title: p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase.
abstract: A hallmark of p53 function is to regulate a transcriptional program in response to extracellular and intracellular stress that directs cell cycle arrest, apoptosis, and cellular senescence. Independent of the role of p53 in the nucleus, some of the anti-proliferative functions of p53 reside within the mitochondria [1]. p53 can arrest cell growth in response to mitochondrial p53 in an EJ bladder carcinoma cell environment that is naïve of p53 function until induced to express p53 [2]. TP53 can independently partition with endogenous nuclear and mitochondrial proteins consistent with the ability of p53 to enact senescence. In order to address the role of p53 in navigating cellular senescence through the mitochondria, we identified SirT3 to rescue EJ/p53 cells from induced p53-mediated growth arrest. Human SirT3 function appears coupled with p53 early during the initiation of p53 expression in the mitochondria by biochemical and cellular localization analysis. Our evidence suggests that SirT3 partially abrogates p53 activity to enact growth arrest and senescence. Additionally, we identified the chaperone protein BAG-2 in averting SirT3 targeting of p53 -mediated senescence. These studies identify a complex relationship between p53, SirT3, and chaperoning factor BAG-2 that may link the salvaging and quality assurance of the p53 protein for control of cellular fate independent of transcriptional activity.
authors.affiliation: Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: SiDe
authors.initials: S
authors.lastname: Li
authors.forename: Michaela
authors.initials: M
authors.lastname: Banck
authors.forename: Shiraz
authors.initials: S
authors.lastname: Mujtaba
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.forename: Mary M
authors.initials: MM
authors.lastname: Sugrue
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D017353:Gene Deletion; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D018832:Molecular Chaperones; D009243:NAD / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism*; D013347:Subcellular Fractions / Q000201:enzymology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000473:pathology
chemical_list: C492980:BAG2 protein, human; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D009243:NAD; C466093:SIRT3 protein, human; D056566:Sirtuin 3
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