SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways.
SIRT3, one of seven mammalian sirtuins, is a NAD-dependent deacetylase. SIRT3 localizes to mitochondria where it deacetylates and thus activates acetyl-CoA synthetase 2 (AceCS2), indicating a role for SIRT3 in metabolism. Here we provide evidence that SIRT3 also impacts upon apoptosis and cell growth control. Using RNAi under basal (non-stress) conditions we show that SIRT3 is required for apoptosis induced by selective silencing of Bcl-2 in HCT116 human epithelial cancer cells. Identical treatment of ARPE19 epithelial non-cancer cells induces G(1) growth arrest which also proved to be SIRT3-dependent. Previously we have identified SIRT1 and JNK2 as constitutive suppressors of apoptosis in HCT116 cells. We now demonstrate that SIRT3 functions in JNK2-regulated apoptosis but is dispensable for SIRT1-regulated apoptosis. SIRT3 is also dispensable for stress-induced apoptosis. Thus the pro-apoptotic functioning of SIRT3 is selectively coupled with defined pathways regulating cell survival under basal conditions.
Allison
Simon J
SJ
Yorkshire Cancer Research p53 Laboratory, Department of Biology, University of York, York, UK.
Milner
Jo
J
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D006131:Growth Inhibitors / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D024101:Mitochondrial Proteins / Q000502:physiology*; D034741:RNA, Small Interfering / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D056566:Sirtuin 3; D037761:Sirtuins / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D006131:Growth Inhibitors; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D037761:Sirtuins