Regulation and function of FoxO transcription factors in normal and cancer stem cells: What have we learned?

Current Drug Targets

Volumn 12, Issue 9, 2011, Pages 1267-1283

  Zhang, Xin ^a   Rielland, Maité ^a   Yalcin, Safak ^a   Ghaffari, Saghi ^a  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

Author keywords

Foxo3; Hematopoietic stem cells; Leukemia stem cell; Oxidative stress; Quiescence; ROS; Self renewal; Stem cells

Indexed keywords

ADENYLATE KINASE; ANTINEOPLASTIC AGENT; CREATINE KINASE BB; CYCLIN DEPENDENT KINASE 1; I KAPPA B KINASE BETA; MIXED LINEAGE LEUKEMIA PROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; REACTIVE OXYGEN METABOLITE; SOMATOMEDIN C RECEPTOR; STRESS ACTIVATED PROTEIN KINASE; TRANSCRIPTION FACTOR DAF 16; TRANSCRIPTION FACTOR FKHR; TRANSCRIPTION FACTOR FKHRL1; TRANSCRIPTION FACTOR FOXO; TRANSCRIPTION FACTOR FOXO4; TRANSCRIPTION FACTOR FOXO6; TUMOR SUPPRESSOR PROTEIN; UNCLASSIFIED DRUG;

ACETYLATION; ACUTE GRANULOCYTIC LEUKEMIA; ANTIOXIDANT ACTIVITY; ARTICLE; ATYPICAL CHRONIC MYELOID LEUKEMIA; AUTOPHAGY; BLADDER CANCER; BREAST CANCER; CANCER CHEMOTHERAPY; CANCER RADIOTHERAPY; CANCER STEM CELL; CARCINOGENIC ACTIVITY; CELL TYPE; COLON CANCER; DRUG TARGETING; GLIOMA; HUMAN; HYPOXIA; IN VIVO STUDY; IONIZING RADIATION; LEIOMYOMA; LIVER CELL CARCINOMA; LUNG NON SMALL CELL CANCER; LYMPHOMA; MEDULLOBLASTOMA; MELANOMA; NEURAL STEM CELL; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OVARY CANCER; OXIDATIVE STRESS; PLURIPOTENT STEM CELL; PROMYELOCYTIC LEUKEMIA; PROSTATE CANCER; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; REGULATORY MECHANISM; RHABDOMYOSARCOMA; TRANSCRIPTION REGULATION; TUMOR SUPPRESSOR GENE; X RAY CRYSTALLOGRAPHY;

ANIMALS; CELL DIFFERENTIATION; DRUG DELIVERY SYSTEMS; DRUG DESIGN; FORKHEAD TRANSCRIPTION FACTORS; GENE EXPRESSION REGULATION; HUMANS; NEOPLASMS; NEOPLASTIC STEM CELLS; OXIDATIVE STRESS; STEM CELLS;

EID: 79959918521     PISSN: 13894501     EISSN: 18735592     Source Type: Journal    
DOI: 10.2174/138945011796150325     Document Type: Article

References (217)

1. Lessard J, Faubert A, Sauvageau G. Genetic programs regulating HSC specification, maintenance and expansion. Oncogene 2004; 23(43): 7199-7209.
2. Orford KW, Scadden DT. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet 2008; 9(2): 115-128.
3. Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8(9): 729-740.
4. Fontana L, Partridge L, Longo VD. Extending healthy life span-- from yeast to humans. Science 2010; 328(5976): 321-326.
5. He S, Nakada D, Morrison SJ. Mechanisms of stem cell selfrenewal. Annu Rev Cell Dev Biol 2009; 25: 377-406.
6. Sahin E, Depinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 2010; 464(7288): 520-528.
7. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3(7): 730-737.
8. Barabe F, Kennedy JA, Hope KJ, Dick JE. Modeling the initiation and progression of human acute leukemia in mice. Science 2007; 316(5824): 600-604.
