The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4

被引：854

作者：

Kang, Chanhee ^{[1
]}

Xu, Qikai ^{[1
]}

Martin, Timothy D. ^{[1
]}

Li, Mamie Z. ^{[1
]}

Demaria, Marco ^{[2
]}

Aron, Liviu ^{[3
]}

Lu, Tao ^{[3
]}

Yankner, Bruce A. ^{[3
]}

Campisi, Judith ^{[2
]}

Elledge, Stephen J. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Genet, Div Genet,Brigham & Womens Hosp,Howard Hughes Med, Boston, MA 02115 USA

[2] Buck Inst Res Aging, Novato, CA 94945 USA

[3] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

来源：

SCIENCE | 2015年 / 349卷 / 6255期

关键词：

CELLULAR SENESCENCE; SECRETORY PHENOTYPE; TUMOR-SUPPRESSOR; TRANSCRIPTION FACTORS; TRIGGERS SENESCENCE; P53; CELLS; CANCER; CLEARANCE; INDUCTION;

D O I：

10.1126/science.aaa5612

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：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-kB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16INK4a. GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.

引用

页数：1

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