Regulation of the FOXO transcription factor network
The FOXO family of transcription factors promotes longevity downstream of the insulin signaling pathway in a variety of organisms. Single nucleotide polymorphisms in FOXO3, one of the four FOXO isoforms in humans, have recently been associated with exceptional longevity in five independent centenarian studies, suggesting that FOXO3 is a key determinant of human longevity. However, the mechanisms of action of the FOXO family in mammalian cells are not completely understood.
We have played a major role in determining the molecular mechanisms that regulate FOXO3 expression, localization, and activity, which is a crucial step in understanding how this family of transcription factors regulates organismal lifespan. FOXO3 transcriptional activity is regulated in response to insulin/growth factors and to oxidative stress stimuli, by phosphorylation and acetylation (Brunet et al, Cell, 1999; Brunet et al, Science, 2004). Data from our lab also revealed that FOXO3 activity is also controlled by low nutrient levels via AMP-dependent protein kinase (AMPK). AMPK phosphorylation of FOXO3 induces changes in the expression of specific FOXO3 target genes, including energy metabolism and stress resistance genes (Greer et al, J. Biol Chem, 2007). We proposed that specific combinations of post-translational modifications serve as a ‘molecular code’ to sense external stimuli and recruit FOXO3 to specific regions of the genome (Calnan et al, Oncogene, 2008). Our studies were the first to show that FOXO3 integrates information about growth factor availability, cellular nutrient levels, and oxidative stress to regulate specific programs of genes involved in adaptive cellular responses, such as stress resistance, that are likely to be crucial for longevity.
While the regulation of FOXO3 activity has been extensively studied, the control of FOXO3 gene expression is largely unexplored. The regulation of FOXO3 expression is likely to play a crucial role to determine the longevity and aging rate of an individual. We recently showed that p53 regulates the expression of FOXO3 in response to DNA damaging agents in both mouse embryonic fibroblasts and thymocytes (Renault et al. Oncogene 2011). We found 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. FoxO3 appears to modulate p53-dependent apoptosis. 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.
Brunet A, Bonni A, Zigmond, M, Lin MZ, Juo P, Hu L, Anderson M, Arden K, Blenis J and Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell, 96: 857-868. Abstract PDF
Brunet A, Sweeney L, Sturgill F, Chua K, Greer P, Lin Y, Tran H, Ross S, Mostoslavsky R, Cohen H, Hu L, Cheng H, Jedrychowsky M, Gygi S, Sinclair D, Alt F and Greenberg ME (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 303: 2011-2015. Abstract PDF
Greer EL, Oskoui PR, Banko, MR, Maniar JM, Gygi MP, Gygi SP and Brunet A (2007) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. Journal of Biological Chemistry, 282: 30107-30119. Abstract PDF
Renault VM, Thekkat PU, Hoang KL, White JL, Brady CA, Kenzelmann Broz D, Venturelli OS, Johnson TM, Oskoui PR, Xuan Z, Santo EE, Zhang MQ, Vogel H, Attardi LD and Brunet A (2011) The pro-longevity gene FoxO3 is a direct target gene of the p53 tumor suppressor. Oncogene, 30: 3207-3221. Abstract PDF