The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor
Open Access
- 21 March 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 30 (29), 3207-3221
- https://doi.org/10.1038/onc.2011.35
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.This publication has 96 references indexed in Scilit:
- Drosophila foxo acts in males to cause sexual-dimorphism in tissue-specific p53 life span effectsExperimental Gerontology, 2010
- FoxO3 Regulates Neural Stem Cell HomeostasisCell Stem Cell, 2009
- FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell HomeostasisCell Stem Cell, 2009
- Knockin mice expressing a chimeric p53 protein reveal mechanistic differences in how p53 triggers apoptosis and senescenceProceedings of the National Academy of Sciences of the United States of America, 2008
- An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegansCurrent Biology, 2007
- FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell HomeostasisCell, 2007
- Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3aProceedings of the National Academy of Sciences of the United States of America, 2006
- Overview of caloric restriction and ageingMechanisms of Ageing and Development, 2005
- The Plasticity of Aging: Insights from Long-Lived MutantsCell, 2005
- Live or let die: the cell's response to p53Nature Reviews Cancer, 2002