GATA4 Is a Critical Regulator of Senescence and Inflammation

Cellular senescence is induced by various stresses, including DNA damage, oncogene activation, and recurrent proliferation, and has been suggested both to suppress tumorigenesis and, in other contexts, to contribute to aging and tumorigenesis. Senescence is characterized by growth arrest and increased expression of proinflammatory factors, known as the senescence-associated secretory phenotype (SASP), which is controlled by NFκB signaling. Autophagy has also been implicated in senescence and the SASP, but the mechanisms by which autophagy regulates senescence remain unclear. Kang and colleagues found that expression of the transcription factor GATA4, but not other members of the GATA family, upregulated the expression of senescence-associated genes, including many SASP genes, and induced senescence in human fibroblasts. GATA4 was degraded under normal conditions via interaction with p62 and selective autophagy, thereby inhibiting senescence; however, senescence-inducing stimuli suppressed selective autophagy, resulting in GATA4 stabilization, suggesting that autophagy both negatively and positively regulates senescence. Expression of GATA4 promoted the SASP via activation of NFκB, which was mediated in part via TNF receptor–associated factor 3–interacting protein 2 and IL1A. The GATA4 senescence pathway was activated by the DNA damage response (DDR) kinases ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), but was independent of p53 and p16^INNK4A/RB, core senescence pathways that are critical for senescence growth arrest, indicating that GATA4 functions as a distinct branch of the DDR that induces the SASP to facilitate senescence. Consistent with these findings, induction of senescence by ionizing radiation resulted in accumulation of GATA4 in mouse tissues in vivo. Furthermore, GATA4 expression was increased in the organs of aged mice compared with those of young animals, and was increased in brain samples from older humans. These findings identify GATA4 as a previously unidentified regulator of the SASP and senescence, and suggest that the GATA4 pathway may play a role in age-associated inflammation and pathologies such as cancer.

Kang C, Xu Q, Martin TD, Li MZ, Demaria M, Aron L, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 2015;349:aaa5612.

• ©2015 American Association for Cancer Research.