P53 and ATM/ATR regulate 7,12-Dimethylbenz[a]anthracene-induced immunosuppression
P53 and ATM/ATR regulate 7,12-Dimethylbenz[a]anthracene-induced immunosuppression
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DOI：
10.1124/mol.107.039230
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发表时间：
2008-01-01
影响因子：
3.6
通讯作者：
Burchiel, Scott W.
中科院分区：
文献类型：
--
作者：
Gao, Jun;Mitchell, Leah A.;Burchiel, Scott W.
肿瘤抑制蛋白p53是一种转录因子，调节由遗传毒性剂产生的凋亡反应。先前的研究已经报道了7，12-二甲基苯并[a]蒽（DMBA）诱导的骨髓毒性是p53依赖性的。我们的实验室已经表明DMBA诱导的脾免疫抑制是CYP 1B 1和微粒体环氧化物水解酶（mEH）依赖性的，这表明DMBA-3，4-二氢二醇-1，2-环氧化物代谢物（DMBA-DE）可能是DMBA诱导的免疫抑制的原因。已知DMBA-DE与DNA结合导致链断裂。因此，我们推测p53通路是DBMA诱导的免疫抑制所必需的。在目前的研究中，我们的数据表明，激活的p53积累在脾细胞核中的WT和AhR-null小鼠DMBA治疗后，但不是在CYP 1B 1-null或mEH-null小鼠。这些结果表明，DMBA在体内以CYP 1B 1和mEH依赖性方式激活p53，但不依赖于AhR。共济失调毛细血管扩张突变（ATM）和ATM和Rad 3相关蛋白（ATR）是DNA损伤的传感器，信号p53激活。在WT、p53-null和AhR- null小鼠中观察到DMBA处理后ATM、磷酸化ATM（Ser 1987）和ATR水平增加，但在CYP 1B 1- null或mEH-null小鼠中未观察到。因此，ATM和ATR似乎作为DNA损伤的传感器作用于p53的上游。离体免疫功能研究表明，在不存在细胞毒性的情况下产生免疫抑制的DMBA剂量下，DMBA诱导的脾脏免疫抑制是p53依赖性的。高剂量DMBA的细胞毒性可能与p53非依赖性途径有关。这项研究提供了新的见解DMBA诱导的免疫抑制在体内的遗传毒性的要求，并强调了ATM/ATR信号p53的作用。
The tumor suppressor protein p53 is a transcription factor that regulates apoptotic responses produced by genotoxic agents. Previous studies have reported that 7,12-dimethylbenz[a] anthracene (DMBA)-induced bone marrow toxicity is p53-dependent in vivo. Our laboratory has shown that DMBA-induced splenic immunosuppression is CYP1B1- and microsomal epoxide hydrolase (mEH)-dependent, demonstrating that the DMBA-3,4dihydrodiol- 1,2-epoxide metabolite (DMBA-DE) is probably responsible for DMBA-induced immunosuppression. DMBA-DE is known to bind to DNA leading to strand breaks. Therefore, we postulated that a p53 pathway is required for DBMA-induced immunosuppression. In the present studies, our data show that activated p53 accumulated in the nuclei of spleen cells in WT and AhR-null mice after DMBA treatment, but not in CYP1B1-null or mEH-null mice. These results suggest that DMBA activates p53 in a CYP1B1- and mEH-dependent manner in vivo but is not AhR- dependent. Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein (ATR) are sensors for DNA damage that signal p53 activation. Increased ATM, phospho-ATM (Ser1987), and ATR levels were observed after DMBA treatment in WT, p53-null, and AhR- null mice but not in CYP1B1- null or mEH-null mice. Therefore, ATM and ATR seem to act upstream of p53 as sensors of DNA damage. Ex vivo immune function studies demonstrated that DMBA-induced splenic immunosuppression is p53-dependent at doses of DMBA that produce immunosuppression in the absence of cytotoxicity. High-dose DMBA cytotoxicity may be associated with p53-independent pathways. This study provides new insights into the requirement of genotoxicity for DMBA-induced immunosuppression in vivo and highlights the roles of ATM/ATR in signaling p53.