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首页> 外文期刊>Journal of biochemical and molecular toxicology >Mechanism of diepoxybutane-induced p53 regulation in human cells.
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Mechanism of diepoxybutane-induced p53 regulation in human cells.

机译：二环氧丁烷诱导人细胞中p53调控的机制。

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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.
机译：二环氧丁烷（DEB）是环境化学1,3-丁二烯（BD）中最有效的活性代谢产物。 BD是已知的诱变剂和人类致癌物，并具有多系统器官毒性。先前我们报道了经历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调节该p53积累的机制。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归因于p53蛋白的稳定。 DEB增加了lys-382处p53的乙酰化作用，大大减少了p53及其调节蛋白mdm2之间的复合物形成，并诱导了人类淋巴母细胞中丝氨酸15、20、37、46和392处p53的磷酸化。与DEB暴露的ATM缺陷人类淋巴母细胞相比，DEB暴露的共济失调毛细血管扩张突变（ATM）熟练的人类淋巴母细胞中丝氨酸15处p53的磷酸化与总p53水平显着增加;这暗示了ATM激酶在暴露于DEB的细胞中p53水平的升高。总的来说，这些发现首次解释了p53在暴露于DEB的细胞中积累的机理，并有助于理解DEB和BD的分​​子毒性。

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