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)

Bone morphogenetic protein-6 (BMP-6) has been strongly implicated in prostate cancer development and bone metastasis. Our previous data showed that BMP-6 mRNA was absent in patients with benign prostatic hyperplasia, but evident in primary tumours with established secondary skeletal metastases. To examine the role of BMP-6 in prostate cancer progression, we have developed a BMP-6-regulatable, doxycycline-inducible gene expression system. BMP-6 induction by doxycycline addition led to increased levels of BMP-6 RNA and protein, associated with nuclear translocation of SMADs and activation of the downstream target gene Id-1. BMP-6 protein did not enhance the proliferation rate of PC3M cells but did significantly increase the rate of migration and invasion in both PC3M and DU145 cells. Increased metalloproteinase (MMP-1 and MMP-9) mRNA levels were also observed following BMP-6 induction. Luciferase reporter assays confirmed BMP-6-mediated activation of MMP-1 and MMP-9 promoters, indicating direct transcriptional activation of MMPs by BMP-6. BMP-6 stimulation also led to an increase in phosphorylation levels of MAPK proteins. We next examined the effects of BMP-6 on the downstream gene Id-1 in a cohort of prostate cancer patients. A tissue microarray (TMA) was constructed and samples stained for BMP-6 and Id-1 expression. We observed a significant increase in the intensity of staining of epithelial BMP-6 in the cancer cases compared to the benign cases (Mann-Whitney U test, p < 0.0005) and in the intensity of staining of epithelial Id-1 in the cancer cases compared to the benign cases (Mann-Whitney U test, p = 0.015). We further observed a significant positive correlation between epithelial staining for Id-1 and BMP-6 (p = 0.001) across all samples for both benign and cancer cases. These data demonstrate that BMP-6 promotes migration and invasion of prostate cancer cells, potentially through activation of Id-1 and MMP activation.
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PMID:BMP-6 over-expression in prostate cancer is associated with increased Id-1 protein and a more invasive phenotype. 1807 88

Diseases such as atherosclerosis, arthritis and cancer have been related with imbalance in ROS production and failures in regulation of the MMPs. Authors suggested a relationship between MPP activity and ROS. Our research group has demonstrated that retinol 7 microM induced changes in Sertoli cell metabolism linking retinol treatment and oxidative stress. We verified MMP activity in Sertoli cells treated with vitamin A using gelatin zymography. We found that retinol (7 microM) and retinoic acid (1 nM) induced MMP-2 activity in Sertoli cells. Antioxidants reversed retinol-induced but not retinoic acid-induced MMP-2 activity. Moreover, retinol but not retinoic acid increased ROS production quantified by DCFH-DA oxidation. We found that retinol and retinoic acid induced ERK1/2 phosphorylation, but only retinol-increased MMP-2 activity was inhibited by UO126, an ERK1/2 phosphorylation inhibitor. Our findings suggested that retinol-induced MMP-2 activity, but not retinoic acid-induced MMP-2 activity, was related to ERK1/2 phosphorylation and ROS production.
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PMID:Retinol and retinoic acid increase MMP-2 activity by different pathways in cultured Sertoli cells. 1807 36

C-reactive protein (CRP) is present in the atherosclerotic plaques and appears to promote atherogenesis. Intraplaque CRP colocalizes with oxidized low density lipoprotein (OxLDL) and macrophages in human atherosclerotic lesions. Matrix metalloproteinase-9 (MMP-9) has been implicated in plaque rupture. CRP promotes OxLDL uptake and MMP induction in vitro; however, these have not been investigated in vivo. We examined the effect of CRP on OxLDL uptake and MMP-9 production in vivo in Wistar rats. CRP significantly increased OxLDL uptake in the peritoneal and sterile pouch macrophages compared with human serum albumin (huSA). CRP also significantly increased intracellular cholesteryl ester accumulation compared with huSA. The increased uptake of OxLDL by CRP was inhibited by pretreatment with antibodies to CD32, CD64, CD36, and fucoidin, suggesting uptake by both scavenger receptors and Fc-gamma receptors. Furthermore, CRP treatment increased MMP-9 activity in macrophages compared with huSA, which was abrogated by inhibitors to p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), and nuclear factor (NF)-kappaB but not Jun N-terminal kinase (JNK) before human CRP treatment. Because OxLDL uptake by macrophages contributes to foam cell formation and MMP release contributes to plaque instability, this study provides novel in vivo evidence for the role of CRP in atherosclerosis.
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PMID:Human C-reactive protein promotes oxidized low density lipoprotein uptake and matrix metalloproteinase-9 release in Wistar rats. 1824 17

