Mammalian SIRT1 represses forkhead transcription factors.
The NAD-dependent deacetylase SIR2 and the forkhead transcription factor DAF-16 regulate lifespan in model organisms, such as yeast and C. elegans. Here we show that the mammalian SIR2 ortholog SIRT1 deacetylates and represses the activity of the forkhead transcription factor Foxo3a and other mammalian forkhead factors. This regulation appears to be in the opposite direction from the genetic interaction of SIR2 with forkhead in C. elegans. By restraining mammalian forkhead proteins, SIRT1 also reduces forkhead-dependent apoptosis. The inhibition of forkhead activity by SIRT1 parallels the effect of this deacetylase on the tumor suppressor p53. We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Maria Carla
MC
Motta
Nullin
N
Divecha
Madeleine
M
Lemieux
Christopher
C
Kamel
Delin
D
Chen
Wei
W
Gu
Yvette
Y
Bultsma
Michael
M
McBurney
Leonard
L
Guarente
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases; D056564:Sirtuin 1; D037761:Sirtuins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C085126:FOXO1 protein, human; C494929:PTEN protein, human; C447939:SIRT1 protein, human