title: FOXO3a potentiates hTERT gene expression by activating c-MYC and extends the replicative life-span of human fibroblast.
abstract: 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.
authors.affiliation: Graduate School of Systems Life Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ikei
authors.affiliation: Faculty of Agriculture, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Fujiki
authors.affiliation: Graduate School of Systems Life Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan; Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan; Faculty of Agriculture, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katakura
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D016922:Cellular Senescence; D005347:Fibroblasts / Q000166:cytology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D019098:Telomerase / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; C509186:TERT protein, human; D019098:Telomerase; C447939:SIRT1 protein, human; D056564:Sirtuin 1