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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to test the hypothesis that differences exist in the activity and/or expression of mitogen-activated protein kinases (MAPKs) between spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) and that these differences may account for the enhanced activity of the Na(+)/H(+) exchanger (NHE) previously observed in the renal proximal tubule of SHR. Therefore, the activities of c-jun N-terminal kinase(1) (JNK(1)), extracellular signal-regulated kinase(1/2) (ERK(1/2)), and p38 were investigated. A reduced amount of ERK(1) and JNK(1) protein was found in renal cortex specimens of SHR as compared with WKY; however, their activities were the same. To study the cellular basis of this difference, immortalized proximal tubule cell lines were grown on Millicell-CM filter inserts where the cell lines organize as polarized monolayers with separate access to apical and basolateral compartments. Although basal JNK(1) and ERK(1/2) activities were not significantly different between WKY and SHR cells, anisomycin stimulated JNK(1) activity in WKY cells more than in SHR cells (eg, at 15 minutes 300% versus 30%, respectively). Similarly, angiotensin II increased JNK(1) and ERK(1/2) activity in a time- and concentration-dependent manner in WKY cells but not in SHR cells. Western blot analyses showed a deficit in JNK(1) and ERK(1) protein in SHR (0.25 and 0.5, respectively, of the levels in WKY cells), although ERK(2) and p38 protein levels were the same. These observations suggest that, although angiotensin II activates MAPKs and MAPKs have been shown to regulate NHE, this regulatory pathway is unlikely to account for the increased activity of NHE in the proximal tubular epithelium of SHR.
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PMID:Activation of MAPKs in proximal tubule cells from spontaneously hypertensive and control Wistar-Kyoto rats. 1081 81

Inhibition of signaling through Ras in BCR-ABL-positive pluripotent K562 cells leads to apoptosis and spontaneous differentiation. However, Ras-induced activation of the mitogen-activated protein kinase ERK has been suggested to play a critical role in either growth or differentiation in different model systems. We studied the role of ERK activation in the growth-promoting and anti-apoptotic effect of Ras and its involvement in hemin-induced nonterminal erythroid differentiation using the BCR-ABL-positive K562 cell line as a model. K562 cells were stably transfected with ERK1 or the dominant inhibitory mutant of ERK1 (ERK1-KR). Overexpression of ERK1-KR inhibited cell growth with an approximately fourfold increase in doubling time and induced apoptosis in K562 cells. Incubation with the MEK1 inhibitor UO126 inhibited cell growth and induced apoptosis in K562 cells in a dose-dependent manner as well. In the presence of exogenously added hemin, K562 cells differentiate into erythroblasts, as indicated by the production of large amounts of fetal hemoglobin. We examined the activation of MAP kinases during hemin-induced differentiation. The ERK1 and 2 activity increased within 2 h post hemin treatment and remained elevated for 24-48 h. During this time, fetal hemoglobin synthesis also increases from 0.8 to 10 pg/cell. There was no activation of JNK or p38 protein kinases. The hemin-induced accumulation of hemoglobin was inhibited in ERK1-KR overexpressing cells and was enhanced in the wild-type ERK1 transfectants. Our results suggest that ERK activation is involved in both growth and hemin-induced erythroid differentiation in the BCR-ABL-positive K562 cell line.
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PMID:Role of ERK activation in growth and erythroid differentiation of K562 cells. 1126 76

