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.
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Acknowledgements
We thank Dr Ron DePinho for his generous gift of the FoxO3−/− mice. We thank Julien Sage for critical discussion, reading of the manuscript, help with tumor analysis and for taking the pictures for Figure 8d. We thank Jamie Brett for reading the manuscript. We thank Pauline Chu (Comparative Medicine Department, Stanford Medical School) for her help in processing the histopathology samples. We thank Dan Calnan for participating in earlier aspects of this work. This work was supported by NIH R01 AG026648 and a McCormick Award for Women in Science (AB). ZX, EES and MQZ were supported partly by NIH R01 HG001696. VMR received support from the Dean's Fellowship at Stanford University.
Author contributions: VMR designed, performed and analyzed the lifespan and tumor spectrum of compound FoxO3/p53 mice (Figure 8). PUT completed Figure 1b, Figure 5b, Figure 6b, Figure 6e, Figure 7a and helped with Figure 2 and Figure 6d. KLH completed Figure 5d, Figure 5e, Figure 6a, Figure 6b and Figure 6c. JLW completed Figure 2, Figure 6d, and helped with Figure 3 and Figure 7b. CAB completed Figure 3 and Figure 7b. DKB completed Figure 5c. OSV initiated this project as her Honors Thesis and completed Figure 1a. TMJ completed Figure 4b. PRO completed Figure 6f. ZX and EES identified p53 binding sites in FoxO3 regulatory regions (Figure 5a) under the supervision of MQZ. HV performed the tumor identification (Figure 8b). LDA supervised CAB, DKB and TMJ, and provided ideas. AB supervised VMR, PUT, KLH, JLW, OSV and PRO. The manuscript was written by AB, VMR and OSV, with input from LDA.
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Renault, V., Thekkat, P., Hoang, K. et al. The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor. Oncogene 30, 3207–3221 (2011). https://doi.org/10.1038/onc.2011.35
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