9. Zumkeller W. The insulin-like growth factor system in hematopoietic cells. Leuk Lymphoma 2002; 43(3): 487-491.
10. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414(6859): 105-111.
11. Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005; 15(9): 494-501.
12. Jordan CT. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 2009; 4(3): 203-205.
13. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficient tumour formation by single human melanoma cells. Nature 2008; 456(7222): 593-598.
14. Wijchers PJ, Burbach JP, Smidt MP. In control of biology: of mice, men and Foxes. Biochem J 2006; 397(2): 233-246.
15. Pierrou S, Hellqvist M, Samuelsson L, Enerback S, Carlsson P. Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending. EMBO J 1994; 13(20): 5002-5012.
16. Weigel D, Jackle H. Novel homeotic genes in Drosophila melanogaster. Biochem Cell Biol 1989; 67(8): 393-396.
17. Weigel D, Jurgens G, Kuttner F, Seifert E, Jackle H. The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo. Cell 1989; 57(4): 645-658.
18. Hacker U, Grossniklaus U, Gehring WJ, Jackle H. Developmentally regulated Drosophila gene family encoding the fork head domain. Proc Natl Acad Sci U S A 1992; 89(18): 8754-8758.
19. Weigel D, Jackle H. The fork head domain: a novel DNA binding motif of eukaryotic transcription factors? Cell 1990; 63(3): 455-456.
20. Brennan RG. The winged-helix DNA-binding motif: another helixturn-helix takeoff. Cell 1993; 74(5): 773-776.
21. Clark KL, Halay ED, Lai E, Burley SK. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 1993; 364(6436): 412-420.
22. Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC. Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics 1998; 47(2): 187-199.
23. Lin K, Dorman JB, Rodan A, Kenyon C. Daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 1997; 278(5341): 1319-1322.
24. Ogg S, Paradis S, Gottlieb S, et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 1997; 389(6654): 994-999.
25. Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 2004; 429(6991): 562-566.
26. Giannakou ME, Goss M, Junger MA, Hafen E, Leevers SJ, Partridge L. Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science 2004; 305(5682): 361.
27. Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP. FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 2003; 278(38): 35959-35967.
28. Obsil T, Obsilova V. Structure/function relationships underlying regulation of FOXO transcription factors. Oncogene 2008; 27(16): 2263-2275.
29. van der Horst A, Burgering BM. Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 2007; 8(6): 440-450.
30. Wang M, Zhang X, Zhao H, Wang Q, Pan Y. FoxO gene family evolution in vertebrates. BMC Evol Biol 2009; 9: 222.
31. Marinkovic D, Zhang X, Yalcin S, et al. Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest 2007; 117(8): 2133-2144.
32. Yalcin S, Zhang X, Luciano JP, et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stressmediated homeostasis of hematopoietic stem cells. J Biol Chem 2008; 283(37): 25692-25705.
33. Yalcin S, Marinkovic D, Mungamuri SK, et al. ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice. EMBO J 2010; 29(24): 4118-4131.
34. Miyamoto K, Araki KY, Naka K, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 2007; 1: 101-112.
35. Yamazaki S, Iwama A, Takayanagi S, et al. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO J 2006; 25(15): 3515-3523.
36. Zhao Y, Yang J, Liao W, et al. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 2010; 12(7): 665-675.
37. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96(6): 857-868.
38. Biggs WH, 3rd, Meisenhelder J, Hunter T, Cavenee WK, Arden KC. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA 1999; 96(13): 7421-7426.
39. Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 1999; 398(6728): 630-634.
40. Rena G, Guo S, Cichy SC, Unterman TG, Cohen P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem 1999; 274(24): 17179-17183.
41. Nakae J, Park BC, Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem 1999; 274(23): 15982-15985.
42. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999; 13(22): 2905-2927.
43. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2(7): 489-501.
44. Obsilova V, Vecer J, Herman P, et al. 14-3-3 Protein interacts with nuclear localization sequence of forkhead transcription factor FoxO4. Biochemistry 2005; 44(34): 11608-11617.
