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Atg7 Modulates p53 Activity to Regulate Cell Cycle and Survival During Metabolic Stress

Science  13 Apr 2012:
Vol. 336, Issue 6078, pp. 225-228
DOI: 10.1126/science.1218395

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Starvation and Autophagy

Starvation stimulates withdrawal from the cell cycle, as well as stimulating autophagy. Are these two events connected? Lee et al. (p. 225) show a direct and nutrient-sensitive interaction between the tumor suppressor p53 and the essential autophagy gene Atg7. Further, in the absence of Atg7, the p53-dependent induction of the cyclin-dependent kinase inhibitor p21 is inhibited. This leads to Atg7-deficient cells being unable to properly withdraw from the cell cycle under starved conditions. While Atg7 deletion leads to an impairment of p53-mediated cell-cycle arrest, the Atg7-deficient cells hyperactivate p53-mediated cell-death pathways. The physiological importance of this hyperactivation is underscored by the observation that genetic blocking of p53-mediated cell death significantly extended neonatal survival of mice in which Atg7 had been deleted.

Abstract

Withdrawal of nutrients triggers an exit from the cell division cycle, the induction of autophagy, and eventually the activation of cell death pathways. The relation, if any, among these events is not well characterized. We found that starved mouse embryonic fibroblasts lacking the essential autophagy gene product Atg7 failed to undergo cell cycle arrest. Independent of its E1-like enzymatic activity, Atg7 could bind to the tumor suppressor p53 to regulate the transcription of the gene encoding the cell cycle inhibitor p21CDKN1A. With prolonged metabolic stress, the absence of Atg7 resulted in augmented DNA damage with increased p53-dependent apoptosis. Inhibition of the DNA damage response by deletion of the protein kinase Chk2 partially rescued postnatal lethality in Atg7−/− mice. Thus, when nutrients are limited, Atg7 regulates p53-dependent cell cycle and cell death pathways.

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