JNK2-dependent regulation of SIRT1 protein stability

Jack Ford, Shafiq Ahmed, Simon Allison, Ming Jiang, Jo Milner

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Mammalian SIRT1 is an NAD-dependent deacetylase with critical roles in the maintenance of homeostasis and cell survival. Elevated levels of SIRT1 protein are evident in cancer in which SIRT1 can function as a cancer-specific survival factor. Here we demonstrate that elevated SIRT1 protein in human cells is not attributable to increased SIRT1 mRNA levels but, instead, reflects SIRT1 protein stability. RNAi-mediated depletion of JNK2 reduced the half-life of SIRT1 protein from >9 h to <2 h and this correlated with lack of SIRT1 protein phosphorylation at serine 27. In contrast, depletion of JNK1 had no effect upon SIRT1 protein stability and SIRT1 phosphorylation at serine 47 showed no correlation with SIRT1 protein stability. Thus we show that JNK2 is linked, directly or indirectly, with SIRT1 protein stability and that this function is coupled with SIRT1 phosphorylation at serine 27. Our observations identify a route for therapeutic modulation of SIRT1 protein levels in SIRT1-linked diseases including cancer, neurodegeneration and diabetes.

Original languageEnglish
Pages (from-to)3091-3097
Number of pages7
JournalCell Cycle
Volume7
Issue number19
DOIs
Publication statusPublished - 1 Oct 2008
Externally publishedYes

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    Ford, J., Ahmed, S., Allison, S., Jiang, M., & Milner, J. (2008). JNK2-dependent regulation of SIRT1 protein stability. Cell Cycle, 7(19), 3091-3097. https://doi.org/10.4161/cc.7.19.6799