerular visceral epithelial cell (podocyte) in the development and progression of diabetic nephropathy. We investigated the high-glucose (HG)-triggered signaling pathway and its role in matrix metalloproteinase (MMP) production in murine podocytes. The activity of 92-kDa (MMP-9) gelatinase, but not of 72 kDa (MMP-2), in an HG medium significantly increased during incubation of 2 to 3 days and decreased during incubation of more than 5 days revealed by Gelatin zymography. Opposite to the increases in MMP-9 activity, HG medium produced significant decreases in the protein levels of alpha5(IV) collagen. Changes in MMP-9 activity were associated with the same pattern as MMP-9 mRNA levels in podocytes exposed to HG media. HG medium rapidly activated ERK1/2 MAPK in podocytes. Moreover, ERK1/2 activation was required for HG-induced enhancement of MMP-9 activity and a decrease in the level of alpha5(IV) collagen. HG incubation rapidly induced an increase in the nuclear accumulation of Ets-1 protein. Blocking the ERK pathway suppressed HG-induced expression and nuclear accumulation of transcriptional factor Ets-1, and MMP-9 mRNA expression. We suggest that short- or long-term exposure to HG concentrations increases or decreases MMP-9 production and alpha5(IV) collagen expression in podocytes, this may contribute to the GBM abnormality caused by an imbalance in extracellular matrix (ECM) synthesis and degradation, and may play a critical role in the pathogenesis of proteinuria in diabetic nephropathy.
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PMID:High ambient glucose levels modulates the production of MMP-9 and alpha5(IV) collagen by cultured podocytes. 1654 22

The net balance of matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) system has been known to be a key factor in tumor cell invasion. In the present study, we investigated the molecular mechanisms of anti-invasive and antimigrative activity of transforming growth factor (TGF)-beta1 on HT1080 human fibrosarcoma cells. In in vitro Matrigel invasion and Transwell migration assays, TGF-beta1 dose-dependently inhibited the invasion and migration of HT1080 cells, respectively. Gelatin zymography, Western blot, and real-time PCR analysis showed that TGF-beta1 enhanced the expression and secretion of MMP-2, TIMP-1, and, to a lesser degree, MMP-9 but not membrane type 1-MMP and TIMP-2. The addition of recombinant TIMP-1 protein reduced the Matrigel invasion and Transwell migration of HT1080 cells, similar to TGF-beta1. Because augmentation of TIMP-1 might be the major factor for the anti-invasive and antimigrative activity of TGF-beta1, we investigated possible molecular mechanisms responsible for the expression of TIMP-1 induced by TGF-beta1. Treatment of HT1080 cells with TGF-beta1 rapidly phosphorylated three mitogen-activated protein kinases [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase] and Akt. Among these kinases, the inhibition of only ERK1/2 pathway by PD98059, a specific inhibitor of MAPK/ERK kinase(MEK)-1, and transfection of dominant-negative MEK 1 effectively blocked the TIMP-1 induction by TGF-beta1. Mithramycin, a specific inhibitor of Sp1 transcription factor, but not curcumin, an inhibitor of activator protein-1, and transfection of Sp1 small interfering RNA significantly inhibited the TGF-beta1-induced expression of TIMP-1. In addition, electrophoretic mobility shift assay showed that TGF-beta1 up-regulated Sp1 DNA-binding activity, and PD98059 and mithramycin effectively inhibited these events. Finally, pretreatment of HT1080 cells with PD98059 and mithramycin, but not curcumin, restored the invasive activity of these cells. Taken together, these data suggest that TGF-beta1 modulates the net balance of the MMPs/TIMPs the systems in HT1080 cells for anti-invasion and antimigration by augmenting TIMP-1 through ERK1/2 pathway and Sp1 transcription factor.
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PMID:Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. 1654 58

