Public Release: 

Key control mechanism of cellular deterioration identified

American Association for the Advancement of Science

This news release is available in Japanese.

Old or abnormal cells enter a state of cellular senescence, in which they are no longer able to progress through the cell cycle, and now new research has identified a key mechanism that induces this biological process. The accumulation of senescent cells is thought to promote aging-associated diseases, including cancer and neurodegeneration; thus understanding the mechanisms behind this deterioration of cells has important implications for human health. As cells enter a senescent state, they display extensive changes in gene expression, including a pro-inflammatory response characterized by increased expression of secreted inflammatory cytokines. Such cells have what is called a senescence-associated secretory phenotype (SASP). To learn more about this process, Chanhee Kang et al. induced senescence in human fibroblasts and looked for genetic elements that are highly expressed by senescent but not nonsenescent cells. They found that a particular transcription factor, GATA4, plays a key role in activating senescence. Further research revealed that GATA4 is normally suppressed by a process (autophagy) that degrades cellular components, but as cells age or become damaged, this controlled depletion of GATA4 ceases and senescence takes over. These findings help solve a mystery; previous studies have found that autophagy is required for senescence, while some evidence hints that it helps inhibit senescence. But results from Kang and colleagues suggest that a selective process is at play, where general autophagy establishes senescence and targeted autophagy of GATA4 blocks it. Indeed, depletion of certain autophagy components increased the abundance of GATA4 protein. Further manipulation reveals that expression of GATA4 induces the expression of genes associated with the SASP, while depletion of GATA4 suppressed the expression of several SASP genes. A Perspective by Liam Cassidy and Masashi Narita discusses these findings in greater detail.

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Article #11: "The DNA damage response activates inflammation and senescence by protecting GATA4 from selective autophagy," by C. Kang; Q. Xu; T.D. Martin; M.Z. Li; S.J. Elledge; L. Aron; T. Lu; B.A. Yankner at Harvard Medical School in Boston, MA; C. Kang; Q. Xu; T.D. Martin; M.Z. Li; S.J. Elledge at Brigham and Women's Hospital in Boston, MA; C. Kang; Q. Xu; T.D. Martin; M.Z. Li; S.J. Elledge at Howard Hughes Medical Institute in Boston, MA; M. Demaria; J. Campisi at Buck Institute for Research on Aging in Novato, CA.

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