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首页> 外文期刊>Cellular Signalling >Adrenomedullin promotes cell cycle transit and up-regulates cyclin D1 protein level in human glioblastoma cells through the activation of c-Jun/JNK/AP-1 signal transduction pathway
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Adrenomedullin promotes cell cycle transit and up-regulates cyclin D1 protein level in human glioblastoma cells through the activation of c-Jun/JNK/AP-1 signal transduction pathway

机译：肾上腺髓质素通过激活c-Jun / JNK / AP-1信号转导通路促进人胶质母细胞瘤细胞的细胞周期迁移并上调cyclin D1蛋白水平

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Adrenomedullin is a secreted peptide hormone with multiple functions. Although a number of reports have indicated that adrenomedullin may be involved in tumor progression, its mechanism of action remains obscure. In this study, we have analysed the signal transduction pathway activated by adrenomedullin in human glioma cells. Our results revealed that adrenomedullin induced the phosphorylation of both c-Jun and JNK in glioblastoma cells. Silencing JNK expression with siRNA reversed the phosphorylation of c-Jun induced by adrenomedullin, indicating that JNK is responsible of c-Jun activation. In addition, electrophoretic mobility-shift assays showed that the increase in phosphorylation of c-Jun was associated with increased AP-1 DNA binding activity. Supershift assays and co-immunoprecipitation demonstrated that c-Jun and JunD are part of the AP-1 complex, indicating that activated c-Jun is dimerized with JunD in response to adrenomedullin. Furthermore, adrenomedullin was shown to promote cell transit beyond cell cycle phases with a concomittant increase in cyclin D1 protein level, suggesting that adrenomedullin effect cell proliferation through up-regulation of cyclin D1. The inhibition of JNK activation or the suppression of c-Jun or JunD expression with siRNA impaired the effects of adrenomedullin on cell proliferation and on cyclin D1. Taken together, these data demonstrate that activation of cJun/JNK pathway is involved in the growth regulatory activity of adrenomedullin in glioblastoma cells.
机译：肾上腺髓质素是一种具有多种功能的分泌肽激素。尽管许多报道表明肾上腺髓质素可能参与了肿瘤的发展，但其作用机理仍然不清楚。在这项研究中，我们已经分析了肾上腺髓质素在人神经胶质瘤细胞中激活的信号转导途径。我们的结果表明，肾上腺髓质素可诱导胶质母细胞瘤细胞中c-Jun和JNK的磷酸化。用siRNA沉默JNK表达可逆转肾上腺髓质素诱导的c-Jun磷酸化，表明JNK负责c-Jun激活。此外，电泳迁移率迁移分析表明，c-Jun磷酸化的增加与AP-1 DNA结合活性的增加有关。 Supershift分析和免疫共沉淀表明c-Jun和JunD是AP-1复合物的一部分，表明活化的c-Jun与JunD响应肾上腺髓质素而二聚化。此外，显示肾上腺髓质素可促进细胞迁移超过细胞周期阶段，并伴随细胞周期蛋白D1蛋白水平的增加，这表明肾上腺髓质素通过细胞周期蛋白D1的上调影响细胞增殖。用siRNA抑制JNK激活或抑制c-Jun或JunD表达会削弱肾上腺髓质素对细胞增殖和细胞周期蛋白D1的作用。综上，这些数据表明，cJun / JNK途径的激活与胶质母细胞瘤细胞中肾上腺髓质素的生长调节活性有关。

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