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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Direct regulation of CREB transcriptional activity by ATM in response to genotoxic stress
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Direct regulation of CREB transcriptional activity by ATM in response to genotoxic stress

机译：响应遗传毒性胁迫，ATM直接调节CREB转录活性

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摘要

Ataxia-telangiectasia (A-T) is a syndrome of cancer susceptibility, immune dysfunction, and neurodegeneration that is caused by mutations in the A-T-mutated (ATM) gene. ATM has been implicated as a critical regulator of cellular responses to DNA damage, including the activation of cell cycle checkpoints and induction of apoptosis. Although defective cell cycle-checkpoint regulation and associated genomic instability presumably contribute to cancer susceptibility in A-T, the mechanism of neurodegeneration in A-T is not well understood. In addition, although ATM is required for the induction of the p53 transcriptional program in response to DNA damage, the identities of the relevant transcription factors that mediate ATM-dependent changes in gene expression remain largely undetermined. In this article, we describe a signal transduction pathway linking ATM directly to the Ca2+/cAMP response element-binding protein, CREB, a transcription factor that regulates cell growth, homeostasis, and survival. ATM phosphorylated CREB in vitro and in vivo in response to ionizing radiation (IR) and H2O2 on a stress-inducible domain. IR-induced phosphorylation of CREB correlated with a decrease in CREB transactivation potential and reduced interaction between CREB and its transcriptional coactivator, CREB-binding protein (CBP). A CREB mutant containing Ala substitutions at ATM phosphorylation sites displayed enhanced transactivation potential, resistance to inhibition by IR, and increased binding to CBP. We propose that ATM-mediated phosphorylation of CREB in response to DNA damage modulates CREB-dependent gene expression and that dysregulation of the ATM-CREB pathway may contribute to neurodegeneration in A-T.
机译：共济失调毛细血管扩张症（A-T）是由A-T突变（ATM）基因突变引起的癌症易感性，免疫功能障碍和神经退行性疾病的综合征。 ATM被认为是细胞对DNA损伤反应的关键调节剂，包括激活细胞周期检查点和诱导细胞凋亡。尽管缺陷的细胞周期检查点调节和相关的基因组不稳定性可能会导致A-T的癌症易感性，但对A-T的神经退行性机制尚不甚了解。另外，尽管在响应DNA损伤时需要ATM来诱导p53转录程序，但是介导基因表达中ATM依赖性变化的相关转录因子的身份仍未确定。在本文中，我们描述了一个信号转导途径，将ATM直接连接到Ca2 + / cAMP响应元件结合蛋白CREB，一种调节细胞生长，体内稳态和存活的转录因子。 ATM在体外和体内将CREB磷酸化，以响应应激诱导域上的电离辐射（IR）和H2O2。 IR诱导的CREB磷酸化与CREB反式激活潜力的降低和CREB及其转录共激活剂CREB结合蛋白（CBP）之间的相互作用降低有关。在ATM磷酸化位点包含Ala取代的CREB突变体显示出增强的反式激活潜力，对IR抑制的抵抗力以及与CBP的结合力增加。我们提出响应DNA损伤的ATM介导的CREB的磷酸化调节CREB依赖的基因表达，并且ATM-CREB通路的失调可能有助于A-T中的神经变性。

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