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)

We have previously shown that, in bovine retina pericytes, amyloid beta(1-42) and its truncated form containing amino acids 25-35, after 24 h treatment, stimulate arachidonic acid (AA) release and phosphatidylcholine hydrolysis, by activation of both cytosolic (cPLA(2)) and Ca(2+)-independent (iPLA(2)) phospholipase A(2). A putative role for MAP kinases in this process emerged. Here we studied the role of the MAP-kinase family as well as both cPLA(2) and iPLA(2) mRNA expression by a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the same sublethal model of amyloid-beta (Abeta) damage to pericytes in vitro. Abeta(25-35) peptide evoked AA release as well as stimulated phosphorylation of ERK1/2, p38 MAPKs and cPLA(2), but not c-Jun N-terminal kinase (JNK/SAPK). PD98059, an inhibitor of ERK-activating kinase MEK-1, and SB203580, an inhibitor of p38 protein kinase, abolished the stimulation of AA release and MAPK activities. In cells stimulated by Abeta(25-35) peptide, Western blotting and confocal microscopy analyses confirmed either an increase in the phosphorylated form of ERKs and p38 or their nuclear translocation. A complete inhibition of MAPK activation and AA release was also observed when pericytes were treated with GF109203X, a general PKC inhibitor, indicating the important role of both PKC and the two MAPKs in mediating the Abeta peptide response. Compared with samples untreated or treated with reverse Abeta(35-25) peptide, pretreatment with 50 microM Abeta(25-35) for 24 h significantly increased the level of constitutively expressed iPLA(2) mRNA by 25%, which seems to depend on the activation of kinases. By contrast, the level of cPLA(2) mRNA remained unchanged. Together, these data link either the stimulation of PKC-ERK-p38 cascades or PLA(2) activity by Abeta peptide to prooxidant mechanism induced by amyloid, which may initially stimulate the cell reaction as well as metabolic repair, such as during inflammation.
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PMID:MAPKs mediate the activation of cytosolic phospholipase A2 by amyloid beta(25-35) peptide in bovine retina pericytes. 1586 64

Previous results indicate that the polyphenol resveratrol inhibits cell growth of colon carcinoma cells via modulation of polyamine metabolic key enzymes. The aim of this work was to specify the underlying molecular mechanisms and to identify a possible role of transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma). Cell growth was determined by bromodeoxyuridine incorporation and crystal violet staining. Protein levels were examined by Western blot analysis. Spermine/spermidine acetyltransferase (SSAT) activity was determined by a radiochemical assay. PPARgamma ligand-dependent transcriptional activity was measured by a luciferase assay. A dominant-negative PPARgamma mutant was transfected in Caco-2 cells to suppress PPARgamma-mediated functions. Resveratrol inhibits cell growth of both Caco-2 and HCT-116 cells in a dose- and time-dependent manner (P < 0.001). In contrast to Caco-2-wild type cells (P < 0.05), resveratrol failed to increase SSAT activity in dominant-negative PPARgamma cells. PPARgamma involvement was further confirmed via ligand-dependent activation (P < 0.01) as well as by induction of cytokeratin 20 (P < 0.001) after resveratrol treatment. Coincubation with SB203580 abolished SSAT activation significantly in Caco-2 (P < 0.05) and HCT-116 (P < 0.01) cells. The involvement of p38 mitogen-activated protein kinase (MAPK) was further confirmed by a resveratrol-mediated phosphorylation of p38 protein in both cell lines. Resveratrol further increased the expression of PPARgamma coactivator PGC-1alpha (P < 0.05) as well as SIRT1 (P < 0.01) in a dose-dependent manner after 24 hours of incubation. Based on our findings, p38 MAPK and transcription factor PPARgamma can be considered as molecular targets of resveratrol in the regulation of cell proliferation and SSAT activity, respectively, in a cell culture model of colon cancer.
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PMID:Peroxisome proliferator-activated receptor gamma as a molecular target of resveratrol-induced modulation of polyamine metabolism. 1684 86