Chronic exposure of the skeletal muscle microcirculation to elevated shear stress-induces angiogenesis. Previous studies observed that shear stress-induced capillary growth involves luminal sprouting, or internal division, of the capillaries, which is characterized by a minimal proliferative response and the retention of an intact basement membrane. Matrix metalloproteinases (MMPs) are associated with the process of abluminal sprouting angiogenesis, but may not be required for the process of luminal division during capillary growth. We analyzed the production of MMP-2, using both the in vivo model of prazosin-induced angiogenesis in rat skeletal muscle, and cultured microvascular endothelial cells exposed to laminar shear stress. We found that MMP-2 was not elevated in capillaries of shear stress-stimulated skeletal muscle, despite a significant increase in capillary number in response to a shear stress stimulus. In cultured microvascular endothelial cells, MMP-2 mRNA and protein levels were attenuated significantly in response to shear stress exposure. This effect on MMP-2 was reversed by nitric oxide (NO) synthase inhibition using LNNA. In contrast, exposure of static cultures of endothelial cells to NO donors significantly reduced MMP-2 production. Shear stress exposure and NO donors both modified phosphorylation levels of several members of the MAPK family. Treatment of shear stress-exposed cells with the p38 MAPK inhibitor, SB203580, abolished the shear stress-mediated reduction in MMP-2 mRNA. Thus, our data provide strong evidence that elevated shear stress inhibits MMP-2 production in microvascular endothelial cells, an effect that is mediated by signal pathways involving both production of NO and activation of p38 MAPK.
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PMID:Nitric oxide and p38 MAP kinase mediate shear stress-dependent inhibition of MMP-2 production in microvascular endothelial cells. 1657 6

Diabetic nephropathy is associated with increased accumulation of the extracellular matrix (ECM) in the kidney, which ultimately leads to kidney failure. This may occur due to excessive synthesis of ECM components or reduced degradation, a process primarily mediated by matrix metalloproteinases (MMPs). The direct effect of insulin on ECM synthesis and degradation in glomerular mesangial cells (GMCs) is unclear. Here, we show an increased gelatinase activity in conditioned media from insulin-treated rat GMCs, determined by gelatin zymography. Furthermore, we show using the specific inhibitors LY294002 and PD98059 that insulin induced increased gelatinase activity via an intracellular signalling mechanism involving phosphatidylinositol-3 kinase (PI-3K) and the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPKs) respectively. In addition, we demonstrate that PI-3 kinase and ERK1/2 MAPK are activated by insulin in GMCs. The appearance of protease activity at approximately 72 kDa suggested that MMP-2 activity may be induced by insulin, however, we did not detect an increase in MMP-2 expression by Western blotting. In summary, our results suggest that insulin can induce gelatinase activity in GMCs, and it is possible that loss of this input in insulin-resistant type 2 diabetic individuals may contribute to ECM accumulation and the development of nephropathy.
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PMID:Insulin increases gelatinase activity in rat glomerular mesangial cells via ERK- and PI-3 kinase-dependent signalling. 1663 87

Osteopontin (OPN) is a secreted, non-collagenous, sialic-acid rich, glycosylated adhesive phospho- protein. Several highly metastatic transformed cells synthesized a higher level of OPN compared with non-tumorigenic cells. We have recently reported that OPN induces nuclear factor-kappaB (NF-kappaB)-mediated promatrix metalloproteinase-2 activation through IkappaBalpha/IKK signaling pathways. However, the molecular mechanism(s) by which OPN regulates pro-matrix metalloproteinase-9 (pro-MMP-9) activation and involvement of upstream kinases in regulation of these processes that ultimately control cell motility and tumor growth in murine melanoma cells are not well defined. Here we report that OPN induces alphavbeta3 integrin-mediated phosphorylation and activation of nuclear factor inducing kinase (NIK) and enhances the interaction between phosphorylated NIK and IkappaBalpha kinase alpha/beta (IKKalpha/beta) in B16F10 cells. Moreover, NIK is involved in OPN-induced phosphorylations of MEK-1 and ERK1/2 in these cells. OPN induces NIK-dependent NF-kappaB activation through ERK/IKKalpha/beta-mediated pathways. Furthermore, OPN enhances NIK-regulated urokinase-type plasminogen activator (uPA) secretion, uPA-dependent pro-MMP-9 activation, and cell motility. Pretreatment of cells with anti-MMP-2 antibody along with anti-MMP-9 antibody drastically inhibited the OPN-induced cell migration and chemoinvasion, whereas cells pretreated with anti-MMP-2 antibody had no effect on OPN-induced pro-MMP-9 activation suggesting that OPN induces pro-MMP-2 and pro-MMP-9 activations through two distinct pathways. Taken together, NIK acts as crucial regulator in OPN-induced MAPK/IKK-mediated NF-kappaB-dependent uPA secretion and MMP-9 activation thereby controlling melanoma cell motility and chemoinvasion.
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PMID:Nuclear factor inducing kinase: a key regulator in osteopontin- induced MAPK/IkappaB kinase dependent NF-kappaB-mediated promatrix metalloproteinase-9 activation. 1669 5

