Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperhomocysteinemia has been identified as an independent risk factor for atherosclerosis. The infiltration of monocytes into the arterial wall is one of the key events during atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that stimulates the migration of monocytes into the intima of the arterial wall. The mechanism by which increased monocyte infiltration occurs in atherosclerotic lesions in patients with hyperhomocysteinemia has not been delineated. The objective of the present study was to investigate the effect of homocysteine on MCP-1 production in endothelial cells. Cells were incubated with homocysteine. The secretion of MCP-1 protein was significantly increased (195% as compared to the control) in cells treated with pathological concentrations of homocysteine. Such effect was accompanied by an increased expression of MCP-1 mRNA (176% as compared to the control) in endothelial cells which resulted in enhanced monocyte chemotaxis. The p38 MAP kinase as well as other members of the p38 MAP kinase pathway, including MKK3, MKK6, ATF-2 and Elk-1, were activated in homocysteine-treated cells. Homocysteine-induced MCP-1 expression and subsequent monocyte chemotaxis were blocked by a p38 MAP kinase inhibitor (SB203580) suggesting that the p38 MAP kinase pathway might be involved in homocysteine-induced MCP-1 expression in endothelial cells. In contrast, staurosporine, a protein kinase C inhibitor, had no effect on homocysteine-induced MCP-1 expression. In conclusion, our results indicate that homocysteine stimulates MCP-1 expression in endothelial cells leading to enhanced monocyte chemotaxis.
Mol Cell Biochem 2001 Jan
PMID:Homocysteine stimulates the expression of monocyte chemoattractant protein-1 in endothelial cells leading to enhanced monocyte chemotaxis. 1121 56

The adipocyte-derived hormone leptin plays an important role as a relayer of nutritional status to several organ systems. Evidence is accumulating that leptin plays an important role in the adequate functioning and maintenance of the immune system. Here we show that leptin induces sustained phosphorylation of p38 MAP kinase in human peripheral blood mononuclear cells (PBMCs). We show furthermore that leptin induces two routes to phosphorylation of the 40S ribosomal protein S6, one is activation of the p90 ribosomal S6 kinase (RSK) via the MEK/p42/p44 MAP kinase pathway, the other is via activation of p70 S6 kinase. Thus, these results give new insight in the mechanism that underlies the immunomodulatory effects of leptin.
Mol Cell Biol Res Commun 2000 Sep
PMID:Leptin signaling in human peripheral blood mononuclear cells, activation of p38 and p42/44 mitogen-activated protein (MAP) kinase and p70 S6 kinase. 1128 28

The protective adaptive response to electrophiles and reactive oxygen species is mediated by enhanced expression of phase II detoxifying genes, including glutathione S-transferases, through activation of antioxidant response element (ARE). The current study was designed to investigate the role of phosphatidylinositol 3-kinase (PI3-kinase)-Akt and mitogen-activated protein (MAP) kinase signaling pathways in the induction of rGSTA2 by tert-butylhydroquinone (t-BHQ). Nuclear ARE complex was activated 1 to 6 h after treatment of H4IIE cells with t-BHQ. The rGSTA2 mRNA level was elevated 6 to 24 h after t-BHQ treatment, which led to the enzyme induction. Activities of PI3-kinase and Akt were increased 10 min through 6 h after t-BHQ treatment, whereas wortmannin or LY294002, PI3-kinase inhibitors, completely abolished ARE binding activity and increases in rGSTA2 mRNA and protein. Extracellular signal-regulated kinase (ERK), p38 MAP kinase, and c-Jun N-terminal kinase (JNK) were all activated by t-BHQ. Treatment with PD98059, an ERK inhibitor, however, increased rGSTA2 mRNA and further enhanced t-BHQ-induced expression of rGSTA2. Neither SB203580 nor overexpression of JNK1 dominant negative mutant altered t-BHQ-inducible rGSTA2 expression. These results demonstrated that t-BHQ activated PI3-kinase and Akt, which was responsible for ARE-mediated rGSTA2 induction, and that ERK might negatively regulate rGSTA2 expression, whereas activation of p38 MAP kinase or of JNK by t-BHQ was not associated with the enzyme induction.
Mol Pharmacol 2001 May
PMID:Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells. 1130 98

This study has demonstrated the mechanism of protein kinase A (PKA)-dependent inhibition of astrocytic nitric oxide production and inducible NO synthase mRNA expression induced by lipopolysaccharide. In C6 glioma cells, the stimulation with lipopolysaccharide (LPS; 1 microg/ml) evoked increases of nitric oxide (NO) production, NO synthase (iNOS) mRNA expression, phosphorylation of p38 mitogen activated protein kinase (p-p38), and the activation of NF kappa B. LPS-induced NO production and iNOS mRNA expression were inhibited by the pretreatment with forskolin (FSK; 5 microM) in a dose-dependent manner, and which were reversed by PKA inhibition by compound H89. Furthermore, LPS-induced increases of p-p38, but not activation of NF kappa B, were also reduced by FSK and H89 reversed the FSK-induced inhibition response. The dose-dependent inhibition of NO production and iNOS mRNA expression by compound SB203580 (p38 inhibitor) suggests the participation of p38 in PKA-dependent inhibition of LPS-induced NO production and iNOS mRNA expression. However, the activation of NF kappa B by LPS also not affected by SB203580. Therefore, our results suggest that, in C6 glioma cells, LPS-induced NO production and iNOS gene expression may be regulated by PKA pathway through the reduction of activity of p38 kinase. This inhibitory role of PKA may not involve the activation of NF kappa B.
Brain Res Mol Brain Res 2001 Apr 18
PMID:Forskolin inhibits expression of inducible nitric oxide synthase mRNA via inhibiting the mitogen activated protein kinase in C6 cells. 1131 70

