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The Pro-Longevity Gene Foxo3 Is a Direct Target of the P53 Tumor Suppressor

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The Pro-Longevity Gene Foxo3 Is a Direct Target of the P53 Tumor Suppressor Oncogene (2011) 1–15 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor VM Renault1, PU Thekkat1, KL Hoang1, JL White1, CA Brady2,3, D Kenzelmann Broz2, OS Venturelli1, TM Johnson2,3, PR Oskoui1, Z Xuan4, EE Santo5, MQ Zhang4,6, H Vogel7, LD Attardi1,2,3 and A Brunet1,3 1Department of Genetics, Stanford University, Stanford, CA, USA; 2Department of Radiation Oncology, Stanford University, Stanford, CA, USA; 3Cancer Biology Graduate Program, Stanford University, Stanford, CA, USA; 4Department of Molecular and Cell Biology, Center for Systems Biology, University of Texas at Dallas, Richardson, TX, USA; 5Department of Human Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 6MOE Key Laboratory of Bioinformatics & Bioinformatics Division, TNLIS, Tsinghua University, Beijing, China and 7Department of Pathology, Stanford University, Stanford, CA, USA FoxO transcription factors have a conserved role in 2005). The connection between aging and cancer raises longevity, and act as tissue-specific tumor suppressors the possibility that genes that extend lifespan may also in mammals. Several nodes of interaction have been be part of a molecular network that suppresses identified between FoxO transcription factors and p53, a tumorigenesis. An example for such genes is provided major tumor suppressor in humans and mice. However, by FoxO transcription factors, which have a pivotal role the extent and importance of the functional interaction at the interface between longevity and tumor suppres- between FoxO and p53 have not been fully explored. sion (Greer and Brunet, 2005). In invertebrates, FoxO Here, we show that p53 regulates the expression of factors are necessary to extend lifespan downstream of FoxO3, one of the four mammalian FoxO genes, in the insulin pathway (Kenyon, 2005). In mammals, the response to DNA damaging agents in both mouse four FoxO family members (FoxO1, FoxO3, FoxO4 embryonic fibroblasts and thymocytes. We find that p53 and FoxO6) also function downstream of the insulin- transactivates FoxO3 in cells by binding to a site in the signaling pathway (Greer and Brunet, 2005). Single- second intron of the FoxO3 gene, a genomic region nucleotide polymorphisms in the FoxO3 gene have recently found to be associated with extreme longevity in recently been found to be associated with extreme humans. While FoxO3 is not necessary for p53-dependent longevity in humans, suggesting a conserved function cell cycle arrest, FoxO3 appears to modulate p53- for FoxO3 in longevity (Willcox et al., 2008; Anselmi dependent apoptosis. We also find that FoxO3 loss does et al., 2009; Flachsbart et al., 2009; Pawlikowska et al., not interact with p53 loss for tumor development in vivo, 2009). Interestingly, the FoxO family has also been although the tumor spectrum of p53-deficient mice appears found to act as a lineage-specific tumor suppressor in to be affected by FoxO3 loss. Our findings indicate that mammals (Paik et al., 2007). Combined somatic deletion FoxO3 is a p53 target gene, and suggest that FoxO3 and of FoxO1, FoxO3 and FoxO4 in mice leads to the p53 are part of a regulatory transcriptional network that development of tumors, particularly thymic lymphomas may have an important role during aging and cancer. and hemangiomas (Paik et al., 2007). FoxO3À/À mice can Oncogene advance online publication, 21 March 2011; also develop cancer, but at a lesser frequency and later doi:10.1038/onc.2011.35 in life than FoxO1/FoxO3/FoxO4 compound mutant mice (Paik et al., 2007). In humans, FoxO3 inactivation Keywords: FoxO transcription factors; p53; tumor is correlated with poor prognosis of breast cancers (Hu suppression; cancer; aging; longevity et al., 2004). Conversely, ectopic expression of FoxO3 in human cells is sufficient to delay tumor development in xenograft models (Hu et al., 2004; Seoane et al., 2004). Thus, FoxO3 may be an important part of a regulatory Introduction network that controls both aging and cancer. FoxO3 is a potent transcriptional activator that Aging and cancer are intimately linked. Many cancers triggers the expression of a program of genes involved have a striking age-dependent onset. Interventions that in cell cycle arrest, DNA repair, hypoxia response and extend lifespan, such as dietary restriction, decrease the apoptosis (Brunet et al., 1999; Medema et al., 2000; incidence of tumors (Hursting et al., 2003; Masoro, Tran et al., 2002; Seoane et al., 2004; You et al., 2006a; Bakker et al., 2007; Tothova et al., 2007; Paik et al., 2009; Renault et al., 2009). FoxO3 transcriptional Correspondence: Dr A Brunet, Department of Genetics, Stanford activity is inhibited in response to insulin and growth University, 300 Pasteur Drive, Alway M336, Stanford, CA 94305, USA. factors through phosphorylation-dependent nuclear E-mail: [email