Trypsin is involved in colorectal carcinogenesis and promotes proliferation, invasion, and metastasis. Although a well-known pancreatic digestive enzyme, trypsin has also been found in other tissues and various cancers, most importantly of the colorectum. Moreover, colorectal cancers with trypsin expression have a poor prognosis and shorter disease-free survival. Biological understanding of how trypsin causes cancer progression is emerging. It seems to act both directly and indirectly through a 'proteinase-antiproteinase-system', and by activation of other proteinase cascades. Invasion of the basal membrane by cancer cells may be promoted directly by trypsin digestion of type I collagen. Trypsin activates, and is co-expressed with matrix metalloproteinases (MMPs), which are known to facilitate invasion and metastasis. MMP-2, MMP-7, and MMP-9 are co-expressed together with trypsin and seem to be of particular importance in proliferation, progression, and invasion. MMPs may play a role in both conversion from adenoma to carcinoma, and in the initiation of invasion and metastasis. Co-segregation of trypsin and MMPs within the tumour environment is important for the activation of MMPs, and may explain the deleterious effect of trypsin on prognosis in colorectal cancer. Trypsin and proteinase-activated receptor 2 (PAR-2) act together in an autocrine loop that promotes proliferation, invasion, and metastasis through various mechanisms, of which prostaglandin synthesis is important. Stimulated by trypsin, both MMP and PAR-2 may activate the mitogenic MAPK-ERK pathway through activation of the epidermal growth factor receptor. Experimental trypsin inhibition is feasible but not very effective, and trypsin as a target for clinical therapy is unlikely to be successful owing to its universal distribution. However, as the pathways of trypsin and co-activated protein cascades emerge, biological understanding of colorectal carcinogenesis will be further illuminated and may pave the way for prognosticators, predictors, and novel targets of therapy.
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PMID:Trypsin in colorectal cancer: molecular biological mechanisms of proliferation, invasion, and metastasis. 1669 44

Adrenomedullin (AM), a peptide isolated from human pheochromocytoma, can be produced and secreted by various types of cells including hepatic stellate cells (HSCs), and its possible role in HSCs is not clear now. In the present study, the interactive regulation between transforming growth factor (TGF)-beta1 and AM and the effect of AM on TGF-beta1-induced matrix metalloproteinase (MMP)-2 expression in HSCs were investigated. TGF-beta1 and AM inhibited gene transcript level mutually (real-time reverse transcription-polymerase chain reaction). AM suppressed the protein expression level of TGF-beta1 (Western blot), but TGF-beta1 might have no effect on AM secretion level. MMP-2 protein expression in HSCs was increased in response to TGF-beta1, and upregulation of MMP-2 expression stimulated with TGF-beta1 was suppressed by AM in dose-dependent manner (Western blot). AM decreased the phosphorylation level of extracellular signal-regulated kinase (ERK) in HSCs treated with TGF-beta1, and TGF-beta1-induced MMP-2 expression was suppressed by adding Mitogen-activated protein Kinase/ERK (MEK) inhibitor U(0126) (Western blot)(.) Our results suggest that AM may intervene the activation of HSCs by inhibiting TGF-beta1 production and TGF-beta1-induced MMP-2 expression; AM may suppress the upregulation of MMP-2 expression induced by TGF-beta1 partially through ERK pathway.
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PMID:Adrenomedullin regulates expressions of transforming growth factor-beta1 and beta1-induced matrix metalloproteinase-2 in hepatic stellate cells. 1670 26