Previous studies have suggested that p53 is required for apoptosis induction by phenethyl isothiocyanate (PEITC), which is a highly promising cancer chemopreventive agent. Here, we report that p53 is not required for PEITC-induced apoptosis in the PC-3 human prostate cancer cell line and that the PEITC-induced apoptosis is mediated by extracellular signal-regulated kinases (ERK1/2). Exposure of PC-3 cells to an apoptosis-inducing concentration of PEITC (10 microM) resulted in a rapid and sustained activation of ERK1/2 that was evident as early as 1 h after PEITC treatment and persisted for the duration of the experiment (24-h after PEITC exposure). The PEITC-mediated activation of ERK1/2 was associated with an increase in phosphorylation of its substrate Elk-1 at Ser383. The PEITC-induced activation of ERK1/2 as well as apoptosis was abolished in the presence of mitogen-activated protein/ERK kinase 1 (a kinase upstream of ERK1/2) inhibitor PD98059. Exposure of PC-3 cells to 10 microM PEITC also resulted in a time-dependent activation of p38 protein kinase that was associated with increased phosphorylation of activating transcription factor 2 at Thr71. Even though the PEITC-induced activation of p38 protein kinase was abrogated in the presence of its specific inhibitor SB202190, inhibition of p38 protein kinase activation did not prevent PEITC-induced apoptosis. In contrast to previous reports in other cellular systems, c-Jun NH(2)-terminal kinases were not activated by PEITC treatment in PC-3 human prostate carcinoma cell line. In conclusion, the results of the present study indicate that p53 is not essential for PEITC-induced apoptosis and that the PEITC-induced apoptosis in PC-3 human prostate carcinoma cell line is mediated by ERKs. Thus, it seems reasonable to postulate that PEITC may be effective against tumors with normal as well as mutant p53.
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PMID:Phenethyl isothiocyanate-induced apoptosis in p53-deficient PC-3 human prostate cancer cell line is mediated by extracellular signal-regulated kinases. 1209 62

Hyperglycemia is considered a primary cause of diabetic vascular complications. A hallmark of vascular disease is endothelial cell dysfunction characterized by diminished nitric-oxide (NO)-dependent phenomena such as vasodilation, angiogenesis, and vascular maintenance. This study was designed to investigate the effects of a high level of D-glucose on endothelial NO response, oxidative stress, and glucose metabolism. Bovine aortic endothelial cells (BAECs) were pretreated with a high concentration of glucose (HG) (22 mmol/L) for at least 2 weeks and compared with control cells exposed to 5 mmol/L glucose (NG). The effect of chronic hyperglycemia on endothelial NO-synthase (eNOS) activity and expression, glycogen synthase (GS) activity, extracellular-signal-regulated kinase (ERK 1,2), p38, Akt expression, and Cu/Zn superoxide-dismutse (SOD-1) activity and expression were determined. Western blot analysis showed that eNOS protein expression decreased in HG cells and was accompanied by diminished eNOS activity. The activity of GS was also significantly lower in the HG cells than in NG cells, 25.0+/-17.4 and 89+/-22.5 nmol UDP-glucose.mg protein(-1)x min(-1), respectively. Western blot analysis revealed a 40-60% decrease in ERK 1,2 and p38 protein levels, small modification of phosphorylated Akt expression, and a 30% increase in SOD-1 protein expression in HG cells. Although SOD expression was increased, no change was observed in SOD activity. These results support the findings that vascular dysfunction due to exposure to pathologically high D-glucose concentrations may be caused by impairment of the NO pathway and increased oxidative stress accompanied by altered glucose metabolism.
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PMID:Hyperglycemia reduces nitric oxide synthase and glycogen synthase activity in endothelial cells. 1238 15

Phosphorylation of eIF4E is associated with increased activity of the translational machinery. Oxidative stress of resident vascular cells and macrophages potently enhances eIF4E phosphorylation. Oxidative stress activates numerous intracellular signaling pathways, including MAP-family kinase pathways and pathways leading to S6 kinase activation. The activation of MAP-family kinase pathways leads to the activation of Mnk and hence eIF4E phosphorylation, whereas the S6 kinase pathway is not involved, based on insensitivity to its inhibitors rapamycin and wortmannin. Ca-dependent pathways have been implicated in eIF4E phosphorylation, but the oxidative stress response pathway targeting eIF4E does not appear to require their participation. The results suggest that the potent activation of ERK and p38 protein kinases is sufficient to account for the enhanced eIF4E phosphorylation. Either is independently sufficient to effect the change, as neither PD098059 (Erk pathway inhibitor) nor SB202190 (p38 pathway inhibitor) alone can block the response, but when combined the response is almost completely abrogated. Mnk activation by oxidative stress leading to enhanced eIF4E phosphorylation may play a role in promoting stress-induced hyperproliferative diseases, such as smooth muscle cell proliferation and hypertrophy in cardiovascular disease, as the synthesis of several key regulators of cell growth has been shown to be held in check by moderation of eIF4E activity.
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PMID:Signal transduction pathways leading to increased eIF4E phosphorylation caused by oxidative stress. 1568 19

