Cellular senescence is a program of arrested proliferation and altered gene expression triggered by many stresses. Although it is a potent tumor-suppressive mechanism, senescence has been implicated in several pathological processes including aging, age-associated diseases, and (counterintuitively) tumorigenesis. One potential mechanism through which senescent cells exert such pleiotropic effects is the secretion of proinflammatory cytokines, chemokines, growth factors, and proteases, termed the senescence-associated secretory phenotype (SASP), which affects senescent cells and their microenvironment. The mechanism by which the SASP is initiated and maintained is not well characterized beyond the classical regulators of inflammation, including the transcription factors NF-κB and C/EBPβ.
Our results indicate that GATA4 connects autophagy and the DDR to senescence and inflammation through TRAF3IP2 and IL1A activation of NF-κB. These findings establish GATA4 as a key switch activated by the DDR to regulate senescence, independently of p53 and p16INK4a.
Our in vivo data indicate a potential role of GATA4 during aging and its associated inflammation. Because accumulation of senescent cells is thought to promote aging and aging-associated diseases through the resulting inflammatory response, inhibiting the GATA4 pathway may provide an avenue for therapeutic intervention.