45. Rinner O, Mueller LN, Hubalek M, Muller M, Gstaiger M, Aebersold R. An integrated mass spectrometric and computational framework for the analysis of protein interaction networks. Nat Biotechnol 2007; 25(3): 345-352.
46. Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulinlike growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem 1999; 274(24): 17184-17192.
47. Brunet A, Kanai F, Stehn J, et al. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J Cell Biol 2002; 156(5): 817-828.
48. Silhan J, Vacha P, Strnadova P, et al. 14-3-3 protein masks the DNA binding interface of forkhead transcription factor FOXO4. J Biol Chem 2009; 284(29): 19349-19360.
49. Rena G, Woods YL, Prescott AR, et al. Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J 2002; 21(9): 2263-2271.
50. Zhao X, Gan L, Pan H, et al. Multiple elements regulate nuclear/cytoplasmic shuttling of FOXO1: characterization of phosphorylation-and 14-3-3-dependent and -independent mechanisms. Biochem J 2004; 378(Pt 3): 839-849.
51. Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001; 21(3): 952-965.
52. 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 2004; 5(1): 60-65.
53. Woods YL, Rena G, Morrice N, et al. The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem J 2001; 355(Pt 3): 597-607.
54. von Groote-Bidlingmaier F, Schmoll D, Orth HM, Joost HG, Becker W, Barthel A. DYRK1 is a co-activator of FKHR (FOXO1a)-dependent glucose-6-phosphatase gene expression. Biochem Biophys Res Commun 2003; 300(3): 764-769.
55. Greer EL, Dowlatshahi D, Banko MR, et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 2007; 17(19): 1646-1656.
56. Greer EL, Oskoui PR, Banko MR, et al. The energy sensor AMP activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 2007; 282(41): 30107-30119.
57. Huang H, Regan KM, Lou Z, Chen J, Tindall DJ. CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 2006; 314(5797): 294-297.
58. Hu MC, Lee DF, Xia W, et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 2004; 117(2): 225-237.
59. Yang JY, Zong CS, Xia W, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 2008; 10(2): 138-148.
60. Asada S, Daitoku H, Matsuzaki H, et al. Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell Signal 2007; 19(3): 519-527.
61. Plas DR, Thompson CB. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem 2003; 278(14): 12361-12366.
62. Huang H, Regan KM, Wang F, et al. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci U S A 2005; 102(5): 1649-1654.
63. Essers MA, Weijzen S, de Vries-Smits AM, et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 2004; 23(24): 4802-4812.
64. De Ruiter ND, Burgering BM, Bos JL. Regulation of the forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451. Mol Cell Biol 2001; 21(23): 8225-8235.
65. Wang MC, Bohmann D, Jasper H. JNK signaling confers tolerance to oxidative stress and extends lifespan in Drosophila. Dev Cell 2003; 5(5): 811-816.
66. Wang MC, Bohmann D, Jasper H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 2005; 121(1): 115-125.
67. Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc Natl Acad Sci U S A 2005; 102(12): 4494-4499.
68. Sunayama J, Tsuruta F, Masuyama N, Gotoh Y. JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3. J Cell Biol 2005; 170(2): 295-304.
69. Tsuruta F, Sunayama J, Mori Y, et al. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J 2004; 23(8): 1889-1899.
70. Lehtinen MK, Yuan Z, Boag PR, et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 2006; 125(5): 987-1001.
71. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 2010; 40(2): 310-322.
72. Mahmud DL, M GA, Deb DK, Platanias LC, Uddin S, Wickrema A. Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells. Oncogene 2002; 21(10): 1556-1562.
73. Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004; 303(5666): 2011-2015.
74. Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 2004; 116(4): 551-563.
75. Daitoku H, Hatta M, Matsuzaki H, et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A 2004; 101(27): 10042-10047.
76. van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem 2004; 279(28): 28873-28879.
