Protein kinase Cε regulates nuclear translocation of extracellular signal-regulated kinase, which contributes to bradykinin-induced cyclooxygenase-2 expression.
Protein kinase Cε regulates nuclear translocation of extracellular signal-regulated kinase, which contributes to bradykinin-induced cyclooxygenase-2 expression.
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DOI：
10.1038/s41598-018-26473-7
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发表时间：
2018-06-04
影响因子：
4.6
通讯作者：
Sugiya H
中科院分区：
文献类型：
--
作者：
Nakano R;Kitanaka T;Namba S;Kitanaka N;Sugiya H
促炎介质缓激肽刺激真皮成纤维细胞环氧合酶-2(COX-2)的表达，进而促进前列腺素E2的合成。通过使用药物抑制剂，提示B2受体和G-α-Q参与了缓激肽的作用。PKC激活剂PMA刺激COX-2mRNA表达。在有PKC抑制剂存在的情况下，缓激肽不能诱导COX-2mRNA的表达，而在没有细胞外钙离子的情况下，缓激肽有诱导COX-2mRNA表达的作用。缓激肽诱导的COX-2mR NA在PKCε小干扰RNA细胞中的表达受到抑制。这些观察结果表明，新的蛋白激酶Cε与缓激肽诱导的COX-2表达有关。3-磷酸肌醇依赖性蛋白激酶-1的抑制剂可抑制缓激肽诱导的蛋白激酶ε的磷酸化和COX-2mRNA的表达，磷脂酶D可抑制缓激肽诱导的蛋白激酶-1的磷酸化，提示磷脂酶D/磷脂酶-1信号通路参与了缓激肽诱导的蛋白激酶Cε的激活。药理学和基因敲除研究表明，细胞外信号调节激酶1(ERK1)MAPK信号转导通路参与了缓激肽诱导的COX-2表达。缓激肽诱导的ε磷酸化在PKC抑制剂处理或pKC siRNA转染的细胞中被减弱。通过免疫共沉淀实验观察了PKC、ε与ERK之间的相互作用。这些观察结果表明，PKCERK1的激活参与了ε激活的调节。缓激肽可刺激胞核中磷酸化的ERK的积聚，而在PKC抑制剂处理的细胞或转染PKCεsiRNA的细胞中，这一作用被抑制。因此，我们得出结论，缓激肽通过pld/pdk-1途径激活PKCERK-1，从而诱导ε的激活和转位到细胞核内，并参与COX-2的表达，促进真皮成纤维细胞合成前列腺素E_2。
The proinflammatory mediator bradykinin stimulated cyclooxygenase-2 (COX-2) expression and subsequently prostaglandin E2 synthesis in dermal fibroblasts. The involvement of B2 receptors and Gαq in the role of bradykinin was suggested by using pharmacological inhibitors. The PKC activator PMA stimulated COX-2 mRNA expression. Bradykinin failed to induce COX-2 mRNA expression in the presence of PKC inhibitors, whereas the effect of bradykinin was observed in the absence of extracellular Ca2+. Bradykinin-induced COX-2 mRNA expression was inhibited in cells transfected with PKCε siRNA. These observations suggest that the novel PKCε is concerned with bradykinin-induced COX-2 expression. Bradykinin-induced PKCε phosphorylation and COX-2 mRNA expression were inhibited by an inhibitor of 3-phosphoinositide-dependent protein kinase-1 (PDK-1), and bradykinin-induced PDK-1 phosphorylation was inhibited by phospholipase D (PLD) inhibitors, suggesting that PLD/PDK-1 pathway contributes to bradykinin-induced PKCε activation. Pharmacological and knockdown studies suggest that the extracellular signal-regulated kinase 1 (ERK1) MAPK signaling is involved in bradykinin-induced COX-2 expression. Bradykinin-induced ERK phosphorylation was attenuated in the cells pretreated with PKC inhibitors or transfected with PKCε siRNA. We observed the interaction between PKCε and ERK by co-immunoprecipitation experiments. These observations suggest that PKCε activation contributes to the regulation of ERK1 activation. Bradykinin stimulated the accumulation of phosphorylated ERK in the nuclear fraction, that was inhibited in the cells treated with PKC inhibitors or transfected with PKCε siRNA. Consequently, we concluded that bradykinin activates PKCε via the PLD/PDK-1 pathway, which subsequently induces activation and translocation of ERK1 into the nucleus, and contributes to COX-2 expression for prostaglandin E2 synthesis in dermal fibroblasts.
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影响因子：
6.5
作者：
Bjorndal, B;Helleland, C;Lillehaug, JR
通讯作者：
Lillehaug, JR
影响因子：
4.8
作者：
Hsieh, Hsi-Lung;Wang, Hui-Hsin;Yang, Chuen-Mao
通讯作者：
Yang, Chuen-Mao
DOI：
10.1038/nrd3871
发表时间：
2012-12
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/s1357-2725(03)00210-3
发表时间：
2004-02-01
影响因子：
4
作者：
Aksoy, E;Goldman, M;Willems, F
通讯作者：
Willems, F
影响因子：
16
作者：
Chuderland, Dana;Konson, Alexander;Seger, Rony
通讯作者：
Seger, Rony