FOXOs: Signalling integrators for homeostasis maintenance

Nature Reviews Molecular Cell Biology

Volumn 14, Issue 2, 2013, Pages 83-97

  Eijkelenboom, Astrid ^a   Burgering, Boudewijn M T ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MICRORNA; TRANSCRIPTION FACTOR FKHR; TRANSCRIPTION FACTOR FKHRL1; TRANSCRIPTION FACTOR FOXO;

APOPTOSIS; CELL CYCLE; CELL CYCLE ARREST; CELL FATE; CELL SURVIVAL; DIABETES MELLITUS; GENOTOXICITY; HOMEOSTASIS; HUMAN; IMMUNE SYSTEM; METABOLIC STRESS; METABOLISM; NEOPLASM; NONHUMAN; OXIDATION; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; STEM CELL; STRESS; TRANSLATION REGULATION; UPREGULATION;

FORKHEAD TRANSCRIPTION FACTORS; HOMEOSTASIS; HUMANS; MODELS, BIOLOGICAL; OXIDATIVE STRESS; PROTEIN PROCESSING, POST-TRANSLATIONAL; SIGNAL TRANSDUCTION; STRESS, PHYSIOLOGICAL; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84872899284     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm3507     Document Type: Review

References (160)

1. van der Horst, A. & Burgering, B. M. Stressing the role of FoxO proteins in lifespan and disease. Nature Rev. Mol. Cell Biol. 8, 440-450 (2007).
2. Dansen, T. B. & Burgering, B. M. Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol. 18, 421-429 (2008).
3. Kenyon, C. J. The genetics of ageing. Nature 464, 504-512 (2010).
4. Paik, J. H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309-323 (2007).
5. Bridge, D. et al. FoxO and stress responses in the cnidarian Hydra vulgaris. PLoS ONE 5, e11686 (2010).
6. van den Berg, M. C. & Burgering, B. M. Integrating opposing signals toward forkhead box O. Antioxid. Redox Signal. 14, 607-621 (2011).
7. Calnan, D. R. & Brunet, A. The FoxO code. Oncogene 27, 2276-2288 (2008).
8. Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Rev. Mol. Cell Biol. 13, 251-262 (2012).
9. Greer, E. L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107-30119 (2007).
10. Greer, E. L. et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr. Biol. 17, 1646-1656 (2007).
11. Wang, F. et al. Structures of KIX domain of CBP in complex with two FOXO3a transactivation domains reveal promiscuity and plasticity in coactivator recruitment. Proc. Natl Acad. Sci. USA 109, 6078-6083 (2012).
12. Huang, H., Regan, K. M., Lou, Z., Chen, J. & Tindall, D. J. CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 314, 294-297 (2006).
13. Yuan, Z. et al. Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science 319, 1665-1668 (2008).
14. Liu, P., Kao, T. P. & Huang, H. CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene 27, 4733-4744 (2008).
15. Yata, K. & Esashi, F. Dual role of CDKs in DNA repair: to be, or not to be. DNA Repair (Amst.) 8, 6-18 (2009).
16. Matsuoka, S. et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160-1166 (2007).
17. Tsai, W. B., Chung, Y. M., Takahashi, Y., Xu, Z. & Hu, M. C. Functional interaction between FOXO3a and ATM regulates DNA damage response. Nature Cell Biol. 10, 460-467 (2008).
18. Yalcin, S. et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J. Biol. Chem. 283, 25692-25705 (2008).
19. Kress, T. R. et al. The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Mol. Cell 41, 445-457 (2011).
20. Nakae, J. et al. Novel repressor regulates insulin sensitivity through interaction with Foxo1. EMBO J. 31, 2275-2295 (2012).
21. Yang, Y., Hou, H., Haller, E. M., Nicosia, S. V. & Bai, W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J. 24, 1021-1032 (2005).
22. Wang, Y. C. & Li, C. Evolutionarily conserved protein arginine methyltransferases in non-mammalian animal systems. FEBS J. 279, 932-945 (2012).
23. Yamagata, K. et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol. Cell 32, 221-231 (2008).
24. Takahashi, Y. et al. Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16. Cell Metab. 13, 505-516 (2011).
25. Xie, Q. et al. Lysine methylation of FOXO3 regulates oxidative stress-induced neuronal cell death. EMBO Rep. 13, 371-377 (2012).