77. Frescas D, Valenti L, Accili D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 2005; 280(21): 20589-20595.
78. Kobayashi Y, Furukawa-Hibi Y, Chen C, et al. SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. Int J Mol Med 2005; 16(2): 237-243.
79. Pervaiz S, Taneja R, Ghaffari S. Oxidative stress regulation of stem and progenitor cells. Antioxid Redox Signal 2009; 11(11): 2777-2789.
80. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 2000; 279(6): L1005-L1028.
81. Ghaffari S. Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Antioxid Redox Signal 2008; 10(11): 1923-1940.
82. van der Horst A, de Vries-Smits AM, Brenkman AB, et al. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat Cell Biol 2006; 8(10): 1064-1073.
83. Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 2005; 308(5725): 1181-1184.
84. Hoogeboom D, Essers MA, Polderman PE, Voets E, Smits LM, Burgering BM. Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity. J Biol Chem 2008; 283(14): 9224-9230.
85. Dansen TB, Smits LM, van Triest MH, et al. Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nat Chem Biol 2009; 5(9): 664-672.
86. Murata H, Ihara Y, Nakamura H, Yodoi J, Sumikawa K, Kondo T. Glutaredoxin exerts an antiapoptotic effect by regulating the redox state of Akt. J Biol Chem 2003; 278(50): 50226-50233.
87. Sarbassov DD, Sabatini DM. Redox regulation of the nutrientsensitive raptor-mTOR pathway and complex. J Biol Chem 2005; 280(47): 39505-39509.
88. Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem 2002; 277(23): 20336-20342.
89. Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J 2003; 22(20): 5501-5510.
90. Singh A, Ye M, Bucur O, et al. Protein phosphatase 2A reactivates FOXO3a through a dynamic interplay with 14-3-3 and AKT. Mol Biol Cell 2010; 21(6): 1140-1152.
91. Yan L, Lavin VA, Moser LR, Cui Q, Kanies C, Yang E. PP2A regulates the pro-apoptotic activity of FOXO1. J Biol Chem 2008; 283(12): 7411-7420.
92. Qiang L, Banks AS, Accili D. Uncoupling of acetylation from phosphorylation regulates FOXO1 function independent of its subcellular localization. J Biol Chem 2010; 285(35): 27396-27401.
93. Hosokawa K, Arai F, Yoshihara H, et al. Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction. Biochem Biophys Res Commun 2007; 363(3): 578-583.
94. Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007; 128(2): 325-339.
95. Dijkers PF, Medema RH, Pals C, et al. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol Cell Biol 2000; 20(24): 9138-9148.
96. Kops GJ, Medema RH, Glassford J, et al. Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol Cell Biol 2002; 22(7): 2025-2036.
97. Schmidt M, Fernandez de Mattos S, van der Horst A, et al. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 2002; 22(22): 7842-7852.
98. Bouchard C, Marquardt J, Bras A, Medema RH, Eilers M. Mycinduced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins. EMBO J 2004; 23(14): 2830-2840.
99. Stahl M, Dijkers PF, Kops GJ, et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 2002; 168(10): 5024-5031.
100. Alvarez B, Martinez AC, Burgering BM, Carrera AC. Forkhead transcription factors contribute to execution of the mitotic programme in mammals. Nature 2001; 413(6857): 744-747.
101. Martinez-Gac L, Marques M, Garcia Z, Campanero MR, Carrera AC. Control of cyclin G2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead. Mol Cell Biol 2004; 24(5): 2181-2189.
102. Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N. FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J Biol Chem 2002; 277(30): 26729-26732.
103. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 2000; 10(19): 1201-1204.
104. Gilley J, Coffer PJ, Ham J. FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 2003; 162(4): 613-622.
105. Ghaffari S, Jagani Z, Kitidis C, Lodish HF, Khosravi-Far R. Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci U S A 2003; 100(11): 6523-6528.
