Phosphorylation of HuR by Chk2 regulates SIRT1 expression

Kotb Abdelmohsen; Rudolf Pullmann Jr; Ashish Lal; Hyeon Ho Kim; Stefanie Galban; Xiaoling Yang; Justin D Blethrow; Mark Walker; Jonathan Shubert; David A Gillespie; Henry Furneaux; Myriam Gorospe

doi:10.1016/j.molcel.2007.01.011

Phosphorylation of HuR by Chk2 regulates SIRT1 expression

Mol Cell. 2007 Feb 23;25(4):543-57. doi: 10.1016/j.molcel.2007.01.011.

Authors

Kotb Abdelmohsen¹, Rudolf Pullmann Jr, Ashish Lal, Hyeon Ho Kim, Stefanie Galban, Xiaoling Yang, Justin D Blethrow, Mark Walker, Jonathan Shubert, David A Gillespie, Henry Furneaux, Myriam Gorospe

Affiliation

¹ Laboratory of Cellular and Molecular Biology, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.

Abstract

The RNA binding protein HuR regulates the stability of many target mRNAs. Here, we report that HuR associated with the 3' untranslated region of the mRNA encoding the longevity and stress-response protein SIRT1, stabilized the SIRT1 mRNA, and increased SIRT1 expression levels. Unexpectedly, oxidative stress triggered the dissociation of the [HuR-SIRT1 mRNA] complex, in turn promoting SIRT1 mRNA decay, reducing SIRT1 abundance, and lowering cell survival. The cell cycle checkpoint kinase Chk2 was activated by H(2)O(2), interacted with HuR, and was predicted to phosphorylate HuR at residues S88, S100, and T118. Mutation of these residues revealed a complex pattern of HuR binding, with S100 appearing to be important for [HuR-SIRT1 mRNA] dissociation after H(2)O(2). Our findings demonstrate that HuR regulates SIRT1 expression, underscore functional links between the two stress-response proteins, and implicate Chk2 in these processes.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Antigens, Surface / metabolism*
Base Sequence
Cellular Senescence / drug effects
Checkpoint Kinase 2
ELAV Proteins
ELAV-Like Protein 1
Fibroblasts / drug effects
Fibroblasts / enzymology
Gene Expression Regulation* / drug effects
HeLa Cells
Humans
Hydrogen Peroxide / pharmacology
Molecular Sequence Data
Oxidative Stress / drug effects
Phosphorylation / drug effects
Point Mutation / genetics
Protein Binding / drug effects
Protein Serine-Threonine Kinases / metabolism*
RNA Stability / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA-Binding Proteins / metabolism*
Ribonucleoproteins / metabolism
Sirtuin 1
Sirtuins / genetics*
Sirtuins / metabolism*
Substrate Specificity / drug effects

Substances

Antigens, Surface
ELAV Proteins
ELAV-Like Protein 1
ELAVL1 protein, human
RNA, Messenger
RNA-Binding Proteins
Ribonucleoproteins
Hydrogen Peroxide
Checkpoint Kinase 2
CHEK2 protein, human
Protein Serine-Threonine Kinases
SIRT1 protein, human
Sirtuin 1
Sirtuins

Grants and funding

Z01 AG000511-10/Intramural NIH HHS/United States