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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Bibliographic Details
Published in:PloS one 2014-07, Vol.9 (7), p.e101864-e101864
Main Authors: Yamashita, Shuntaro, Ogawa, Kaori, Ikei, Takahiro, Fujiki, Tsukasa, Katakura, Yoshinori
Format: Article
Language:English
Subjects:
Adenoviruses
Base Sequence
Biology and Life Sciences
c-Myc protein
Cancer
Cell Line
Cellular Senescence
Fibroblasts
Fibroblasts - cytology
Forkhead Box Protein O3
Forkhead Transcription Factors - metabolism
FOXO3 protein
Gene expression
Gene Expression Regulation, Enzymologic
Genes
Humans
Infections
Kinases
Life sciences
Metabolism
Molecular modelling
Myc protein
Potentiation
Promoter Regions, Genetic - genetics
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Senescence
SIRT1 protein
Sirtuin 1 - metabolism
Telomerase
Telomerase - genetics
Telomerase reverse transcriptase
Transcription
Transcription factors
Transcription, Genetic
Tumorigenesis
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0101864