106. Modur V, Nagarajan R, Evers BM, Milbrandt J. FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem 2002; 277(49): 47928-47937.
107. Kikuchi S, Nagai T, Kunitama M, Kirito K, Ozawa K, Komatsu N. Active FKHRL1 overcomes imatinib resistance in chronic myelogenous leukemia-derived cell lines via the production of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Sci 2007; 98(12): 1949-1958.
108. Sakoe Y, Sakoe K, Kirito K, Ozawa K, Komatsu N. FOXO3A as a key molecule for all-trans retinoic acid-induced granulocytic differentiation and apoptosis in acute promyelocytic leukemia. Blood 2010; 115(18): 3787-3795.
109. You H, Pellegrini M, Tsuchihara K, et al. FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Med 2006; 203(7): 1657-1663.
110. Tran H, Brunet A, Grenier JM, et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 2002; 296(5567): 530-534.
111. Kops GJ, Dansen TB, Polderman PE, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 2002; 419(6904): 316-321.
112. Nemoto S, Finkel T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 2002; 295(5564): 2450-2452.
113. Nakae J, Biggs WH, 3rd, Kitamura T, et al. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet 2002; 32(2): 245-253.
114. Nakae J, Kitamura T, Kitamura Y, Biggs WH, 3rd, Arden KC, Accili D. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell 2003; 4(1): 119-129.
115. Brunelle JK, Bell EL, Quesada NM, et al. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab 2005; 1(6): 409-414.
116. Guzy RD, Hoyos B, Robin E, et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 2005; 1(6): 401-408.
117. Bakker WJ, Harris IS, Mak TW. FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell 2007; 28(6): 941-953.
118. Emerling BM, Weinberg F, Liu JL, Mak TW, Chandel NS. PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci U S A 2008; 105(7): 2622-2627.
119. Naka K, Hoshii T, Muraguchi T, et al. TGF-beta-FOXO signaling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 2010; 463(7281): 676-680.
120. Sneddon JB, Werb Z. Location, location, location: the cancer stem cell niche. Cell Stem Cell 2007; 1(6): 607-611.
121. Zhao J, Brault JJ, Schild A, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 2007; 6(6): 472-483.
122. Sandri M, Sandri C, Gilbert A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004; 117(3): 399-412.
123. Davis RJ, D'Cruz CM, Lovell MA, Biegel JA, Barr FG. Fusion of PAX7 to FKHR by the variant t(1; 13)(p36; q14) translocation in alveolar rhabdomyosarcoma. Cancer Res 1994; 54(11): 2869-2872.
124. Galili N, Davis RJ, Fredericks WJ, et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 1993; 5(3): 230-235.
125. Borkhardt A, Repp R, Haas OA, et al. Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X; 11)(q13; q23). Oncogene 1997; 14(2): 195-202.
126. Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA. AF6q21, a novel partner of the MLL gene in t(6; 11)(q21; q23), defines a forkhead transcriptional factor subfamily. Blood 1997; 90(9): 3714-3719.
127. Scheijen B, Ngo HT, Kang H, Griffin JD. FLT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins. Oncogene 2004; 23(19): 3338-3349.
128. Gu TL, Tothova Z, Scheijen B, Griffin JD, Gilliland DG, Sternberg DW. NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a. Blood 2004; 103(12): 4622-4629.
129. Tsai WB, Chung YM, Takahashi Y, Xu Z, Hu MC. Functional interaction between FOXO3a and ATM regulates DNA damage response. Nat Cell Biol 2008; 10(4): 460-467.
130. You H, Jang Y, You-Ten AI, et al. P53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Proc Natl Acad Sci U S A 2004; 101(39): 14057-14062.
131. You H, Mak TW. Crosstalk between p53 and FOXO transcription factors. Cell Cycle 2005; 4(1): 37-38.
132. Burgering BM, Medema RH. Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol 2003; 73(6): 689-701.
133. Castrillon DH, Miao L, Kollipara R, Horner JW, DePinho RA. Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science 2003; 301(5630): 215-218.
