FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast

FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast

In our previous studies, we reported that SIRT1 prevents cellular senescence in human fibroblast, and that SIRT1-induced inhibition of cellular senescence is due to enhanced hTERT gene expression. In this study, we investigate the molecular mechanisms behind SIRT1-induced potentiation of hTERT trans...

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Main Authors: Yamashita, Shuntaro, Ogawa, Kaori, Ikei, Takahiro, Fujiki, Tsukasa, Katakura, Yoshinori
Format: Online
Language:English
Published: Public Library of Science 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085005/
id pubmed-4085005
recordtype oai_dc
spelling pubmed-40850052014-07-09 FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast Yamashita, Shuntaro Ogawa, Kaori Ikei, Takahiro Fujiki, Tsukasa Katakura, Yoshinori Research Article In our previous studies, we reported that SIRT1 prevents cellular senescence in human fibroblast, and that SIRT1-induced inhibition of cellular senescence is due to enhanced hTERT gene expression. In this study, we investigate the molecular mechanisms behind SIRT1-induced potentiation of hTERT transcription and show that FOXO3a functions downstream of SIRT1 and prevents the induction of cellular senescence by enhancing hTERT gene expression. Furthermore, we found that FOXO3a-induced potentiation of hTERT gene expression is regulated in a c-MYC/E-box dependent manner. In addition, we found that FOXO3a binds to the novel binding element in the c-MYC promoter, and this interaction activates the transcription of the c-MYC gene. The resulting increase in c-MYC leads to higher levels of c-MYC recruited to the hTERT promoter and, in turn, activates hTERT gene expression. Taken together, this pathway might constitute the molecular basis for the anti-senescence effects of SIRT1 and FOXO3a. Public Library of Science 2014-07-07 /pmc/articles/PMC4085005/ /pubmed/25000517 http://dx.doi.org/10.1371/journal.pone.0101864 Text en © 2014 Yamashita et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Yamashita, Shuntaro
Ogawa, Kaori
Ikei, Takahiro
Fujiki, Tsukasa
Katakura, Yoshinori
spellingShingle Yamashita, Shuntaro
Ogawa, Kaori
Ikei, Takahiro
Fujiki, Tsukasa
Katakura, Yoshinori
FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast
author_facet Yamashita, Shuntaro
Ogawa, Kaori
Ikei, Takahiro
Fujiki, Tsukasa
Katakura, Yoshinori
author_sort Yamashita, Shuntaro
title FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast
title_short FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast
title_full FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast
title_fullStr FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast
title_full_unstemmed FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast
title_sort foxo3a potentiates htert gene expression by activating c-myc and extends the replicative life-span of human fibroblast
description In our previous studies, we reported that SIRT1 prevents cellular senescence in human fibroblast, and that SIRT1-induced inhibition of cellular senescence is due to enhanced hTERT gene expression. In this study, we investigate the molecular mechanisms behind SIRT1-induced potentiation of hTERT transcription and show that FOXO3a functions downstream of SIRT1 and prevents the induction of cellular senescence by enhancing hTERT gene expression. Furthermore, we found that FOXO3a-induced potentiation of hTERT gene expression is regulated in a c-MYC/E-box dependent manner. In addition, we found that FOXO3a binds to the novel binding element in the c-MYC promoter, and this interaction activates the transcription of the c-MYC gene. The resulting increase in c-MYC leads to higher levels of c-MYC recruited to the hTERT promoter and, in turn, activates hTERT gene expression. Taken together, this pathway might constitute the molecular basis for the anti-senescence effects of SIRT1 and FOXO3a.
publisher Public Library of Science
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085005/
_version_ 1613109301593767936

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