JNK2-dependent regulation of SIRT1 protein stability.
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.
Yorkshire Cancer Research p53 Research Unit, Department of Biology, University of York, York, United Kingdom.
Jack
J
Ford
Shafiq
S
Ahmed
Simon
S
Allison
Ming
M
Jiang
Jo
J
Milner
D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D012694:Serine; D048056:Mitogen-Activated Protein Kinase 9; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins