The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor

Abstract

FoxO transcription factors play 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 transactivates the expression of FoxO3, one of the four mammalian FoxO genes, in response to DNA damaging agents in both mouse embryonic fibroblasts and in thymocytes. We show 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 may 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 play an important role during aging and cancer.

Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

“…ChIPs were performed as previously described. 52 Orthotopic transplantations and tumour watch. For longitudinal tumour growth and dissemination experiments, 10 000 mILC1 cells were transplanted in the fourth inguinal mouse mammary gland of Nude-recipient mice as described previously.…”

FOXO3a Is a Major Target of Inactivation by PI3K/AKT Signaling in Aggressive Neuroblastoma

“…FOXO1/3/ 4 have been identified as bona fide tumor suppressors when simultaneously knocked out in mice (7). Recently, FOXO3a knockout has been found to expand the tumor spectrum of p53 knockout mice (8). Human alveolar rhabdomyosarcoma have frequent translocations of FOXO1 to PAX3 or PAX7, whereas FOXO3a and FOXO4 are commonly fused to MLL in mixed lineage leukemia, creating oncogenes in both cases (9)(10)(11)(12).…”

Bien vieillir

“…Enfin, les facteurs de transcription FOXO peuvent être également régulés de façon transcriptionnelle. Par exemple, le stress cellulaire augmente l'expression de l'ARN messager de FOXO3, une des isoformes de FOXO chez les mammifères, et ce de manière dépendante du suppresseur de tumeur p53 [25]. Les facteurs de transcription FOXO jouent donc le rôle de rhéostat De façon remarquable, l'effet d'une mutation du récepteur de l'insuline sur le prolongement de la durée de vie ne se limite pas au ver C. elegans [2].…”

“…On peut donc faire l'hypothèse que les polymorphismes de FOXO3 liés à la longévité exceptionnelle pourraient influencer les niveaux d'expression du gène FOXO3. En accord avec cette hypothèse, les introns du gène FOXO3 contiennent de nombreux sites de liaisons pour d'autres facteurs de transcription, comme p53, connus comme régulateurs de l'expression du gène FOXO3 [25]. Il est possible que ces sites soient directement affectés par un polymorphisme.…”