The members of the mitogen-activated protein (MAP) kinase family -- p44/p42 MAP kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAP kinase (p38) are known to be important mediators of the physiological plasticity or neurotoxicity induced in the striatum by activation of ionotropic glutamate receptors. However, our knowledge of the class of glutamate receptor and the intracellular pathways involved derives totally from studies on embryonic neurons, where the mechanisms are likely to be totally different from those operating in mature neurons. In superfused striatal slices from adult rats, NMDA and kainate, but not AMPA, were found to activate ERK. No activation of p38 or JNK was detected following treatment with any ionotropic glutamate receptor agonist. The activation of ERK by kainate was blocked by the ERK kinase (MEK) inhibitor PD98059, and the PI3 kinase inhibitor wortmannin, but not by the p38 MAP kinase inhibitor SB203580. This provides evidence for a novel pathway linking striatal kainate receptors to ERK activation via PI3 kinase and MEK.
Brain Res Mol Brain Res 2001 Apr 18
PMID:Activation of p44/p42 MAP kinase in striatal neurons via kainate receptors and PI3 kinase. 1131 83

We compared stimulus-coupling pathways involved in bovine pulmonary artery (PA) and lung microvascular endothelial cell migration evoked by sphingosine-1-phosphate (S1P), a potent bioactive lipid released from activated platelets, and by vascular endothelial growth factor (VEGF), a well-recognized angiogenic factor. S1P-induced endothelial cell migration was maximum at 1 microM (approximately 8-fold increase with PA endothelium) and surpassed the maximal response evoked by either VEGF (10 ng/ml) (approximately 2.5-fold increase) or hepatocyte growth factor (HGF) (approximately 2.5-fold increase). Migration induced by S1P, but not by VEGF, was significantly inhibited by treatment with antisense oligonucleotides directed to Edg-1 and Edg-3 (endothelial differentiation gene) S1P receptors and by G protein modification. These strategies included pretreatment with pertussis toxin, or transfection with mini-genes encoding a betagamma subunit inhibitory peptide of the beta-adrenergic receptor kinase, or an 11-amino-acid peptide that inhibits G(1alpha2) signaling. Various strategies to interrupt Rho family signaling, including C(3) exotoxin, dominant/negative Rho, or the addition of Y27632, a cell-permeable Rho kinase inhibitor, significantly attenuated S1P- but not VEGF-induced migration. Conversely, pharmacologic inhibition of either myosin light chain kinase, src family tyrosine kinases, or phosphatidylinositol-3' kinase reduced basal endothelial cell migration and abolished VEGF-induced endothelial cell migration but did not inhibit the increase in S1P-induced migration. Whereas VEGF and S1P increased both p42/p44 extracellular regulated kinase and p38 mitogen-activated protein (MAP) kinase activities, only p38 MAP kinase inhibition significantly reduced VEGF- and S1P-stimulated migration. These data confirm S1P as a potent endothelial cell chemoattractant through G(1alpha2)-coupled Edg receptors linked to Rho-associated kinase and p38 MAP kinase activation. The divergence in signaling pathways evoked by S1P and VEGF suggests complex and agonist-specific regulation of endothelial cell angiogenic responses.
Am J Respir Cell Mol Biol 2001 Jun
PMID:Differential regulation of sphingosine-1-phosphate- and VEGF-induced endothelial cell chemotaxis. Involvement of G(ialpha2)-linked Rho kinase activity. 1141 36

The stability of several oncogene, cytokine, and growth factor transcripts is tightly regulated by signaling pathways through an ARE (AU-rich element) present in their 3'-UTRs. We have identified a yeast transcript, TIF51A, whose stability is regulated through its AU-rich 3'-UTR. We demonstrate that the mammalian TNFalpha and c-fos AREs regulate turnover of a reporter yeast transcript in a similar manner. AREs stabilize the transcript in glucose media and function as destabilizing elements in media lacking glucose or when the Hog1p/p38 MAP kinase pathway is inhibited. Significantly, both yeast and mammalian AREs promote deadenylation-dependent decapping in the yeast system. Furthermore, the yeast ELAV homolog, Pub1p, regulates the stability mediated by the TNFalpha ARE. These results demonstrate that yeast possess a regulatable mechanism for ARE-mediated decay and suggest conservation of this turnover process from yeast to humans.
Mol Cell 2001 Jun
PMID:Regulated ARE-mediated mRNA decay in Saccharomyces cerevisiae. 1143 Aug 22

The procoagulant thrombin promotes the adhesion of polymorphonuclear leukocytes to endothelial cells by a mechanism involving expression of intercellular adhesion molecule 1 (ICAM-1) via an NF-kappaB-dependent pathway. We now provide evidence that protein kinase C-delta (PKC-delta) and the p38 mitogen-activated protein (MAP) kinase pathway play a critical role in the mechanism of thrombin-induced ICAM-1 gene expression in endothelial cells. We observed the phosphorylation of PKC-delta and p38 MAP kinase within 1 min after thrombin challenge of human umbilical vein endothelial cells. Pretreatment of these cells with the PKC-delta inhibitor rottlerin prevented the thrombin-induced phosphorylation of p38 MAP kinase, suggesting that p38 MAP kinase signals downstream of PKC-delta. Inhibition of PKC-delta or p38 MAP kinase by pharmacological and genetic approaches markedly decreased the thrombin-induced NF-kappaB activity and resultant ICAM-1 expression. The effects of PKC-delta inhibition were secondary to inhibition of IKKbeta activation and of subsequent NF-kappaB binding to the ICAM-1 promoter. The effects of p38 MAP kinase inhibition occurred downstream of IkappaBalpha degradation without affecting the DNA binding function of nuclear NF-kappaB. Thus, PKC-delta signals thrombin-induced ICAM-1 gene transcription by a dual mechanism involving activation of IKKbeta, which mediates NF-kappaB binding to the ICAM-1 promoter, and p38 MAP kinase, which enhances transactivation potential of the bound NF-kappaB p65 (RelA).
Mol Cell Biol 2001 Aug
PMID:Protein kinase C-delta regulates thrombin-induced ICAM-1 gene expression in endothelial cells via activation of p38 mitogen-activated protein kinase. 1146 37

Our previous studies have shown that 5-hydroxytryptamine (5-HT) induces cellular hyperplasia/hypertrophy through protein tyrosine phosphorylation, rapid formation of superoxide (O(2)(-)), and extracellular signal-regulated kinase (ERK)1/ERK2 mitogen-activated protein (MAP) kinase activation. Intracellularly released O(2)(-) is rapidly dismuted by superoxide dismutase (SOD) to H(2)O(2), another possible cellular growth mediator. In the present study, we assessed whether H(2)O(2) participates in 5-HT-induced mitogenic signaling. Inactivation of cellular Cu/Zn SOD by copper-chelating agents inhibited 5-HT-induced DNA synthesis of bovine pulmonary artery smooth muscle cells (BPASMCs). Infection of BPASMCs with an adenovirus containing catalase inhibited both ERK1/ERK2 MAP kinase activation and DNA synthesis induced by 5-HT. Although we could not find evidence of p38 MAP kinase activation by 5-HT, SB-203580 and SB-202190, reported inhibitors of p38 MAP kinase, inhibited the 5-HT-induced growth of BPASMCs. However, these inhibitors also inhibited 5-HT-induced O(2)(-) release. Thus quenching of O(2)(-) may be their mechanism for inhibition of cellular growth unrelated to p38 MAP kinase inhibition. These data indicate that generation of O(2)(-) in BPASMCs in response to 5-HT is followed by an increase in intracellular H(2)O(2) that mediates 5-HT-induced mitogenesis through activation of ERK1/ERK2 but not of p38 MAP kinase.
Am J Physiol Lung Cell Mol Physiol 2001 Sep
PMID:H(2)O(2) signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells. 1150 92

Genes that are regulated by androgens in the human prostate are believed to play an essential role in prostate physiology and they may also be involved in the proliferative response of prostate cancer cells to androgens. We used a cDNA subtraction approach to identify novel androgen-regulated transcripts in LNCaP cells that were exposed to 0.1 nM R1881 for 24 h. We report here that SPAK, a recently identified STE20/SPS1-related kinase that modulates p38 MAP kinase activity, exhibited increased expression in androgen-treated LNCaP cells. Androgen regulation of SPAK was both dose- and time-dependent. R1881-induced SPAK expression was completely abrogated by the antiandrogen casodex and by actinomycin D indicating that androgen induction of SPAK requires the androgen receptor and transcription. Cycloheximide caused a partial inhibition of R1881-induced SPAK expression which suggests that androgen induction of SPAK expression may require synthesis of additional proteins. Northern blot and ribonuclease protection assays demonstrated that SPAK is expressed at high levels in normal human testes and prostate, as well as in a number of breast and prostate cancer cell lines. These results identify SPAK, a member of a key cell signalling pathway, as an androgen-responsive gene in LNCaP cells. We hypothesize that SPAK may mediate androgen action in the normal and cancerous prostate gland.
Mol Cell Endocrinol 2001 Sep
PMID:Androgens induce expression of SPAK, a STE20/SPS1-related kinase, in LNCaP human prostate cancer cells. 1151 53


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