Angiogenesis is a critical step in solid tumor progression. The mitogen-activated protein kinase (MAPK) signaling pathways are central to this process, and thus present attractive targets for angiogenesis inhibition. Anthrax Lethal Toxin (LeTx), secreted from the gram positive Bacillus anthracis, demonstrates potent MAPK pathway inhibition. In vivo efficacy studies revealed that LeTx has broad anti-tumor efficacy via the targeting of angiogenesis. However, specificity in animal models was limited due to the presence of receptors on many normal tissues and the ubiquitous expression of furin in tissues. Further, half-life of LeTx was short due to circulating furin-like proteases. Gelatinases are expressed on tumor angiogenic sprouts and only to a limited extent in normal tissues or blood. In order to circumvent nonspecific LeTx activation, enhance tumor vascular targeting, and improve plasma half-life, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. The MMP-activated LeTx showed potent angiogenic inhibition in vivo in the absence of systemic toxicity. Based on these studies, this attenuated toxin has clinical potential as a broad anti-tumor agent.
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PMID:Potent inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin: implications for broad anti-tumor efficacy. 1824 47

Angiogenesis (the growth of new capillaries) occurs in adults in response to physiological stimuli such as wound healing and exercise. The mitogen-activated protein kinase c-jun N-terminal kinase (JNK) has a controversial role in the process of angiogenesis, with previous evidence supporting JNK as both a positive and negative regulator of blood vessel growth. The purpose of this study was to clarify the role of JNK in the angiogenesis process. Phosphorylated JNK was observed in cultured endothelial cells, and levels were constant regardless of extracellular matrix composition. Using SP600125, inhibition of JNK attenuated sprout growth in 3D capillary sprout cultures. Inhibition of JNK reduced endothelial cell proliferation and migration in vitro. JNK inhibition and siRNA knockdown of c-jun (a downstream target of JNK) decreased protein levels of the transcription factor Egr-1, a regulator of genes involved in proliferation and migration. Matrix metalloproteinase-2 (MMP-2) production, and activity also, was reduced in sprout cultures treated with SP600125. c-Jun silencing decreased both MMP-2 and membrane type-1 (MT1)-MMP mRNA in endothelial cells, implicating both JNK and c-jun as activators of proteolysis. Taken together, these results provide evidence that JNK and its downstream target c-jun positively regulate angiogenesis via activation of endothelial cell proliferation, migration and proteolysis.
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PMID:JNK as a positive regulator of angiogenic potential in endothelial cells. 1845 49

We studied cytotoxic mechanism of mitochondrial inhibitors in U937 cells. U937 cells were sensitive to cytotoxicity of mitochondrial inhibitors under glucose deprivation condition, whereas PC12 neuronal cells were not. In glucose deprivation condition, intracellular ATP content is decreased and thereby AMP-activated protein kinase (AMPK) is activated. And also activation of JNK, inactivation of ERK, and enhanced expression of Bcl-2 were observed. Mitochondrial inhibitors such as rotenone, TTFA, antimycin A, sodium azide, oligomycin, and valinomycin were used in this study. Inhibitors did not much influence intracellular ATP contents and activity of AMPK under glucose deprivation condition. Activities of Akt and p38 MAPK, however, were decreased by the inhibitors under glucose deprivation condition except TTFA. Furthermore, intracellular Ca2+ concentration was also greatly increased by the inhibitors. Finally, mitochondrial membrane potential was decreased by the inhibitors but TTFA increase the potential and oligomycin maintains it. In the present study, results suggest that under glucose deprivation condition mitochondrial inhibitors may induce severe cytotoxicity of U937 cells through inhibition of Akt and p38 MAPK, increase of [Ca2+]i, and decrease of MMP, but not through inhibition of ATP production and activation of AMPK.
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PMID:Effects of mitochondrial inhibitors on cell viability in U937 monocytes under glucose deprivation. 1856 57

The COOH-terminal fragment of procollagen type I (C3) is produced in tissues with high synthesis of collagen I, such as in breast cancer stroma and in bone. We previously demonstrated that C3 is chemoattractant for breast carcinoma and endothelial cells, and that in tumor cells it induces expression and activation of metalloproteinases (MMP) -2 and -9. Here we demonstrate that C3 induces expression of vascular-endothelial growth factor (VEGF) and of CXCR4, the receptor of the CXCL12/SDF-1 chemokine, in MDA MB 231 breast cancer cells. We show that the changes in gene expression and motility induced by C3 occur in a timely succession and are mediated by multiple and different signaling pathways. C3 induces early phosphorylation of p38/MAPK. Induction of VEGF expression requires continual activity of p38/MAPK and of Protein Kinase C (PKC). Pro-MMP-2 and -9 are induced through a signaling pathway involving G0alpha.i protein, and cell migration requires the activity of a combination of these signaling pathways. Our results suggest that C3 acts as a stromal-derived, cancer-promoting agent active in inducing the migratory phenotype and the survival of cancer cells and determining timely changes in their gene expression that establish conditions promoting tumor angiogenesis and invasion.
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PMID:Procollagen I COOH-terminal fragment induces VEGF-A and CXCR4 expression in breast carcinoma cells. 1857 Sep 23