Chronic intermittent high altitude (IHA) hypoxia results in long-term adaptation protecting the heart against acute ischemia/reperfusion injury; however, molecular mechanisms of this phenomenon are not completely elucidated so far. The present study was aimed at investigation of a modulating effect of IHA hypoxia on the expression and/or activation of selected regulatory proteins, with particular emphasis on differential responses in the right ventricle (RV) and left ventricle (LV). Adult male Wistar rats were exposed to IHA hypoxia of 7000 m simulated in a hypobaric chamber (8 h/day, 25 exposures), and protein contents and activities in myocardial fractions were determined by Western blot analysis. In markedly hypertrophic RV of hypoxic rats, gelatinolytic activity of MMP-2 and protein levels of carbonic anhydrase IX (a marker of hypoxia) were significantly enhanced. Study of mitogen-activated protein kinases (MAPKs) revealed no differences in the contents of total p38-MAPK in both ventricles between the IHA and normoxic control rats, whereas activation of p38-MAPK was decreased in the RV and moderately increased in the LV of IHA rats as compared to controls. Extracellular signal regulated kinase-2 (ERK-2) was partially up-regulated in the RV of IHA rats, and, in addition, expression of acidic fibroblast growth factor (aFGF), a potential activator of ERK cascade, was also significantly increased. In contrast, expression of ERKs in the LV as well as their activities in both ventricles, were not affected by IHA hypoxia. Differential effects of IHA hypoxia on c-Jun-N-terminal protein kinases (JNKs) in the RV and LV were also observed. As compared with the controls, total content of JNKs was increased in the RV of the IHA rats, while expression of JNKs in the LV was down-regulated. IHA hypoxia changed neither total levels of Akt kinase in both RV and LV, nor Akt kinase activity in the RV. However, increased levels of activated phospho-Akt kinase were found in the LV of IHA rats. The results demonstrate that adaptation of rat hearts to chronic IHA hypoxia is associated with disctinct changes in the levels and/or activation of several regulatory proteins in two ventricles. The latter could be attributed to both myocardial remodeling and cardioprotection induced by chronic hypoxia.
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PMID:Changes in the expression and/or activation of regulatory proteins in rat hearts adapted to chronic hypoxia. 1671 73

HAb18G/CD147 has been identified as a factor that induces MMPs production. SiRNA targeted against HAb18G/CD147 was transfected into FHCC-98 cells (a HCC cell line) to knockdown its expression. The results showed that downregulating HAb18G/CD147 decreased ERK1/2, MMP-2 and FAK levels and inhibited cell motility and invasion, together with rearranged actin stress fiber formation, while had no effects on integrin alpha3beta1 expression. MEK1/2 inhibitor, U0126, inhibited MMP-2, FAK and actin expression in FHCC-98 cell line. The findings indicate that si-HAb18G inhibits gelatinase production, actin and FAK expression in FHCC-98 via an ERK1/2 signaling pathway.
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PMID:siRNA targeted against HAb18G/CD147 inhibits MMP-2 secretion, actin and FAK expression in hepatocellular carcinoma cell line via ERK1/2 pathway. 1681 29

The p75 neurotrophin receptor (p75(NTR)) has been characterized as a metastasis and tumor suppressor in prostate cancer. In order to investigate the mechanism(s) by which the p75(NTR) functions as a metastasis suppressor in prostate cancer cells, we characterized the ectopic expression of p75(NTR) on the urokinase plasminogen activator (uPA) and the type IV collagen matrix metalloproteinases (MMP-2 and MMP-9) in PC-3 human prostate cancer cells. Rank-order expression of p75(NTR) greatly reduced protein levels and enzymatic activities of uPA, MMP-2, and MMP-9 as shown by immunoblot and zymography analyses. Conversely, expression of the MMP-9 antagonist, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) exhibited an increase in protein levels with an increase in p75(NTR) levels, whereas TIMP-2 was not detected. Transient transfection with an inducible dominant negative antagonist Deltap75(NTR) rescued uPA, MMP-2, and MMP-9 protein levels and protease activities, and conversely suppressed TIMP-1 levels. Since p75(NTR) signal transduction occurs via the NFkappaB and JNK pathways, antagonism of signaling intermediates in these pathways, using dominant negative IKKbeta or dominant negative MKK-4, respectively, was shown to further decrease expression of uPA, MMP-2, and MMP-9 protein and enzymatic activity levels, and conversely up-regulate levels of TIMP-1. These results indicate that expression of uPA, MMP-2, MMP-9, and TIMP-1 are directly regulated by expression of p75(NTR) and its downstream signal transduction cascade. These results suggest that the metastasis suppressor activity of p75(NTR) is mediated, in part, by down-regulation of specific proteases (uPA, type IV collagenases) implicated in cell migration and metastasis.
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PMID:The p75(NTR) metastasis suppressor inhibits urokinase plasminogen activator, matrix metalloproteinase-2 and matrix metalloproteinase-9 in PC-3 prostate cancer cells. 1691 16


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