title: The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor.
abstract: FoxO transcription factors have a conserved role in longevity, and act as tissue-specific tumor suppressors in mammals. Several nodes of interaction have been identified between FoxO transcription factors and p53, a major tumor suppressor in humans and mice. However, the extent and importance of the functional interaction between FoxO and p53 have not been fully explored. Here, we show that p53 regulates the expression of FoxO3, one of the four mammalian FoxO genes, in response to DNA damaging agents in both mouse embryonic fibroblasts and thymocytes. We find that p53 transactivates FoxO3 in cells by binding to a site in the second intron of the FoxO3 gene, a genomic region recently found to be associated with extreme longevity in humans. While FoxO3 is not necessary for p53-dependent cell cycle arrest, FoxO3 appears to modulate p53-dependent apoptosis. We also find that FoxO3 loss does not interact with p53 loss for tumor development in vivo, although the tumor spectrum of p53-deficient mice appears to be affected by FoxO3 loss. Our findings indicate that FoxO3 is a p53 target gene, and suggest that FoxO3 and p53 are part of a regulatory transcriptional network that may have an important role during aging and cancer.
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Renault
authors.forename: P U
authors.initials: PU
authors.lastname: Thekkat
authors.forename: K L
authors.initials: KL
authors.lastname: Hoang
authors.forename: J L
authors.initials: JL
authors.lastname: White
authors.forename: C A
authors.initials: CA
authors.lastname: Brady
authors.forename: D
authors.initials: D
authors.lastname: Kenzelmann Broz
authors.forename: O S
authors.initials: OS
authors.lastname: Venturelli
authors.forename: T M
authors.initials: TM
authors.lastname: Johnson
authors.forename: P R
authors.initials: PR
authors.lastname: Oskoui
authors.forename: Z
authors.initials: Z
authors.lastname: Xuan
authors.forename: E E
authors.initials: EE
authors.lastname: Santo
authors.forename: M Q
authors.initials: MQ
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Vogel
authors.forename: L D
authors.initials: LD
authors.lastname: Attardi
authors.forename: A
authors.initials: A
authors.lastname: Brunet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage; D017931:DNA Primers; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D007093:Imidazoles / Q000494:pharmacology; D008136:Longevity / Q000235:genetics*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D007093:Imidazoles; D010879:Piperazines; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C482203:nutlin 1