Targeting of transforming growth factor beta (TGF-beta) to the extracellular matrix (ECM) by latent TGF-beta binding proteins (LTBPs) regulates the availability of TGF-beta for interactions with endothelial cells during their quiescence and activation. However, the mechanisms which release TGF-beta complexes from the ECM need elucidation. We find here that morphological activation of endothelial cells by phorbol 12-myristate 13-acetate (PMA) resulted in membrane-type 1 matrix metalloproteinase (MT1-MMP) -mediated solubilization of latent TGF-beta complexes from the ECM by proteolytic processing of LTBP-1. These processes required the activities of PKC and ERK1/2 signaling pathways and were coupled with markedly increased MT1-MMP expression. The functional role of MT1-MMP in LTBP-1 release was demonstrated by gene silencing using lentiviral short-hairpin RNA as well as by the inhibition with tissue inhibitors of metalloproteinases, TIMP-2 and TIMP-3. Negligible effects of TIMP-1 and uPA/plasmin system inhibitors indicated that secreted MMPs or uPA/plasmin system did not contribute to the release of LTBP-1. Current results identify MT1-MMP-mediated proteolytic processing of ECM-bound LTBP-1 as a mechanism to release latent TGF-beta from the subendothelial matrix.
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PMID:MT1-MMP releases latent TGF-beta1 from endothelial cell extracellular matrix via proteolytic processing of LTBP-1. 1860 1

To gain insight into the pathogenesis of hepatic fibrosis related to insulin resistance, we have examined the effects of euglycemic hyperinsulinemia on three matrix metalloproteinases (MMP-2, MMP-9, and MT1-MMP) and on two major tissue inhibitors of MMPs (TIMP-1 and TIMP-2) in liver of insulin-sensitive and insulin-resistant rats. Four hours of insulin infusion (4.8 mU.kg(-1).min(-1)) without or with lipid-heparin infusion (to produce insulin resistance) decreased hepatic MMP-2 mRNA (by RT-PCR), pro-MMP-2, MMP-2, MMP-9, and MT1-MMP (all by Western blots) and the gelatinolytic activity of MMP-2 (by gelatin zymography) by approximately 60-80%. Hyperinsulinemia ( approximately 1.6 mmol/l) increased TIMP-1 and TIMP-2 concentrations (by ELISA) in insulin-sensitive and insulin-resistant rats. Phosphoinositide 3-kinase was activated by insulin in insulin-sensitive rats and inhibited in insulin-resistant rats. Extracellular signal-regulated kinases 1/2 (ERK1/2) were activated by insulin in insulin-sensitive rats and partially inhibited in insulin-resistant rats; c-jun NH(2)-terminal kinase-1 (JNK1), JNK2/3, or p38 MAPK were only activated by lipid but not by insulin. We conclude that hyperinsulinemia, whether or not associated with insulin resistance, shifts the MMP/TIMP balance toward reduction of extracellular matrix degradation and thus may promote the development of hepatic fibrosis.
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PMID:Effects of hyperinsulinemia on hepatic metalloproteinases and their tissue inhibitors. 1866 96

We have previously reported that tissue inhibitor of metalloproteinases-2 (TIMP-2), an endogenous inhibitor of matrix metalloproteinase, modulates angiogenic responses through the MMP inhibition-independent activity. In this study, we investigate the molecular mechanisms of TIMP-2-mediated growth inhibition in response to fibroblast growth factor-2 (FGF-2). Pre-treatment with a protein tyrosine phosphatase inhibitor orthovanadate or expression of a dominant negative Shp-1 mutant fails to induce TIMP-2 inactivation of FGF-2 signaling pathways in human microvascular endothelial cells. We also show that TIMP-2 inhibition of FGF-2-induced p42/44(MAPK) activation and cell proliferation is associated with TIMP-2 binding to integrin alpha3beta1 on endothelial cell surfaces, as demonstrated by use of anti-integrin alpha3 or beta1 blocking antibodies, or disruption of integrin alpha3 expression by siRNA. Collectively, our results indicate that TIMP-2 inhibits FGF-2 signaling pathways through association with integrin alpha3beta1 and Shp-1-dependent inhibition of p42/44(MAPK) signaling, which in turn, results in suppression of FGF-2-stimulated endothelial cell mitogenesis.
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PMID:TIMP-2 disrupts FGF-2-induced downstream signaling pathways. 1872 21


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