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首页> 外文期刊>Cellular Physiology and Biochemistry >Dynamic Coregulatory Complex Containing BRCA1, E2F1 and CtIP Controls ATM Transcription
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Dynamic Coregulatory Complex Containing BRCA1, E2F1 and CtIP Controls ATM Transcription

机译：包含BRCA1，E2F1和CtIP的动态Coregulatory复杂控制ATM转录

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Chromosomal instability is a key feature in cancer progression. Recently we have reported that BRCA1 regulates the transcription of several genes in prostate cancer, including ATM (ataxia telangiectasia mutated). Although it is well accepted that ATM is a pivotal mediator in genotoxic stress, it is unknown whether ATM transcription is regulated during the molecular response to DNA damage. Here we investigate ATM transcription regulation in human prostate tumor PC3 cell line. We have found that doxorubicin and mitoxantrone repress ATM transcription in PC3 cells but etoposide and methotrexate do not affect ATM expression. We have demonstrated that BRCA1 binds to ATM promoter and after doxorubicin exposure, it is released. BRCA1 overexpression increases ATM transcription and this enhancement is abolished by BRCA1 depletion. Moreover, BRCA1-BRCT domain loss impairs the ability of BRCA1 to regulate ATM promoter activity, strongly suggesting that BRCT domain is essential for ATM regulation by BRCA1. BRCA1-overexpressing PC3 cells exposed to KU55933 ATM kinase inhibitor showed significant decreased ATM promoter activity compared to untreated cells, suggesting that ATM transcriptional regulation by BRCA1 is partially mediated by the ATM kinase activity. In addition, we have demonstrated E2F1 binding to ATM promoter before and after doxorubicin exposure. E2F1 overexpression diminishes ATM transcription after doxorubicin exposure which is impaired by E2F1 dominant negative mutants. Finally, the co-regulator of transcription CtIP increases ATM transcription. CtIP increases ATM transcription. Altogether, BRCA1/E2F1/CtIP binding to ATM promoter activates ATM transcription. Doxorubicin exposure releases BRCA1 and CtIP from ATM promoter still keeping E2F1 recruited and, in turn, represses ATM expression.
机译：染色体不稳定是癌症进展的关键特征。最近，我们报道了BRCA1调节前列腺癌中几个基因的转录，包括ATM（共济失调的毛细血管扩张症）。尽管人们普遍认为ATM是遗传毒性应激的关键介质，但尚不清楚在对DNA损伤的分子反应过程中ATM转录是否受到调控。在这里，我们研究人类前列腺肿瘤PC3细胞系中的ATM转录调控。我们已经发现阿霉素和米托蒽醌抑制PC3细胞中的ATM转录，但是依托泊苷和甲氨蝶呤不会影响ATM的表达。我们已经证明BRCA1与ATM启动子结合，并且在暴露于阿霉素后被释放。 BRCA1过表达增加ATM转录，而BRCA1耗尽则消除了这种增强。此外，BRCA1-BRCT结构域的缺失会损害BRCA1调节ATM启动子活性的能力，强烈表明BRCT结构域对于BRCA1进行ATM调节至关重要。与未处理的细胞相比，暴露于KU55933 ATM激酶抑制剂的BRCA1过表达PC3细胞显示出显着降低的ATM启动子活性，这表明BRCA1对ATM转录的调控部分是由ATM激酶活性介导的。此外，我们已经证明了阿霉素暴露前后E2F1与ATM启动子的结合。 E2F1过表达会降低阿霉素暴露后的ATM转录，这会受到E2F1显性负突变体的损害。最后，转录共调节因子CtIP增加ATM转录。 CtIP增加ATM转录。总之，结合到ATM启动子的BRCA1 / E2F1 / CtIP激活ATM转录。阿霉素暴露从ATM启动子释放BRCA1和CtIP，仍然保持E2F1的募集，进而抑制ATM表达。

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