Mechanism of diepoxybutane-induced p53 regulation in human cells.
Mechanism of diepoxybutane-induced p53 regulation in human cells.
复制标题
二环氧丁烷诱导人体细胞 p53 调节的机制。
DOI：
10.1002/jbt.20300
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发表时间：
2009
影响因子：
3.6
通讯作者：
Muganda,PerpetuaM
中科院分区：
文献类型：
--
作者：
Yadavilli,Sridevi;Chen,Zhenping;Albrecht,Thomas;Muganda,PerpetuaM
二环氧丁烷 (DEB) 是环境化学物质 1,3-丁二烯 (BD) 最有效的活性代谢物。 BD 是一种已知的诱变剂和人类致癌物，并具有多系统器官毒性。我们之前报道过 DEB 诱导的细胞凋亡的人 TK6 淋巴母细胞中 p53 的升高。在这项研究中，我们表征了 DEB 诱导的 p53 积累，并研究了 DEB 调节 p53 积累的机制。研究发现，暴露于 DEB 的 TK6 淋巴母细胞和人胚肺 (HEL) 人成纤维细胞中 p53 水平的升高很大程度上是由于 p53 蛋白的稳定化所致。 DEB 增加了 p53 在 lys-382 处的乙酰化，显着减少了 p53 与其调节蛋白 mdm2 之间的复合物形成，并诱导人淋巴母细胞中 p53 在丝氨酸 15、20、37、46 和 392 处的磷酸化。与暴露于 DEB 的 ATM 缺陷的人淋巴细胞相比，在暴露于 DEB 的共济失调毛细血管扩张突变 (ATM) 的人淋巴细胞中观察到 p53 在丝氨酸 15 处的磷酸化与总 p53 水平相关的显着增加；这表明 ATM 激酶与暴露于 DEB 的细胞中 p53 水平升高有关。总的来说，这些发现首次解释了 p53 在暴露于 DEB 的细胞中积累的机制，并有助于理解 DEB 和 BD 的分子毒性。 © 2009 Wiley periodicals, Inc. J Biochem Mol Toxicol 23:373–386, 2009；在线发表于 Wiley InterScience (www.interscience.wiley.com)。 DOI 10.1002/jbt.20300
Diepoxybutane (DEB) is the most potent active metabolite of the environmental chemical 1,3‐butadiene (BD). BD is a known mutagen and human carcinogen and possesses multisystems organ toxicity. We previously reported the elevation of p53 in human TK6 lymphoblasts undergoing DEB‐induced apoptosis. In this study, we have characterized the DEB‐induced p53 accumulation and investigated the mechanisms by which DEB regulates this p53 accumulation. The elevation of p53 levels in DEB‐exposed TK6 lymphoblasts and human embryonic lung (HEL) human fibroblasts was found to be largely due to the stabilization of the p53 protein. DEB increased the acetylation of p53 at lys‐382, dramatically reduced complex formation between p53 and its regulator protein mdm2 and induced the phosphorylation of p53 at serines 15, 20, 37, 46, and 392 in human lymphoblasts. A dramatic increase in phosphorylation of p53 at serine 15 in correlation to total p53 levels was observed in DEB‐exposed Ataxia Telangiectasia Mutated (ATM) proficient human lymphoblasts as compared to DEB‐exposed ATM‐deficient human lymphoblasts; this implicates the ATM kinase in the elevation of p53 levels in DEB‐exposed cells. Collectively, these findings explain for the first time the mechanism by which p53 accumulates in DEB‐exposed cells and contributes to the understanding of the molecular toxicity of DEB and BD. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:373–386, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20300