DNA损伤反应通过抑制GATA4的自噬诱导炎症和衰老。
The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
作者信息
Kang Chanhee, Xu Qikai, Martin Timothy D, Li Mamie Z, Demaria Marco, Aron Liviu, Lu Tao, Yankner Bruce A, Campisi Judith, Elledge Stephen J
机构信息
Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA.
Buck Institute for Research on Aging, Novato, CA 94945, USA.
出版信息
Science. 2015 Sep 25;349(6255):aaa5612. doi: 10.1126/science.aaa5612.
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-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.
细胞衰老 是一种由 p53 和 p16(INK4a) 肿瘤抑制蛋白控制的终末应激激活程序。衰老的一个显著特征是衰老相关分泌表型 (SASP)，这是一种与肿瘤促进和衰老相关的促炎反应。我们已确定转录因子 GATA4 为衰老和 SASP 的调节因子。GATA4 在经历衰老的细胞中稳定存在，并且是 SASP 所必需的。正常情况下，GATA4 通过 p62 介导的选择性自噬降解，但这种调节在衰老过程中受到抑制，从而使 GATA4 稳定。GATA4 反过来激活转录因子 NF-κB 以启动 SASP 并促进衰老。GATA4 的激活依赖于 DNA 损伤反应调节因子 ATM 和 ATR，但不依赖于 p53 或 p16(INK4a)。GATA4 在包括衰老大脑在内的多种组织中积累，并可能导致衰老及其相关炎症。
Zotero 插件