Chaga mushroom (Inonotus obliquus) has continued to receive attention as a folk medicine with indications for the treatment of cancers and digestive diseases. The anticarcinogenic effect of Chaga mushroom extract was investigated using a model system of gap junctional intercellular communication (GJIC) in WB-F344 normal rat liver epithelial cells. The cells were pre-incubated with Chaga mushroom extracts (5, 10, 20 microg/ml) for 24 h and this was followed by co-treatment with Chaga mushroom extracts and TPA (12-O-tetradecanoylphorbol-13-acetate, 10 ng/ml) for 1 h. The inhibition of GJIC by TPA (12-O-tetradecanoylphorbol-13-acetate), promoter of cancer, was prevented with treatment of Chaga mushroom extracts. Similarly, the increased phosphorylated ERK1/2 and p38 protein kinases were markedly reduced in Chaga mushroom extracts-treated cells. There was no change in the JNK kinase protein level, suggesting that Chaga mushroom extracts could only block the activation of ERK1/2 and p38 MAP kinase. The Chaga mushroom extracts further prevented the inhibition of GJIC through the blocking of Cx43 phosphorylation. Indeed cell-to-cell communication through gap junctional channels is a critical factor in the life and death balance of cells because GJIC has an important function in maintaining tissue homeostasis through the regulation of cell growth, differentiation, apoptosis and adaptive functions of differentiated cells. Thus Chaga mushroom may act as a natural anticancer product by preventing the inhibition of GJIC through the inactivation of ERK1/2 and p38 MAP kinase.
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PMID:Reversal of the TPA-induced inhibition of gap junctional intercellular communication by Chaga mushroom (Inonotus obliquus) extracts: effects on MAP kinases. 1701 71

An Aedes aegypti p38 (Aap38) mitogen-activated protein kinase was isolated and characterized in this study. The 1761 bp long full-length Aap38 cDNA encodes an open reading frame of 358 amino acids, exhibiting characteristics of Thr/Tyr dual kinase specificities. We showed that bacteria activate both the kinase activity of Aap38 and the expression of the Aedes aegypti defensin A (AaDefA) gene, which is inhibited by a p38 kinase inhibitor SB203580 and dsRNA interference of Aap38. A similar result was obtained by a reporter construct containing the AaDefA regulatory region linked to Ds-Red. The lipopolysaccharide-activated reporter gene was inhibited by SB203580. In addition, Aap38 translocated to the nucleus after lipopolysaccharide induction. Our findings suggest that the p38 protein kinase pathway is involved in the antibacterial peptide synthesis in mosquitoes.
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PMID:A p38 MAP kinase regulates the expression of the Aedes aegypti defensin gene in mosquito cells. 1746 55

Although p38 MAPK is known to be activated in response to various environmental stresses and to have inhibitory roles in cell proliferation and tumor progression, its role in cell cycle progression in the absence of stress is unknown in most cell types. In the case of G(2)/M cell cycle control, p38 activation has been shown to trigger a rapid G(2)/M cell cycle checkpoint after DNA damage stress and a spindle checkpoint after microtubule disruption. In the course of our studies, we observed that p38 became actively phosphorylated, and its kinase activity increased transiently during G(2)/M cell cycle transition. Using an immunocytochemistry approach, the active form of p38 was found at the centrosome from late G(2) throughout mitosis, which suggests functional relevance for active p38 protein during mitotic entry. A closer examination reveals that p38 inhibition by pharmacologic inhibitors significantly accelerated the timing of mitotic entry. In addition, long term exposure of the inhibitor enhanced Cdc2 activity. These results indicate that p38 activity during G(2)/M may be involved in a mechanism for fine tuning the initiation of mitosis and perhaps transit of mitosis. Consistent with our previous findings, Cdc25B was phosphorylated on serine 309 at the centrosome during G(2)/M when p38 was active at this site; Cdc25B phosphorylation inhibits Cdc25B activity, and this phosphorylation was found to be p38-dependent. Taken together, our findings suggest that p38 regulates the timing of mitotic entry via modulation of Cdc25B activity under normal nonstress conditions.
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PMID:A functional role for p38 MAPK in modulating mitotic transit in the absence of stress. 1754 58

