JNK2-dependent regulation of SIRT1 protein stability

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

Research output: Contribution to journalArticle

94 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.

LanguageEnglish
Pages3091-3097
Number of pages7
JournalCell Cycle
Volume7
Issue number19
DOIs
Publication statusPublished - 1 Oct 2008
Externally publishedYes

Fingerprint

Protein Stability
Serine
Phosphorylation
Proteins
Neoplasms
RNA Interference
NAD
Half-Life
Cell Survival
Homeostasis
Maintenance
Messenger RNA
Therapeutics

Cite this

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
Ford, Jack ; Ahmed, Shafiq ; Allison, Simon ; Jiang, Ming ; Milner, Jo. / JNK2-dependent regulation of SIRT1 protein stability. In: Cell Cycle. 2008 ; Vol. 7, No. 19. pp. 3091-3097.
@article{6e513e742e974a2fbd97b431fea0635b,
title = "JNK2-dependent regulation of SIRT1 protein stability",
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.",
keywords = "5-FU, Cancer, JNK2, p53, Phosphorylation, Protein stability, SIRT1",
author = "Jack Ford and Shafiq Ahmed and Simon Allison and Ming Jiang and Jo Milner",
year = "2008",
month = "10",
day = "1",
doi = "10.4161/cc.7.19.6799",
language = "English",
volume = "7",
pages = "3091--3097",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "19",

}

Ford, J, Ahmed, S, Allison, S, Jiang, M & Milner, J 2008, 'JNK2-dependent regulation of SIRT1 protein stability', Cell Cycle, vol. 7, no. 19, pp. 3091-3097. https://doi.org/10.4161/cc.7.19.6799

JNK2-dependent regulation of SIRT1 protein stability. / Ford, Jack; Ahmed, Shafiq; Allison, Simon; Jiang, Ming; Milner, Jo.

In: Cell Cycle, Vol. 7, No. 19, 01.10.2008, p. 3091-3097.

Research output: Contribution to journalArticle

TY - JOUR

T1 - JNK2-dependent regulation of SIRT1 protein stability

AU - Ford, Jack

AU - Ahmed, Shafiq

AU - Allison, Simon

AU - Jiang, Ming

AU - Milner, Jo

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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.

AB - 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.

KW - 5-FU

KW - Cancer

KW - JNK2

KW - p53

KW - Phosphorylation

KW - Protein stability

KW - SIRT1

UR - http://www.scopus.com/inward/record.url?scp=53649100104&partnerID=8YFLogxK

UR - http://www.tandfonline.com/toc/kccy20/current

U2 - 10.4161/cc.7.19.6799

DO - 10.4161/cc.7.19.6799

M3 - Article

VL - 7

SP - 3091

EP - 3097

JO - Cell Cycle

T2 - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 19

ER -