p53-Induced growth arrest is regulated by the Mitochondrial SirT3 deacetylase

Si De Li, Michaela Banck, Shiraz Mujtaba, Ming Ming Zhou, Mary M. Sugrue, Martin J. Walsh

Research output: Contribution to journalArticle

115 Scopus citations

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 antiproliferative 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 nai{dotless}̈ve 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.

Original languageEnglish (US)
Article numbere10486
JournalPloS one
Volume5
Issue number5
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Li, S. D., Banck, M., Mujtaba, S., Zhou, M. M., Sugrue, M. M., & Walsh, M. J. (2010). p53-Induced growth arrest is regulated by the Mitochondrial SirT3 deacetylase. PloS one, 5(5), [e10486]. https://doi.org/10.1371/journal.pone.0010486