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Methylation by Set9 modulates FoxO3 stability and transcriptional activity

The FoxO family of transcription factors plays an important role in longevity and tumor suppression by regulating the expression of a wide range of target genes. FoxO3 has recently been found to be associated with extreme longevity in humans and to regulate the homeostasis of adult stem cell pools i...

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Autores principales: Calnan, Daniel R., Webb, Ashley E., White, Jamie L., Stowe, Timothy R., Goswami, Tapasree, Shi, Xiaobing, Espejo, Alexsandra, Bedford, Mark T., Gozani, Or, Gygi, Steven P., Brunet, Anne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433933/
https://www.ncbi.nlm.nih.gov/pubmed/22820736
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author Calnan, Daniel R.
Webb, Ashley E.
White, Jamie L.
Stowe, Timothy R.
Goswami, Tapasree
Shi, Xiaobing
Espejo, Alexsandra
Bedford, Mark T.
Gozani, Or
Gygi, Steven P.
Brunet, Anne
author_facet Calnan, Daniel R.
Webb, Ashley E.
White, Jamie L.
Stowe, Timothy R.
Goswami, Tapasree
Shi, Xiaobing
Espejo, Alexsandra
Bedford, Mark T.
Gozani, Or
Gygi, Steven P.
Brunet, Anne
author_sort Calnan, Daniel R.
collection PubMed
description The FoxO family of transcription factors plays an important role in longevity and tumor suppression by regulating the expression of a wide range of target genes. FoxO3 has recently been found to be associated with extreme longevity in humans and to regulate the homeostasis of adult stem cell pools in mammals, which may contribute to longevity. The activity of FoxO3 is controlled by a variety of post-translational modifications that have been proposed to form a ‘code’ affecting FoxO3 subcellular localization, DNA binding ability, protein-protein interactions and protein stability. Lysine methylation is a crucial post-translational modification on histones that regulates chromatin accessibility and is a key part of the ‘histone code’. However, whether lysine methylation plays a role in modulating FoxO3 activity has never been examined. Here we show that the methyltransferase Set9 directly methylates FoxO3 in vitro and in cells. Using a combination of tandem mass spectrometry and methyl-specific antibodies, we find that Set9 methylates FoxO3 at a single residue, lysine 271, a site previously known to be deacetylated by Sirt1. Methylation of FoxO3 by Set9 decreases FoxO3 protein stability, while moderately increasing FoxO3 transcriptional activity. The modulation of FoxO3 stability and activity by methylation may be critical for fine-tuning cellular responses to stress stimuli, which may in turn affect FoxO3's ability to promote tumor suppression and longevity.
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spelling pubmed-34339332012-09-11 Methylation by Set9 modulates FoxO3 stability and transcriptional activity Calnan, Daniel R. Webb, Ashley E. White, Jamie L. Stowe, Timothy R. Goswami, Tapasree Shi, Xiaobing Espejo, Alexsandra Bedford, Mark T. Gozani, Or Gygi, Steven P. Brunet, Anne Aging (Albany NY) Research Paper The FoxO family of transcription factors plays an important role in longevity and tumor suppression by regulating the expression of a wide range of target genes. FoxO3 has recently been found to be associated with extreme longevity in humans and to regulate the homeostasis of adult stem cell pools in mammals, which may contribute to longevity. The activity of FoxO3 is controlled by a variety of post-translational modifications that have been proposed to form a ‘code’ affecting FoxO3 subcellular localization, DNA binding ability, protein-protein interactions and protein stability. Lysine methylation is a crucial post-translational modification on histones that regulates chromatin accessibility and is a key part of the ‘histone code’. However, whether lysine methylation plays a role in modulating FoxO3 activity has never been examined. Here we show that the methyltransferase Set9 directly methylates FoxO3 in vitro and in cells. Using a combination of tandem mass spectrometry and methyl-specific antibodies, we find that Set9 methylates FoxO3 at a single residue, lysine 271, a site previously known to be deacetylated by Sirt1. Methylation of FoxO3 by Set9 decreases FoxO3 protein stability, while moderately increasing FoxO3 transcriptional activity. The modulation of FoxO3 stability and activity by methylation may be critical for fine-tuning cellular responses to stress stimuli, which may in turn affect FoxO3's ability to promote tumor suppression and longevity. Impact Journals LLC 2012-07-21 /pmc/articles/PMC3433933/ /pubmed/22820736 Text en Copyright: © 2012 Calnan et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
spellingShingle Research Paper
Calnan, Daniel R.
Webb, Ashley E.
White, Jamie L.
Stowe, Timothy R.
Goswami, Tapasree
Shi, Xiaobing
Espejo, Alexsandra
Bedford, Mark T.
Gozani, Or
Gygi, Steven P.
Brunet, Anne
Methylation by Set9 modulates FoxO3 stability and transcriptional activity
title Methylation by Set9 modulates FoxO3 stability and transcriptional activity
title_full Methylation by Set9 modulates FoxO3 stability and transcriptional activity
title_fullStr Methylation by Set9 modulates FoxO3 stability and transcriptional activity
title_full_unstemmed Methylation by Set9 modulates FoxO3 stability and transcriptional activity
title_short Methylation by Set9 modulates FoxO3 stability and transcriptional activity
title_sort methylation by set9 modulates foxo3 stability and transcriptional activity
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433933/
https://www.ncbi.nlm.nih.gov/pubmed/22820736
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