26. Housley, M. P. et al. O-GlcNAc regulates FoxO activation in response to glucose. J. Biol. Chem. 283, 16283-16292 (2008).
27. Kuo, M., Zilberfarb, V., Gangneux, N., Christeff, N. & Issad, T. O-GlcNAc modification of FoxO1 increases its transcriptional activity: a role in the glucotoxicity phenomenon? Biochimie 90, 679-685 (2008).
28. Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction. Nature 423, 550-555 (2003).
29. Housley, M. P. et al. A PGC-1α-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose. J. Biol. Chem. 284, 5148-5157 (2009).
30. Hanover, J. A., Krause, M. W. & Love, D. C. Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nature Rev. Mol. Cell Biol. 13, 312-321 (2012).
31. Dansen, T. B. et al. Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nature Chem. Biol. 5, 664-672 (2009).
32. Szypowska, A. A. & Burgering, B. M. The peroxide dilemma: opposing and mediating insulin action. Antioxid. Redox Signal. 15, 219-232 (2011).
33. Dyson, H. J. & Wright, P. E. Intrinsically unstructured proteins and their functions. Nature Rev. Mol. Cell Biol. 6, 197-208 (2005).
34. Lacy, E. R. et al. p27 binds cyclin-CDK complexes through a sequential mechanism involving binding-induced protein folding. Nature Struct. Mol. Biol. 11, 358-364 (2004).
35. Wang, Y. et al. Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21. Nature Chem. Biol. 7, 214-221 (2011).
36. Mittag, T. et al. Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor. Proc. Natl Acad. Sci. USA 105, 17772-17777 (2008).
37. Rena, G., Bain, J., Elliott, M. & Cohen, P. D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep. 5, 60-65 (2004).
38. Woods, Y. L. et al. The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem. J. 355, 597-607 (2001).
39. Giannakou, M. E. & Partridge, L. The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol. 14, 408-412 (2004).
40. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-2015 (2004).
41. Banks, A. S. et al. Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice. Cell Metab. 14, 587-597 (2011).
42. van der Horst, A. et al. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature Cell Biol. 8, 1064-1073 (2006).
43. Oshikawa, K., Matsumoto, M., Oyamada, K. & Nakayama, K. I. Proteome-wide identification of ubiquitylation sites by conjugation of engineered lysine-less ubiquitin. J. Proteome Res. 11, 796-807 (2012).
44. Asada, S. et al. Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell. Signal. 19, 519-527 (2007).
45. Guttilla, I. K. & White, B. A. Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. J. Biol. Chem. 284, 23204-23216 (2009).
46. Myatt, S. S. et al. Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res. 70, 367-377 (2010).
47. Hasseine, L. K. et al. miR-139 impacts FoxO1 action by decreasing FoxO1 protein in mouse hepatocytes. Biochem. Biophys. Res. Commun. 390, 1278-1282 (2009).
48. Small, E. M. et al. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc. Natl Acad. Sci. USA 107, 4218-4223 (2010).
49. Yamamoto, M. et al. miR-155, a modulator of FOXO3a protein expression, is underexpressed and cannot be upregulated by stimulation of HOZOT, a line of multifunctional treg. PLoS ONE 6, e16841 (2011).
50. Kong, W. et al. MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. J. Biol. Chem. 285, 17869-17879 (2010).
51. Liu, X. et al. microRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4. Carcinogenesis 32, 1798-1805 (2011).
52. Wang, K. & Li, P. F. Foxo3a regulates apoptosis by negatively targeting miR-21. J. Biol. Chem. 285, 16958-16966 (2010).
53. Gan, B. et al. FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell 18, 472-484 (2010).
54. Brett, J. O., Renault, V. M., Rafalski, V. A., Webb, A. E. & Brunet, A. The microRNA cluster miR-106b~25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiation. Aging (Albany NY) 3, 108-124 (2011).
55. Perl, A. Emerging new pathways of pathogenesis and targets for treatment in systemic lupus erythematosus and Sjogren's syndrome. Curr. Opin. Rheumatol. 21, 443-447 (2009).
