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Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.
Proc Natl Acad Sci U S A. 2004 Jul 06; 101(27):10042-7.PN

Abstract

Longevity regulatory genes include the Forkhead transcription factor FOXO and the NAD-dependent histone deacetylase silent information regulator 2 (Sir2). Genetic studies demonstrate that Sir2 acts to extend lifespan in Caenorhabditis elegans upstream of DAF-16, a member of the FOXO family, in the insulin-like signaling pathway. However, the molecular mechanisms underlying the requirement of DAF-16 activity in Sir2-mediated longevity remain unknown. Here we show that reversible acetylation of Foxo1 (also known as FKHR), the mouse DAF-16 ortholog, modulates its transactivation function. cAMP-response element-binding protein (CREB)-binding protein binds and acetylates Foxo1 at the K242, K245, and K262 residues, the modification of which is involved in the attenuation of Foxo1 as a transcription factor. Conversely, Sir2 binds and deacetylates Foxo1 at residues acetylated by cAMP-response element-binding protein-binding protein. Sir2 is recruited to insulin response sequence-containing promoter and increases the expression of manganese superoxide dismutase and p27(kip1) in a deacetylase-activity-dependent manner. Our findings establish Foxo1 as a direct and functional target for Sir2 in mammalian systems.

Authors+Show Affiliations

Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba, Ibaraki 305-8577, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15220471

Citation

Daitoku, Hiroaki, et al. "Silent Information Regulator 2 Potentiates Foxo1-mediated Transcription Through Its Deacetylase Activity." Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 27, 2004, pp. 10042-7.
Daitoku H, Hatta M, Matsuzaki H, et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004;101(27):10042-7.
Daitoku, H., Hatta, M., Matsuzaki, H., Aratani, S., Ohshima, T., Miyagishi, M., Nakajima, T., & Fukamizu, A. (2004). Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proceedings of the National Academy of Sciences of the United States of America, 101(27), 10042-7.
Daitoku H, et al. Silent Information Regulator 2 Potentiates Foxo1-mediated Transcription Through Its Deacetylase Activity. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7. PubMed PMID: 15220471.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. AU - Daitoku,Hiroaki, AU - Hatta,Mitsutoki, AU - Matsuzaki,Hitomi, AU - Aratani,Satoko, AU - Ohshima,Takayuki, AU - Miyagishi,Makoto, AU - Nakajima,Toshihiro, AU - Fukamizu,Akiyoshi, Y1 - 2004/06/25/ PY - 2004/6/29/pubmed PY - 2004/7/31/medline PY - 2004/6/29/entrez SP - 10042 EP - 7 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 101 IS - 27 N2 - Longevity regulatory genes include the Forkhead transcription factor FOXO and the NAD-dependent histone deacetylase silent information regulator 2 (Sir2). Genetic studies demonstrate that Sir2 acts to extend lifespan in Caenorhabditis elegans upstream of DAF-16, a member of the FOXO family, in the insulin-like signaling pathway. However, the molecular mechanisms underlying the requirement of DAF-16 activity in Sir2-mediated longevity remain unknown. Here we show that reversible acetylation of Foxo1 (also known as FKHR), the mouse DAF-16 ortholog, modulates its transactivation function. cAMP-response element-binding protein (CREB)-binding protein binds and acetylates Foxo1 at the K242, K245, and K262 residues, the modification of which is involved in the attenuation of Foxo1 as a transcription factor. Conversely, Sir2 binds and deacetylates Foxo1 at residues acetylated by cAMP-response element-binding protein-binding protein. Sir2 is recruited to insulin response sequence-containing promoter and increases the expression of manganese superoxide dismutase and p27(kip1) in a deacetylase-activity-dependent manner. Our findings establish Foxo1 as a direct and functional target for Sir2 in mammalian systems. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/15220471/Silent_information_regulator_2_potentiates_Foxo1_mediated_transcription_through_its_deacetylase_activity_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15220471 DB - PRIME DP - Unbound Medicine ER -