protected] export (Brunet et al., 1999, 2001, 2002). Although the Received 20 December 2010; accepted 18 January 2011 regulation of FoxO3 activity by post-translational FoxO3 is a direct target of p53 VM Renault et al 2 modifications, such as phosphorylation, has been well interaction between FoxO3 and p53 loss in cancer studied (Van Der Heide et al., 2004; Calnan and Brunet, progression in the absence of oncogenic stimulation 2008), the molecular mechanisms that regulate the has never been tested. expression of the FoxO3 gene remain mostly unclear. Here, we explore the connections between FoxO3, a Given the connection between aging and cancer, it is ubiquitously expressed FoxO family member, and p53 in interesting to note that there are a number of parallels cells and in mice. We find that p53 acts as a direct between FoxO3 and the tumor suppressor protein p53. upstream transcriptional activator of the FoxO3 gene in Like FoxO3, p53 induces cell cycle arrest, apoptosis and response to DNA damage in mouse embryonic fibro- DNA repair (Vousden and Lu, 2002). Several FoxO3 blasts (MEFs) and in lymphocytes. We show that p53 target genes, such as Gadd45, Wip1, p21Cip1, Puma and regulates the transcription of the FoxO3 gene by binding Sestrin1/PA26, are also regulated by p53 (Kastan et al., to a site in the second intron of the FoxO3 gene. 1992; el-Deiry et al., 1993; Fiscella et al., 1997; Velasco- Although FoxO3 is not necessary for p53-dependent Miguel et al., 1999; Nakano and Vousden, 2001; Yu cell cycle arrest, FoxO3 appears to have a role in et al., 2001). FoxO3 and p53 are extensively modified in p53-dependent apoptosis. While FoxO3 loss does not response to stress stimuli, through phosphorylation synergize with p53 loss for tumor development in vivo, and acetylation (Calnan and Brunet, 2008; Vousden tumor spectrum in p53-deficient mice appears to be and Prives, 2009), and both p53 and FoxO3 bind to and affected by the loss of one or both FoxO3 alleles. These are deacetylated by the Sirt1 deacetylase (Luo et al., results reveal a regulatory mechanism linking FoxO3 2001; Vaziri et al., 2001; Brunet et al., 2004; Motta et al., and p53, two critical molecules involved in the control of 2004). These extensive similarities between FoxO3 and longevity and tumor suppression. p53 suggest that both transcription factors may be part of a common regulatory complex. A number of direct and indirect links between FoxO3 and p53 have already been uncovered. First, FoxO3 Results directly binds to p53, at least in the context of overexpression (Nemoto et al., 2004; Wang et al., DNA damage and nutlin treatment increase FoxO3 2008). Second, FoxO3 leads to stabilization of the p53 protein levels in a p53-dependent manner in fibroblasts protein and activation of p53-dependent apoptosis To test whether p53 regulates FoxO3 expression in (You et al., 2006b). FoxO3 also upregulates p19ARF,a mammalian cells, we compared FoxO3 protein levels in þ / þ À/À positive upstream regulator of p53 (Bouchard et al., p53 and p53 primary MEFs in the absence or 2007). Conversely, p53 has been reported to inhibit presence of doxorubicin, a DNA damaging agent that FoxO3 function indirectly by upregulating serum- and activates endogenous p53. We found that doxorubicin þ / þ glucocorticoid-induced protein kinase (SGK), thereby treatment increased FoxO3 protein expression in p53 MEFs, but not in p53À/À MEFs (Figure 1a). Changes in resulting in the phosphorylation of FoxO3 and its Cip1 sequestration in the cytoplasm (You et al., 2004). In FoxO3 protein levels were similar to those of p21 ,a addition, p53 has been found to inhibit FoxO3 well-known target of p53 (Figure 1a). To activate p53 transcriptional activity under conditions of oxidative in a more specific manner, we used nutlin, a chemical stress (Miyaguchi et al., 2009) and to induce FoxO3 compound that inhibits binding of p53 to Mdm2, a degradation (Fu et al., 2009). Whether FoxO3 and p53 intersect in other ways, for example by regulating each other’s transcription, remains largely unknown. p53+/+ p53-/- p53+/+ p53-/- p53 is a potent tumor suppressor in humans, as Dox: - + - + Nutlin Dox Nutlin Dox underscored by the fact that nearly all human tumors hr: 0 4848 04848 have mutations or deletions in the p53 gene itself or in FoxO3 the p53 pathway (Vogelstein et al., 2000). Mutations in FoxO3 p53 have been linked to poor prognosis in a variety of p21Cip1 human cancers, including lung (Quinlan et al., 1992), p53 breast (Deng et al., 1994) and gastric cancers (Scott p53 et al., 1991), as well as lymphomas (Gaidano et al., 1991; β-actin Lo Coco et al., 1993). Consistent with the prevalence of p53 loss in human tumors, p53À/À mice are highly prone Mek1 to cancer early in life (Donehower et al., 1992; Harvey et al., 1993a, 1993b; Jacks et al., 1994). p53 þ /À mice also Figure 1 Doxorubicin and nutlin elicit an increase in FoxO3 protein develop tumors with high frequency (Donehower et al., expression that is p53-dependent in MEFs.
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