title: Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress.
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 p21(CDKN1A). 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.
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
authors.forename: In Hye
authors.initials: IH
authors.lastname: Lee
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Kawai
authors.forename: Maria M
authors.initials: MM
authors.lastname: Fergusson
authors.forename: Ilsa I
authors.initials: II
authors.lastname: Rovira
authors.forename: Alexander J R
authors.initials: AJ
authors.lastname: Bishop
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D013312:Stress, Physiological; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism*
chemical_list: C502661:Atg7 protein, mouse; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes