Effects of nickel on cyclin expression, cell cycle progression and cell proliferation in human pulmonary cells.
Effects of nickel on cyclin expression, cell cycle progression and cell proliferation in human pulmonary cells.
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镍对人肺细胞细胞周期蛋白表达、细胞周期进展和细胞增殖的影响
DOI：
10.1158/1055-9965.epi-09-0115
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发表时间：
2009-06
期刊：
影响因子：
--
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Ding J;He G;Gong W;Wen W;Sun W;Ning B;Huang S;Wu K;Huang C;Wu M;Xie W;Wang H
经常接触镍化合物被认为是人类肺癌的潜在原因之一。然而，镍诱导肺癌发生的分子机制仍不清楚。在目前的研究中，轻微的S期增加，显着的G2/M细胞周期停滞，并在人支气管上皮细胞（Beas-2B）镍暴露后观察到增殖阻滞。此外，镍诱导细胞周期蛋白D1和细胞周期蛋白E的第一次被证明在人肺细胞，这可能涉及镍触发的G1/S转换和细胞转化。此外，我们还证实了低氧诱导因子-1 α（hypoxia-inducible factor-1α）是镍反应的重要转录因子，它不是诱导细胞周期蛋白D1和细胞周期蛋白E的必需因子。p53在镍诱导的G2/M期阻滞中的作用被排除在外，考虑到其蛋白水平，丝氨酸15磷酸化和转录活性在镍反应中没有改变。进一步的研究表明，cyclin A在镍反应中没有被激活，cyclin B1，它不仅促进G2/M转换，而且如果不及时降解，会阻止细胞退出M期，被镍通过一种不依赖于缺氧诱导因子的方式上调。更重要的是，我们的研究结果证实，过表达的细胞周期蛋白B1，掩盖了细胞周期蛋白D1或细胞周期蛋白E的作用，介导镍引起的M期阻滞和细胞生长抑制，这可能使肺细胞对DNA损伤更敏感，并促进癌症的发生。这些结果不仅加深了我们对镍致癌分子机制的认识，而且也为镍相关癌症的化学预防研究提供了基础。（癌症流行病学生物标志物Prev 2009;18（6）：1720-9）
Frequent exposure to nickel compounds has been considered as one of the potential causes of human lung cancer. However, the molecular mechanism of nickel-induced lung carcinogenesis remains obscure. In the current study, slight S-phase increase, significant G2/M cell cycle arrest, and proliferation blockage were observed in human bronchial epithelial cells (Beas-2B) upon nickel exposure. Moreover, the induction of cyclin D1 and cyclin E by nickel was shown for the first time in human pulmonary cells, which may be involved in nickel-triggered G1/S transition and cell transformation. In addition, we verified that hypoxia-inducible factor-1α, an important transcription factor of nickel response, was not required for the cyclin D1 or cyclin E induction. The role of p53 in nickel-induced G2/M arrest was excluded, respecting that its protein level, ser15 phosphorylation, and transcriptional activity were not changed in nickel response. Further study revealed that cyclin A was not activated in nickel response, and cyclin B1, which not only promotes G2/M transition but also prevents M-phase exit of cells if not degraded in time, was up-regulated by nickel through a manner independent of hypoxia-inducible factor. More importantly, our results verified that overexpressed cyclin B1, veiling the effect of cyclin D1 or cyclin E, mediated nickel-caused M-phase blockage and cell growth inhibition, which may render pulmonary cells more sensitive to DNA damage and facilitates cancer initiation. These results will not only deepen our understanding of the molecular mechanism involved in nickel carcinogenecity, but also lead to the further study on chemoprevention of nickel-associated human cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1720–9)