title: SIRT1 phosphorylation by AMP-activated protein kinase regulates p53 acetylation.
abstract: The deacetylase SIRT1 regulates multiple biological processes including cellular metabolism and aging. Importantly, SIRT1 can also inactivate the p53 tumor suppressor via deacetylation, suggesting a role in oncogenesis. Recently, SIRT1 was shown to be released from its endogenous inhibitor DBC1 by a process requiring AMPK and the phosphorylation of SIRT1 by yet undefined kinase(s). Here we provide further evidence that AMPK directly phosphorylates SIRT1 on T344, releasing it from DBC1. Furthermore, a phospho-mimetic SIRT1 (T334E) showed decreased binding to DBC1, supporting the importance of this phosphorylation in AMPK-mediated regulation of SIRT1 activity. In addition, inhibition of AMPK by Compound C led to increased p53 acetylation, suggesting a role for the AMPK/SIRT1 pathway in regulating p53 signaling. Together, our results support a hypothesis that AMPK negatively regulates p53 acetylation via phosphorylation of SIRT1 on T344. Furthermore, our findings also define the AMPK/SIRT1 axis as a possible targetable pathway to regulate p53 function.
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA.
authors: Alan W
authors: AW
authors: Lau
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA.
authors: Pengda
authors: P
authors: Liu
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA.
authors: Hiroyuki
authors: H
authors: Inuzuka
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA ; State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 320 Yue-Yang Road, Shanghai 200031, China.
authors: Daming
authors: D
authors: Gao
keywords: AMPK; DBC1; SIRT1 deacetylase; acetylation; p53; phosphorylation