The molecular events, which govern growth control upon contact inhibition have not yet been clearly defined. Previous work has indicated that there is an increase in the expression of mitogen-activated protein kinase phosphatases (MKPs) upon the attainment of contact inhibition in normal fibroblasts, concurrently with a decrease in ERK activity. To investigate the potential role of p38 and JNK in the transition to a contact-inhibited state, normal human fibroblasts (BJ) were grown to subconfluent and confluent densities. The total levels and phosphorylation states of p38 and JNK were assayed, and were compared to protein levels seen in HT-1080 fibrosarcoma cells, which lack contact-inhibited growth control. Activation of JNK was not apparent in these cells, though p38 was found to be active in proliferating cells, but attenuated in contact-inhibited cultures. Such fluctuations in p38 activity were not seen in cultures of fibrosarcoma cells of increasing density. This alteration in p38 activity was also reflected by attenuated activation of the downstream transcription factor ATF-2 upon contact inhibition. Overexpression of MKP-1 in fibrosarcoma cells and fibroblasts reduced proliferation, while expression of a phosphatase-resistant p38 protein (p38(N316)) enhanced proliferation of normal fibroblasts. Taken together, these results suggest the involvement of negative regulation of p38 in contact-inhibited growth control.
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PMID:Attenuation of p38 MAPK activity upon contact inhibition in fibroblasts. 1790 19

Cholesterol-rich diets are known to cause hepatic apoptosis, which has been associated with the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanisms and treatments for hepatic apoptosis in SLE are poorly understood. To clarify the effects of taurine on hepatic apoptosis in SLE, NZB/W F1 mice received control, cholesterol, and cholesterol/taurine diets. Significant reductions of caspase-3 activity, TUNEL-positive cells, and Fas- and mitochondrial- dependent apoptosis were detected in liver from the cholesterol/taurine group as compared to the cholesterol group. Moreover, significant increases of phosphorylated AKT, NF-kappaB (p65), and ERK1/2 proteins were detected in liver from the cholesterol/taurine group as compared to the cholesterol group. In contrast, a significant reduction of phosphorylated p38 protein was observed in the cholesterol/taurine group. These experimental results demonstrated positive effects of taurine against hepatic apoptosis in NZB/W F1 mice fed a high-cholesterol diet and suggested the therapeutic potential of taurine in SLE.
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PMID:Treatment with taurine attenuates hepatic apoptosis in NZB/W F1 mice fed with a high-cholesterol diet. 1881 57

MUC13, a transmembrane mucin, is normally expressed in gastrointestinal and airway epithelium. Its aberrant expression has been correlated with gastric colon and cancer. However, the expression and functions of MUC13 in ovarian cancer are unknown. In the present study, the expression profile and functions of MUC13 were analyzed to elucidate its potential role in ovarian cancer diagnosis and pathogenesis. A recently generated monoclonal antibody (clone PPZ0020) was used to determine the expression profile of MUC13 by immunohistochemistry using ovarian cancer tissue microarrays and 56 additional epithelial ovarian cancer (EOC) samples. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with the normal ovary/benign tissues. Among all ovarian cancer types, MUC13 expression was specifically present in EOC. For the functional analyses, a full-length MUC13 gene cloned in pcDNA3.1 was expressed in a MUC13 null ovarian cancer cell line, SKOV-3. Here, we show that the exogenous MUC13 expression induced morphologic changes, including scattering of cells. These changes were abrogated through c-Jun NH(2) kinase (JNK) chemical inhibitor (SP600125) or JNK2 siRNA. Additionally, a marked reduction in cell-cell adhesion and significant (P < 0.05) increases in cell motility, proliferation, and tumorigenesis in a xenograft mouse model system were observed upon exogenous MUC13 expression. These cellular characteristics were correlated with up-regulation of HER2, p21-activated kinase 1, and p38 protein expression. Our findings show the aberrant expression of MUC13 in ovarian cancer and that its expression alters the cellular characteristics of SKOV-3 cells. This implies a significant role of MUC13 in ovarian cancer.
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PMID:Expression and functions of transmembrane mucin MUC13 in ovarian cancer. 1917 98