56. Dai, R. et al. Identification of a common lupus disease-associated microRNA expression pattern in three different murine models of lupus. PLoS ONE 5, e14302 (2010).
57. +-dependent histone deacetylase SIRT1. J. Biol. Chem. 282, 6823-6832 (2007).
58. Mihaylova, M. M. et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145, 607-621 (2011).
59. Wang, B. et al. A hormone-dependent module regulating energy balance. Cell 145, 596-606 (2011).
60. Kitamura, Y. I. et al. FoxO1 protects against pancreatic β-cell failure through NeuroD and MafA induction. Cell Metab. 2, 153-163 (2005).
61. Zhong, S., Salomoni, P. & Pandolfi, P. P. The transcriptional role of PML and the nuclear body. Nature Cell Biol. 2, e85-e90 (2000).
62. Brenkman, A. B., de Keizer, P. L., van den Broek, N. J., Jochemsen, A. G. & Burgering, B. M. Mdm2 induces mono-ubiquitination of FOXO4. PLoS ONE 3, e2819 (2008).
63. Yang, J. Y. et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nature Cell Biol. 10, 138-148 (2008).
64. Fu, W. et al. MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. J. Biol. Chem. 284, 13987-14000 (2009).
65. Ashcroft, M. et al. Phosphorylation of HDM2 by Akt. Oncogene 21, 1955-1962 (2002).
66. Mayo, L. D. & Donner, D. B. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. USA 98, 11598-11603 (2001).
67. Zhou, B. P. et al. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nature Cell Biol. 3, 973-982 (2001).
68. ARF stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc. Natl Acad. Sci. USA 96, 6937-6941 (1999).
69. Bernardi, R. et al. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nature Cell Biol. 6, 665-672 (2004).
70. Kurki, S., Latonen, L. & Laiho, M. Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization. J. Cell Sci. 11 6, 3917-3925 (2003).
71. Jackson, M. W. et al. Hdm2 nuclear export, regulated by insulin-like growth factor-I/MAPK/p90Rsk signaling, mediates the transformation of human cells. J. Biol. Chem. 281, 16814-16820 (2006).
72. Wagner, S. A. et al. A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol. Cell. Proteomics 10, M111.013284 (2011).
73. Aoki, M., Jiang, H. & Vogt, P. K. Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Proc. Natl Acad. Sci. USA 101, 13613-13617 (2004).
74. Meier, R., Alessi, D. R., Cron, P., Andjelkovic, M. & Hemmings, B. A. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bβ. J. Biol. Chem. 272, 30491-30497 (1997).
75. Brownawell, A. M., Kops, G. J., Macara, I. G. & Burgering, B. M. Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX. Mol. Cell. Biol. 21, 3534-3546 (2001).
76. Brunet, A. et al. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J. Cell Biol. 156, 817-828 (2002).
77. Sundaresan, N. R. et al. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci. Signal. 4, ra46 (2011).
78. Yang, W. L. et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325, 1134-1138 (2009).
79. Chan, C. H. et al. The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 149, 1098-1111 (2012).
80. Essers, M. A. et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J. 23, 4802-4812 (2004).
81. Wu, X. et al. Rac1 activation controls nuclear localization of β-catenin during canonical Wnt signaling. Cell 133, 340-353 (2008).
82. Mizukami, Y., Yoshioka, K., Morimoto, S. & Yoshida, K. A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion. J. Biol. Chem. 272, 16657-16662 (1997).
83. Lin, K., Hsin, H., Libina, N. & Kenyon, C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nature Genet. 28, 139-145 (2001).
84. Furuyama, T., Nakazawa, T., Nakano, I. & Mori, N. Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem. J. 349, 629-634 (2000).
85. Ramaswamy, S., Nakamura, N., Sansal, I., Bergeron, L. & Sellers, W. R. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell 2, 81-91 (2002).
86. Barr, F. G. Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. Oncogene 20, 5736-5746 (2001).
87. Burgering, B. M. & Medema, R. H. Decisions on life and death: FOXO forkhead transcription factors are in command when PKB/Akt is off duty. J. Leukoc. Biol. 73, 689-701 (2003).
88. Lalmansingh, A. S., Karmakar, S., Jin, Y. & Nagaich, A. K. Multiple modes of chromatin remodeling by forkhead box proteins. Biochim. Biophys. Acta 1819, 707-715 (2012).
