Mammalian SIRT1 Represses Forkhead Transcription Factors

Maria Carla Motta; Nullin Divecha; Madeleine Lemieux; Christopher Kamel; Delin Chen; Wei Gu; Yvette Bultsma; Michael McBurney; Leonard Guarente

doi:10.1016/S0092-8674(04)00126-6

Mammalian SIRT1 Represses Forkhead Transcription Factors

Maria Carla Motta, Nullin Divecha, Madeleine Lemieux, Christopher Kamel, Delin Chen, Wei Gu, Yvette Bultsma, Michael McBurney, Leonard Guarente

Cancer Research UK Manchester Institute

Research output: Contribution to journal › Article › peer-review

Abstract

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 downregulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.

Original language	English
Pages (from-to)	551-563
Number of pages	12
Journal	Cell
Volume	116
Issue number	4
DOIs	https://doi.org/10.1016/S0092-8674(04)00126-6
Publication status	Published - 20 Feb 2004

Keywords

Acetylation
metabolism: Acetyltransferases
Animals
Apoptosis
Blotting, Northern
Blotting, Western
metabolism: Cell Cycle Proteins
Cell Line
metabolism: DNA-Binding Proteins
Dose-Response Relationship, Drug
Down-Regulation
cytology: Embryo
Forkhead Transcription Factors
Gene Expression Regulation
Genes, Reporter
Hela Cells
Histone Acetyltransferases
metabolism: Histone Deacetylases
Humans
Mice
Mice, Knockout
PTEN Phosphohydrolase
metabolism: Phosphoric Monoester Hydrolases
metabolism: Plasmids
Precipitin Tests
Protein Binding
metabolism: Sirtuins
metabolism: Stem Cells
metabolism: Transcription Factors
Transcription, Genetic
metabolism: Tumor Suppressor Protein p53
metabolism: Tumor Suppressor Proteins
Up-Regulation

Access to Document

10.1016/S0092-8674(04)00126-6

Cite this

@article{2de20c5a7e1d49718afd7ae650bc8083,

title = "Mammalian SIRT1 Represses Forkhead Transcription Factors",

abstract = "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 downregulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.",

keywords = "Acetylation, metabolism: Acetyltransferases, Animals, Apoptosis, Blotting, Northern, Blotting, Western, metabolism: Cell Cycle Proteins, Cell Line, metabolism: DNA-Binding Proteins, Dose-Response Relationship, Drug, Down-Regulation, cytology: Embryo, Forkhead Transcription Factors, Gene Expression Regulation, Genes, Reporter, Hela Cells, Histone Acetyltransferases, metabolism: Histone Deacetylases, Humans, Mice, Mice, Knockout, PTEN Phosphohydrolase, metabolism: Phosphoric Monoester Hydrolases, metabolism: Plasmids, Precipitin Tests, Protein Binding, metabolism: Sirtuins, metabolism: Stem Cells, metabolism: Transcription Factors, Transcription, Genetic, metabolism: Tumor Suppressor Protein p53, metabolism: Tumor Suppressor Proteins, Up-Regulation",

author = "Motta, {Maria Carla} and Nullin Divecha and Madeleine Lemieux and Christopher Kamel and Delin Chen and Wei Gu and Yvette Bultsma and Michael McBurney and Leonard Guarente",

year = "2004",

month = feb,

day = "20",

doi = "10.1016/S0092-8674(04)00126-6",

language = "English",

volume = "116",

pages = "551--563",

journal = "Cell",

issn = "1097-4172",

publisher = "Elsevier BV",

number = "4",

}

TY - JOUR

T1 - Mammalian SIRT1 Represses Forkhead Transcription Factors

AU - Motta, Maria Carla

AU - Divecha, Nullin

AU - Lemieux, Madeleine

AU - Kamel, Christopher

AU - Chen, Delin

AU - Gu, Wei

AU - Bultsma, Yvette

AU - McBurney, Michael

AU - Guarente, Leonard

PY - 2004/2/20

Y1 - 2004/2/20

N2 - 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 downregulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.

AB - 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 downregulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.

KW - Acetylation

KW - metabolism: Acetyltransferases

KW - Animals

KW - Apoptosis

KW - Blotting, Northern

KW - Blotting, Western

KW - metabolism: Cell Cycle Proteins

KW - Cell Line

KW - metabolism: DNA-Binding Proteins

KW - Dose-Response Relationship, Drug

KW - Down-Regulation

KW - cytology: Embryo

KW - Forkhead Transcription Factors

KW - Gene Expression Regulation

KW - Genes, Reporter

KW - Hela Cells

KW - Histone Acetyltransferases

KW - metabolism: Histone Deacetylases

KW - Humans

KW - Mice

KW - Mice, Knockout

KW - PTEN Phosphohydrolase

KW - metabolism: Phosphoric Monoester Hydrolases

KW - metabolism: Plasmids

KW - Precipitin Tests

KW - Protein Binding

KW - metabolism: Sirtuins

KW - metabolism: Stem Cells

KW - metabolism: Transcription Factors

KW - Transcription, Genetic

KW - metabolism: Tumor Suppressor Protein p53

KW - metabolism: Tumor Suppressor Proteins

KW - Up-Regulation

U2 - 10.1016/S0092-8674(04)00126-6

DO - 10.1016/S0092-8674(04)00126-6

M3 - Article

SN - 1097-4172

VL - 116

SP - 551

EP - 563

JO - Cell

JF - Cell

IS - 4

ER -

Mammalian SIRT1 Represses Forkhead Transcription Factors

Abstract

Keywords

Access to Document

Fingerprint

Cite this