Cyclooxygenase-2 (COX-2) overexpression has been associated with the grade, prognosis and recurrence of transitional cell carcinoma (TCC) of the bladder. In this study, sulforaphane, a dietary isothiocyanate, down-regulated COX-2 expression in human bladder transitional cancer T24 cells at both transcriptional- and translational levels. Sulforaphane (5-20 microM) induced nuclear translocation of NF-kappaB and reduced its binding to the COX-2 promoter, a key mechanism for suppressing COX-2 expression by sulforaphane. Moreover, sulforaphane increased expression of p38 and phosphorylated-p38 protein. A specific inhibitor of p38 MAPK, SB202190, was used to further investigate its pivotal role in sulforaphane-mediated down-regulation of COX-2. Exposure of T24 cells to SB202190 1 hour prior to sulforaphane treatment abolished the effect of sulforaphane on COX-2 mRNA down-regulation, but enhanced COX-2 transcription. Furthermore, SB202190 alone induced NF-kappaB translocation to the nucleus, promoted NF-kappaB binding to the COX-2 promoter and resulted in up-regulation of COX-2 expression. Taken together, these data suggest that p38 is essential in sulforaphane-mediated COX-2 suppression and provide new insights into the molecular mechanisms of sulforaphane in the chemoprevention of bladder cancer.
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PMID:Sulforaphane down-regulates COX-2 expression by activating p38 and inhibiting NF-kappaB-DNA-binding activity in human bladder T24 cells. 1928 71

In previous studies, inhibition of mitogen-activated protein kinase (MAP) p38 significantly improved recovery and attenuated apoptosis after retinal ischemia in rats. Yet, ischemic preconditioning (IPC) attenuated the ischemia-induced increase in p38 expression. We hypothesized that p38 was required for induction of ischemic tolerance by IPC. We examined the mechanisms of involvement of p38 in IPC neuroprotection. IPC or ischemia was induced in rat retina in vivo. Recovery after ischemia performed 24h after IPC was assessed functionally (electroretinography) and histologically at 7d after ischemia in the presence or absence of inhibition of p38. We examined the role of p38alpha in the mimicking of IPC produced by opening mitochondrial KATP channels using diazoxide, or stimulation of p38 activation by anisomycin. The importance of adenosine receptors in p38 activation after IPC was assessed using specific blockers of adenosine A1 and A2a receptors. Interfering RNA (siRNA) or SB203580 was used to block p38alpha. Phosphorylated p38 levels were measured. Phosphorylated p38 protein increased with IPC. Interfering RNA (siRNA) to p38alpha prior to IPC, or inhibiting p38 activation with SB203580, with ischemia following 24h later, significantly attenuated the neuroprotective effect of IPC. Anisomycin administered to increase p38 mimicked IPC, an effect blocked by SB203580. IPC-mimicking with diazoxide, an opener of mitochondrial KATP channels, was diminished with p38alpha siRNA. Adenosine receptor blockade did not decrease the elevated levels of phosphorylated p38 after IPC. Specific inhibition of p38alpha suggests that this MAPK is involved in the protective effects of IPC, and that p38 is downstream of mitochondrial KATP channels, but not adenosine receptors, in this neuroprotection.
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PMID:Mitogen-activated protein kinase p38alpha and retinal ischemic preconditioning. 1963 42


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