134. Hosaka T, Biggs WH, 3rd, Tieu D, Boyer AD, Varki NM, Cavenee WK, et al. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci U S A 2004; 101(9): 2975-2980.
135. Paik JH, Kollipara R, Chu G, et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 2007; 128(2): 309-323.
136. Helgason GV, Young GA, Holyoake TL. Targeting chronic myeloid leukemia stem cells. Curr Hematol Malig Rep 2010; 5(2): 81-87.
137. Freitas AA, Rocha B. Homeostasis of naive T cells: the Foxo that fixes. Nat Immunol 2009; 10(2): 133-134.
138. Miyamoto K, Araki KY, Naka K, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 2007; 1(1): 101-112.
139. Renault VM, Rafalski VA, Morgan AA, et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 2009; 5(5): 527-539.
140. Cheng T, Rodrigues N, Dombkowski D, Stier S, Scadden DT. Stem cell repopulation efficiency but not pool size is governed by p27(kip1). Nat Med 2000; 6(11): 1235-1240.
141. Passegue E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med 2005; 202(11): 1599-1611.
142. Cheng T, Rodrigues N, Shen H, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000; 287(5459): 1804-1808.
143. Waldman T, Lengauer C, Kinzler KW, Vogelstein B. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 1996; 381(6584): 713-716.
144. Bunz F, Dutriaux A, Lengauer C, et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 1998; 282(5393): 1497-1501.
145. Paik JH, Ding Z, Narurkar R, et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 2009; 5(5): 540-553.
146. Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 2006; 441(7092): 523-527.
147. Ito K, Bernardi R, Morotti A, et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008; 453(7198): 1072-1078.
148. Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006; 441(7092): 518-522.
149. Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441(7092): 475-482.
150. Kau TR, Schroeder F, Ramaswamy S, et al. A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell 2003; 4(6): 463-476.
151. Groszer M, Erickson R, Scripture-Adams DD, et al. PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proc Natl Acad Sci U S A 2006; 103(1): 111-116.
152. Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the lowoxygenic niche. Blood 2007; 110(8): 3056-3063.
153. Owusu-Ansah E, Banerjee U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 2009; 461(7263): 537-541.
154. Ito K, Hirao A, Arai F, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 2004; 431(7011): 997-1002.
155. Ito K, Hirao A, Arai F, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 2006; 12(4): 446-451.
156. Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Zheng P. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 2008; 205(10): 2397-2408.
157. Lee JY, Nakada D, Yilmaz OH, et al. MTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell 2010; 7(5): 593-605.
158. Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 2009; 458(7239): 780-783.
159. Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 2005; 105(11): 4163-4169.
160. Guzman ML, Rossi RM, Neelakantan S, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 2007; 110(13): 4427-4435.
161. Nakada D, Saunders TL, Morrison SJ. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 2010; 468(7324): 653-658.
162. Gurumurthy S, Xie SZ, Alagesan B, et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 2010; 468(7324): 659-663.
163. Gan B, Hu J, Jiang S, et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 2010; 468(7324): 701-704.
164. Tothova Z, Gilliland DG. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 2007; 1(2): 140-152.
165. Dansen TB, Burgering BM. Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol 2008; 18(9): 421-429.
166. Irvine DA, Heaney NB, Holyoake TL. Optimising chronic myeloid leukaemia therapy in the face of resistance to tyrosine kinase inhibitors--a synthesis of clinical and laboratory data. Blood Rev 2010; 24(1): 1-9.
167. Yamazaki S, Iwama A, Takayanagi S, Eto K, Ema H, Nakauchi H. TGF-beta as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood 2009; 113(6): 1250-1256.
168. Seoane J, Le HV, Shen L, Anderson SA, Massague J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 2004; 117(2): 211-223.
169. Ambrogini E, Almeida M, Martin-Millan M, et al. FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. Cell Metab 2010; 11(2): 136-146.