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

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

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

Pyrrolidine dithiocarbamate (PDTC) is widely used in pesticides, fungicides, insecticides, and herbicides. Copper (Cu) is a toxic heavy metal in the environment, and an essential trace metal element in the body, which is involved in many biological processes as a catalytic cofactor. The present study is designed to investigate the cellular toxicity of PDTC, CuCl(2), and PDTC/Cu complex exposure in lung alveolar epithelial cells that serve primary structural and functional roles in the lungs. The results showed that PDTC or CuCl(2) alone did not affect cell viability, but PDTC/Cu complex significantly decreased lung alveolar epithelial cell viability. PDTC/Cu complex also significantly increased intracellular copper concentration, but PDTC or CuCl(2) alone had low levels of copper. PDTC/Cu complex dramatically enhanced the JNK protein phosphorylation and ERK protein phosphorylation proteins. PDTC/Cu complex did not affect the p38 protein phosphorylation. PDTC/Cu complex was capable of activating the apoptosis-related caspases including caspase-9, caspase-7, and caspase-3, which could be reversed by the addition of JNK inhibitor SP600125 or transfection of MAPK8 short hairpin RNA. PDTC/Cu complex also increased cytosolic cytochrome c and decreased mitochondrial transmembrane potential. The Bcl-2 mRNA and protein expressions were decreased in lung epithelial cells treated with PDTC/Cu complex, which could be reversed by SP600125. Furthermore, PDTC/Cu complex could trigger the expressions of ER stress-associated signaling molecules including Grp78, Grp94, caspase-12, ATF4, and CHOP, which could be reversed by SP600125. Taken together, these results indicate that exposure to PDTC/Cu complex induces cytotoxicity and apoptosis in alveolar epithelial cells via the mitochondria- and ER-stress-related signaling pathways.
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PMID:Pyrrolidine dithiocarbamate (PDTC)/Cu complex induces lung epithelial cell apoptosis through mitochondria and ER-stress pathways. 2092 May 58

The insulin signaling pathway, involving protein kinase B (PKB) and mitogen-activated protein kinase (MAPK), mediates the biological response to insulin and several growth factors and cytokines. To investigate the correlation between glucose transporter (Glut) biosynthesis and the insulin signaling pathway activated by novel compounds of Liriope platyphylla (LP9M80-H), alterations in Glut and key protein expression in the insulin signaling pathway were analyzed in the liver and brain of ICR mice treated with LP9M80-H. An in vitro assay showed that the highest level of insulin concentration was observed in the LP9M80-H-treated group, followed by the LP-H, LP-M, LP-E, and LP9M80-C-treated groups. Therefore, LP9M80-H was selected for use in studying the detailed mechanism of the insulin signaling pathway in animal systems. In an in vivo experiment, LP9M80-H induced a significant increase in glucose levels and a decrease of insulin concentration in the blood of mice, while their body weight remained constant over 5 days. The expression level of Glut-3 was down-regulated in the liver, or maintained at the same level in the brain of LP9MH80-H-treated mice. These changes corresponded to the phosphorylation of the p38 protein rather than to ERK and JNK in the MAPK signaling pathway. In addition, the expression level of Glut-1 increased significantly after LP9MH80-H treatment of both insulin target tissues in mice. Western blot analysis showed that Akt in the PI3-K pathway mainly participated in Glut-1 biosynthesis. Thus, these results suggest the possibility that the LP9M80-H-induced regulation of Glut-1 and Glut-3 biosynthesis may be mediated by the Akt and p38 MAPK signaling of the insulin signaling pathway in the liver and brain of mice.
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PMID:Differential regulation of the biosynthesis of glucose transporters by the PI3-K and MAPK pathways of insulin signaling by treatment with novel compounds from Liriope platyphylla. 2116 49


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