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Science 336 (6078): 225-228

Copyright © 2012 by the American Association for the Advancement of Science

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

In Hye Lee,1 Yoshichika Kawai,1 Maria M. Fergusson,1 Ilsa I. Rovira,1 Alexander J. R. Bishop,2 Noboru Motoyama,3 Liu Cao,4,* Toren Finkel1,*

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.

1 Center for Molecular Medicine, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
2 University of Texas Health Science Center, San Antonio, TX 78229, USA.
3 Department of Cognitive Brain Sciences, Research Institute, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan.
4 Key Laboratory of Medical Cell Biology, China Medical University, Shengyang 110001, China.

* To whom correspondence should be addressed. E-mail: finkelt{at}nih.gov (T.F.); caoliu{at}mail.cmu.edu (L.C.)


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