Benzo[a]pyrene induces complex H2AX phosphorylation patterns by multiple kinases including ATM, ATR, and DNA-PK
Benzo[a]pyrene induces complex H2AX phosphorylation patterns by multiple kinases including ATM, ATR, and DNA-PK
复制标题
苯并[a]芘通过 ATM、ATR 和 DNA-PK 等多种激酶诱导复杂的 H2AX 磷酸化模式
DOI：
10.1016/j.tiv.2010.09.012
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发表时间：
2011-02-01
影响因子：
3.2
通讯作者：
Yang, Jun
中科院分区：
文献类型：
--
作者：
Yan, Chunlan;Lu, Jing;Yang, Jun
H2 AX被磷脂酰肌醇3-激酶（PI 3 K）家族的成员磷酸化（γ H2 AX），包括共济失调毛细血管扩张突变型（ATM）、ATM-和Rad 3-相关型（ATR）以及响应于DNA损伤的DNA-PK。虽然已经报道了苯并[a]芘（BaP）不能在几种细胞系中单独诱导γ H2 AX，但是我们已经证明了单独的BaP可以在人羊膜FL细胞中诱导γ H2 AX。因此，我们进一步检查了BaP在不同细胞系统中诱导γ H2 AX的能力。结果表明，BaP诱导的γ H2 AX在HeLa细胞中的时间和剂量依赖性的方式。BaP还在ATM（-/-）小鼠成纤维细胞、DNA-PKcs（-/-）小鼠成纤维细胞和遗传修饰的人骨肉瘤U2 OS细胞系中诱导γ H2 AX。然后使用PI 3 K抑制剂咖啡因和渥曼青霉素来鉴定负责BaP诱导的γ H2 AX的激酶。出乎意料的是，在BaP处理的HeLa细胞中，咖啡因预处理没有抑制，而是增加了γ H2 AX水平。另一方面，咖啡因或渥曼青霉素可抑制U2 OS、DNA-PKcs（-/-）或ATM（-/-）细胞中BaP诱导的γ H2 AX。总之，这些数据表明，单独的BaP可以诱导某些细胞系统中的H2 AX磷酸化，并且PI 3 K家族的成员，包括ATM、AIR和DNA-PK可以参与各种细胞类型中的H2 AX磷酸化。(C)2010爱思唯尔有限公司版权所有。
H2AX is phosphorylated (gamma H2AX) by members of the phosphatidylinositol 3-kinase (PI3K) family, including ataxia telangiectasia-mutated (ATM), ATM- and Rad3-related (ATR) and DNA-PK in response to DNA damage. While it has been reported that benzo[a]pyrene (BaP) cannot induce gamma H2AX alone in several cell lines, we have shown that BaP alone could induce gamma H2AX in human amnion FL cells. Thus, we further examined the ability of BaP to induce gamma H2AX in different cell systems. It was shown that BaP-induced gamma H2AX in HeLa cells in a time- and dose-dependent manner. BaP also induced gamma H2AX in ATM(-/-) mouse fibroblasts, DNA-PKcs(-/-) mouse fibroblasts, and a genetically modified human osteosarcoma U2OS cell line. PI3K inhibitors caffeine and wortmannin were then used in an effort to identify the kinase(s) responsible for BaP-induced gamma H2AX. Unexpectedly, in BaP-treated HeLa cells, caffeine pretreatment did not inhibit but rather increased gamma H2AX level. On the other hand, caffeine or wortmannin can inhibit BaP-induced gamma H2AX in either U2OS, DNA-PKcs(-/-) or ATM(-/-) cells. Taken together, these data suggest that BaP alone can induce H2AX phosphorylation in certain cell systems, and that members of the PI3K family, including ATM, AIR, and DNA-PK can participate in the phosphorylation of H2AX in the various cell types. (C) 2010 Elsevier Ltd. All rights reserved.