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

Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Oncogene (Impact Factor: 8.46). 03/2011; 30(29):3207-21. DOI: 10.1038/onc.2011.35
Source: PubMed


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.

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    • "Cell cycle arrest mediated by FOXO proteins in response to oxidative stress is an important DDR mechanism (Furukawa-Hibi et al., 2002). In addition, transactivational control of Foxo3a expression by p53 has been reported (Renault et al., 2011). Loss of Foxo3a in HSCs leads to poor DDR, increase in intracellular ROS levels and exit from quiescence (Miyamoto et al., 2007). "
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    • "Consistent with our report, other studies found that FOXO3a was a p53 target gene and that transcriptional activity of FOXO3a was regulated by p53, while the latter was not affected by FOXO3a (33,34). The p53 and FOXO3a formed part of regulation transcriptional network to control cancer cell growth and apoptosis (33,34). In addition, curcumin induced expression of p53 or/and FOXO3a in inhibition of cancer cell growth and other functions have been shown in other cell systems (27,28,35,36). "
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