89. Hatta, M. & Cirillo, L. A. Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J. Biol. Chem. 282, 35583-35593 (2007).
90. Hatta, M., Liu, F. & Cirillo, L. A. Acetylation curtails nucleosome binding, not stable nucleosome remodeling, by FoxO1. Biochem. Biophys. Res. Commun. 379, 1005-1008 (2009).
91. van der Vos, K. E. & Coffer, P. J. FOXO-binding partners: it takes two to tango. Oncogene 27, 2289-2299 (2008).
92. You, H. et al. p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Proc. Natl Acad. Sci. USA 101, 14057-14062 (2004).
93. Renault, V. M. et al. The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor. Oncogene 30, 3207-3221 (2011).
94. Bouchard, C. et al. FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev. 21, 2775-2787 (2007).
95. You, H., Yamamoto, K. & Mak, T. W. Regulation of transactivation- independent proapoptotic activity of p53 by FOXO3a. Proc. Natl Acad. Sci. USA 103, 9051-9056 (2006).
96. Kloet, D. E. & Burgering, B. M. The PKB/FOXO switch in aging and cancer. Biochim. Biophys. Acta 1813, 1926-1937 (2011).
97. Ferber, E. C. et al. FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression. Cell Death Differ. 19, 968-979 (2012).
98. Jensen, K. S. et al. FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function. EMBO J. 30, 4554-4570 (2011).
99. Delpuech, O. et al. Induction of Mxi1-SR α by FOXO3a contributes to repression of Myc-dependent gene expression. Mol. Cell. Biol. 27, 4917-4930 (2007).
100. Hoogeboom, D. & Burgering, B. M. Should I stay or should I go: β-catenin decides under stress. Biochim. Biophys. Acta 1796, 63-74 (2009).
101. Essers, M. A. et al. Functional interaction between β-catenin and FOXO in oxidative stress signaling. Science 308, 1181-1184 (2005).
102. Hoogeboom, D. et al. Interaction of FOXO with β-catenin inhibits β-catenin/T cell factor activity. J. Biol. Chem. 283, 9224-9230 (2008).
103. Almeida, M., Han, L., Martin-Millan, M., O'Brien, C. A. & Manolagas, S. C. Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting β-catenin from T cell factor-to forkhead box O-mediated transcription. J. Biol. Chem. 282, 27298-27305 (2007).
104. Xie, X. W., Liu, J. X., Hu, B. & Xiao, W. Zebrafish foxo3b negatively regulates canonical Wnt signaling to affect early embryogenesis. PLoS ONE 6, e24469 (2011).
105. Kanazawa, A. et al. Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes. Am. J. Hum. Genet. 75, 832-843 (2004).
106. Grant, S. F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genet. 38, 320-323 (2006).
107. Mani, A. et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315, 1278-1282 (2007).
108. Liu, H. et al. Wnt signaling regulates hepatic metabolism. Sci. Signal. 4, ra6 (2011).
109. Hui, R. C. et al. The forkhead transcription factor FOXO3a increases phosphoinositide-3 kinase/Akt activity in drug-resistant leukemic cells through induction of PIK3CA expression. Mol. Cell. Biol. 28, 5886-5898 (2008).
110. Ide, T. et al. SREBPs suppress IRS-2-mediated insulin signalling in the liver. Nature Cell Biol. 6, 351-357 (2004).
111. Puig, O. & Tjian, R. Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev. 19, 2435-2446 (2005).
112. Chen, C. C. et al. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev. Cell 18, 592-604 (2010).
113. Kousteni, S. FoxO1, the transcriptional chief of staff of energy metabolism. Bone 50, 437-443 (2012).
114. Ren, H. et al. FoxO1 target Gpr17 activates AgRP neurons to regulate food intake. Cell 149, 1314-1326 (2012).
115. Lu, M. et al. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nature Med. 18, 388-395 (2012).
116. Paradis, S. & Ruvkun, G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev. 12, 2488-2498 (1998).
117. Selkoe, D. J. Folding proteins in fatal ways. Nature 426, 900-904 (2003).
118. Morley, J. F., Brignull, H. R., Weyers, J. J. & Morimoto, R. I. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 99, 10417-10422 (2002).
119. Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W. & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604-1610 (2006).
120. Cohen, E. et al. Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection. Aging Cell 9, 126-134 (2010).
121. Vilchez, D. et al. RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489, 263-268 (2012).
122. Zhao, J. et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6, 472-483 (2007).
123. Mammucari, C. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458-471 (2007).
124. Mei, Y. et al. FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation. Proc. Natl Acad. Sci. USA 106, 5153-5158 (2009).
125. Sandri, M. et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117, 399-412 (2004).
126. Bodine, S. C. et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704-1708 (2001).
127. Liu, H. Y. et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J. Biol. Chem. 284, 31484-31492 (2009).
128. Sengupta, A., Molkentin, J. D. & Yutzey, K. E. FoxO transcription factors promote autophagy in cardiomyocytes. J. Biol. Chem. 284, 28319-28331 (2009).
129. Zhao, Y. et al. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nature Cell Biol. 12, 665-675 (2010).
130. Junger, M. A. et al. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J. Biol. 2, 20 (2003).
131. Puig, O., Marr, M. T., Ruhf, M. L. & Tjian, R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev. 17, 2006-2020 (2003).
132. Southgate, R. J. et al. FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle. J. Biol. Chem. 282, 21176-21186 (2007).
133. McColl, G. et al. Insulin-like signaling determines survival during stress via posttranscriptional mechanisms in C. elegans. Cell Metab. 12, 260-272 (2010).
134. Boehm, A. M. et al. FoxO is a critical regulator of stem cell maintenance in immortal Hydra. Proc. Natl Acad. Sci. USA 109, 19697-19702 (2012).
135. Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101-112 (2007).
136. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325-339 (2007).
137. Paik, J. H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540-553 (2009).
138. Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527-539 (2009).
139. Pan, G. & Thomson, J. A. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 17, 42-49 (2007).
140. Zhang, X. et al. FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nature Cell Biol. 13, 1092-1099 (2011).
141. Becker, T. et al. FOXO-dependent regulation of innate immune homeostasis. Nature 463, 369-373 (2010).
142. Hedrick, S. M., Hess Michelini, R., Doedens, A. L., Goldrath, A. W. & Stone, E. L. FOXO transcription factors throughout T cell biology. Nature Rev. Immunol. 12, 649-661 (2012).
143. Dejean, A. S., Hedrick, S. M. & Kerdiles, Y. M. Highly specialized role of forkhead box O transcription factors in the immune system. Antioxid. Redox Signal. 14, 663-674 (2011).
144. Dengler, H. S. et al. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nature Immunol. 9, 1388-1398 (2008).
145. Kerdiles, Y. M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nature Immunol. 10, 176-184 (2009).
146. Amin, R. H. & Schlissel, M. S. Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nature Immunol. 9, 613-622 (2008).
147. Harada, Y. et al. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J. Exp. Med. 207, 1381-1391 (2010).
148. Kerdiles, Y. M. et al. Foxo transcription factors control regulatory T cell development and function. Immunity 33, 890-904 (2010).
149. + regulatory T cells. Nature Immunol. 11, 618-627 (2010).
150. Reg cell function. Nature 491, 554-559 (2012).
151. Litvak, V. et al. A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 490, 421-425 (2012).
152. Seoane, J., Le, H. V., Shen, L., Anderson, S. A. & Massague, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 11 7, 211-223 (2004).
153. cip1-dependent senescence. Cancer Res. 70, 8526-8536 (2010).
154. Naka, K. et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676-680 (2010).
155. Sykes, S. M. et al. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 146, 697-708 (2011).
156. Chakrabarty, A., Sanchez, V., Kuba, M. G., Rinehart, C. & Arteaga, C. L. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc. Natl Acad. Sci. USA 109, 2718-2723 (2012).
157. Chandarlapaty, S. et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58-71 (2011).
158. Storz, P., Doppler, H., Copland, J. A., Simpson, K. J. & Toker, A. FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases. Mol. Cell. Biol. 29, 4906-4917 (2009).
159. Tenbaum, S. P. et al. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nature Med. 18, 892-901 (2012).
160. van der Vos, K. E. & Coffer, P. J. The extending network of FOXO transcriptional target genes. Antioxid. Redox Signal. 14, 579-592 (2011).