FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage

被引：83

作者：

Chung, Young Min ^{[1
]}

Park, See-Hyoung ^{[1
]}

Tsai, Wen-Bin ^{[2
]}

Wang, Shih-Ya ^{[3
]}

Ikeda, Masa-Aki ^{[4
]}

Berek, Jonathan S. ^{[1
]}

Chen, David J. ^{[3
]}

Hu, Mickey C. -T. ^{[1
]}

机构：

[1] Stanford Univ, Div Gynecol Oncol, Dept Obstet & Gynecol, Sch Med, Stanford, CA 94305 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA

[3] Univ Texas SW Med Ctr Dallas, Div Mol Radiat Biol, Dept Radiat Oncol, Dallas, TX 75390 USA

[4] Tokyo Med & Dent Univ, Sect Mol Embryol, Grad Sch Med & Dent Sci, Tokyo 1138549, Japan

来源：

NATURE COMMUNICATIONS | 2012年 / 3卷

基金：

美国国家卫生研究院;

关键词：

DOUBLE-STRAND BREAKS; FORKHEAD TRANSCRIPTION FACTOR; INTERACTING PROTEIN KINASE-2; OXIDATIVE STRESS; DEPENDENT PHOSPHORYLATION; PROMOTES TUMORIGENESIS; IONIZING-RADIATION; CARCINOMA-CELLS; ACTIVATION; MDM2;

D O I：

10.1038/ncomms2008

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATM-Chk2-p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATM-Chk2-p53-mediated apoptotic programme following DNA damage.

引用

页数：12

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