MST1 Promotes Apoptosis through Regulating Sirt1-dependent p53 Deacetylation

Fang Yuan,Qi Xie,Junbing Wu,Yujie Bai,Beibei Mao,Yongli Dong,Wenzhi Bi,Guangju Ji,Wufan Tao,Yan Wang,Zengqiang Yuan

doi:10.1074/jbc.m110.182543

Abstract

Mammalian Sterile 20-like kinase 1 (MST1) protein kinase plays an important role in the apoptosis induced by a variety of stresses. The MST1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, JNK/p38, histone H2B and FOXO. It has been reported that overexpression of MST1 initiates apoptosis by activating p53. However, the molecular mechanisms underlying MST1-p53 signaling during apoptosis are unclear. Here, we report that MST1 promotes genotoxic agent-induced apoptosis in a p53-dependent manner. We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity. Collectively, these findings define a novel regulatory mechanism involving the phosphorylation of Sirt1 by MST1 kinase which leads to p53 activation, with implications for our understanding of signaling mechanisms during DNA damage-induced apoptosis.

Highlights

The protein kinase mammalian Sterile 20-like kinase 1 (MST1)4 contains a Ste20-related kinase catalytic domain in the amino-terminal segment followed by a regulatory domain at the COOH terminus [1]
We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity
MST1 Promotion of Cell Death Is p53-dependent—Previous studies have indicated that MST1 induces cell apoptosis upon DNA damage. p53 has been well documented as a major cell death initiator [31, 32]

Summary

Introduction

The protein kinase mammalian Sterile 20-like kinase 1 (MST1)4 contains a Ste20-related kinase catalytic domain in the amino-terminal segment followed by a regulatory domain at the COOH terminus [1]. These findings define a novel regulatory mechanism involving the phosphorylation of Sirt1 by MST1 kinase which leads to p53 activation, with implications for our understanding of signaling mechanisms during DNA damageinduced apoptosis. Sirt1-mediated deacetylation antagonizes p53-dependent transcriptional activation and inhibits p53-dependent apoptosis in response to DNA damage and oxidative stress [29, 30].

Results

Conclusion