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

Chanhee Kang, Qikai Xu, Timothy D. Martin, Mamie Z. Li, Marco Demaria, iviu Aron, Tao Lu, Bruce A. Yankner, Judith Campisi, Stephen J. Elledge

 Science 349, aaa5612 (2015)

Speaker: Cheng-Hao Chen (陳正豪)                    Time: 13:00~14:00, Feb. 24, 2016

Commentator: Dr. Li-Jin Hsu (徐麗君老師)  .     Place: Room 601

Abstract:

Senescence is a state of prolonged cell cycle arrest regulated by p53 and p16^INK4a/Rb pathway which has been associated with a range of pathophysiological processes such as wound healing, aging and tumorigenesis. Senescent cells exhibit several features including growth arrest, increased senescence-associated β-galactosidase (SA-β-gal) activity and secretion of proinflammatory factors, known as the senescence-associated secretory phenotype (SASP)(1). It has been revealed that production of SASP is independent of p53 or p16^INK4a. Thus, the mechanisms that regulate the SASP are not fully understood. Autophagy has recently been identified as an effector of senescence and the SASP(2). However, the role of autophagy in senescence progression is still controversial and the interplays between autophagy and senescence remain unclear. In this study, authors found that ectopic expression of the transcription factor GATA4 upregulated the SASP expression and induced senescence in human fibroblasts. Under normal conditions, GATA4 was found to be degraded by p62-mediated selective autophagy, but this process was blocked during exposure of senescence inducing stimuli, resulting in GATA4 stabilization. GATA4 promoted the SASP via NF-κB activation which in turn facilitated senescence progression. Moreover, GATA4 senescence pathway activation was depend on the DNA damage response (DDR) regulators ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), but was independent of p53 and p16^INK4a /RB pathways. Furthermore, GATA4 protein was accumulated in the organs of aged mice and in brain samples from older humans. Taken together, GATA4 triggers the SASP and senescence through NF-κB activation in response to DNA damage signaling. This study unveils a novel regulator of senescence and inflammation and providing a new insight into the role of autophagy in the regulation of senescence progression.

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