170. Rached MT, Kode A, Xu L, et al. FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell Metab 2010; 11(2): 147-160.
171. Link W, Oyarzabal J, Serelde BG, et al. Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases. J Biol Chem 2009; 284(41): 28392-28400.
172. Zanella F, Rosado A, Garcia B, Carnero A, Link W. Using multiplexed regulation of luciferase activity and GFP translocation to screen for FOXO modulators. BMC Cell Biol 2009; 10: 14.
173. Zhang X, Gan L, Pan H, et al. Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA binding. J Biol Chem 2002; 277(47): 45276-45284.
174. Yamagata K, Daitoku H, Takahashi Y, et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol Cell 2008; 32(2): 221-231.
175. Kobayashi T, Deak M, Morrice N, Cohen P. Characterization of the structure and regulation of two novel isoforms of serum-and glucocorticoid-induced protein kinase. Biochem J 1999; 344 Pt 1: 189-197.
176. Garcia-Martinez JM, Alessi DR. MTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum-and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008; 416(3): 375-385.
177. Guo X, Williams JG, Schug TT, Li X. DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. J Biol Chem 2010; 285(17): 13223-13232.
178. Bois PR, Brochard VF, Salin-Cantegrel AV, Cleveland JL, Grosveld GC. FoxO1a-cyclic GMP-dependent kinase I interactions orchestrate myoblast fusion. Mol Cell Biol 2005; 25(17): 7645-7656.
179. Brent MM, Anand R, Marmorstein R. Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification. Structure 2008; 16(9): 1407-1416.
180. Yuan Z, Kim D, Shu S, et al. Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem 2010; 285(6): 3815-3824.
181. Liu P, Kao TP, Huang H. CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene 2008; 27(34): 4733-4744.
182. Yuan Z, Becker EB, Merlo P, et al. Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science 2008; 319(5870): 1665-1668.
183. Lei H, Quelle FW. FOXO transcription factors enforce cell cycle checkpoints and promote survival of hematopoietic cells after DNA damage. Mol Cancer Res 2009; 7(8): 1294-1303.
184. Hu MC, Hung MC. Role of IkappaB kinase in tumorigenesis. Future Oncol 2005; 1(1): 67-78.
185. Chiacchiera F, Simone C. Inhibition of p38alpha unveils an AMPKFoxO3A axis linking autophagy to cancer-specific metabolism. Autophagy 2009; 5(7): 1030-1033.
186. Puthanveetil P, Wang Y, Wang F, Kim MS, Abrahani A, Rodrigues B. The increase in cardiac pyruvate dehydrogenase kinase-4 after short-term dexamethasone is controlled by an Akt-p38-forkhead box other factor-1 signaling axis. Endocrinology 2010; 151(5): 2306-2318.
187. Schwab TS, Madison BB, Grauman AR, Feldman EL. Insulin-like growth factor-I induces the phosphorylation and nuclear exclusion of forkhead transcription factors in human neuroblastoma cells. Apoptosis 2005; 10(4): 831-840.
188. Perrot V, Rechler MM. Characterization of insulin inhibition of transactivation by a C-terminal fragment of the forkhead transcription factor Foxo1 in rat hepatoma cells. J Biol Chem 2003; 278(28): 26111-26119.
189. Greer EL, Banko MR, Brunet A. AMP-activated protein kinase and FoxO transcription factors in dietary restriction-induced longevity. Ann N Y Acad Sci 2009; 1170: 688-692.
190. Barthel A, Schmoll D, Kruger KD, Roth RA, Joost HG. Regulation of the forkhead transcription factor FKHR (FOXO1a) by glucose starvation and AICAR, an activator of AMP-activated protein kinase. Endocrinology 2002; 143(8): 3183-3186.
191. Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 2004; 117(4): 421-426.
192. Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A. Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci U S A 2005; 102(32): 11278-11283.
193. Kitamura YI, Kitamura T, Kruse JP, et al. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab 2005; 2(3): 153-163.
194. