Independent regulation of cyclo-oxygenase 2 expression by p42/44 mitogen-activated protein kinases and Ca2+/calmodulin-dependent kinase
Independent regulation of cyclo-oxygenase 2 expression by p42/44 mitogen-activated protein kinases and Ca2+/calmodulin-dependent kinase
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DOI：
10.1042/0264-6021:3390329
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发表时间：
1999-04-15
影响因子：
4.1
通讯作者：
Reiser, COA
中科院分区：
文献类型：
--
作者：
Goppelt-Struebe, M;Hahn, A;Reiser, COA
5-羟色胺(5-羟色胺，5-羟色胺)是系膜细胞早期反应基因环氧合酶-2(COX-2；前列腺素G/H合成酶)的有效诱导剂。蛋白激酶C(PKC)、钙依赖酶和丝裂原活化蛋白激酶(P42/44MAPK)是从百日咳不敏感的5-HT2A受体到诱导COX-2mRNA表达的信号通路中的重要模块。在本研究中，PKC的激活与5-羟色胺介导的磷酸化有关，从而激活了p42/44 MAPK：特异性抑制剂GF109203x抑制PKC可阻止p42/44 MAPK的激活。Western印迹法检测肾小球系膜细胞内钙/钙调蛋白依赖性(CaM)激酶II Delta(2)的表达。KN62或KN93抑制CaM激酶可部分抑制5-羟色胺诱导的COX-2mRNA表达，并降低基础水平的COX-2表达，但不影响PMA介导的COX-2表达。5-羟色胺介导的MAPK激活不受KN62或KN93的影响，但不包括作为p42/44 MAPK上游信号模块的CaM激酶。综上所述，这些结果表明，除了PKC和p42/44MAPK的激活这一主要途径外，CaM激酶还参与了5-羟色胺介导的COX-2mRNA表达的调节。
5-Hydroxytryptamine (5-HT, 'serotonin') is a potent inducer of the early response gene cyclo-oxygenase 2 (Cox-2; prostaglandin G/H synthase) in mesangial cells. Protein kinase C (PKC), Ca2+- dependent enzymes and mitogen-activated protein kinase (p42/44 MAPK) have previously been shown to be essential modules of the signalling pathway leading from the pertussis-insensitive 5-HT2A receptor to the induction of Cox-2 mRNA expression. In the present study, PKC activation was linked to the 5-HT-mediated phosphorylation and thus the activation of p42/44 MAPK: the inhibition of PKC by the specific inhibitor GF109203x prevented p42/44 MAPK activation. Ca2+/calmodulin-dependent (CaM) kinase II delta(2) was detected in mesangial cells by Western blot analysis. The inhibition of CaM kinase by the inhibitors KN62 or KN93 led to a partial inhibition of 5-HT-induced Cox-2 mRNA expression and decreased basal, but not PMA-mediated, Cox-2 expression. The 5-HT-mediated activation of MAPK was not decreased by KN62 or KN93, excluding CaM kinase as a signalling module upstream of p42/44 MAPK. Taken together, these results indicate a modulatory involvement of CaM kinase in the regulation of 5-HT-mediated Cox-2 mRNA expression in addition to the main pathway that consists of the activation of PKC and p42/44 MAPK.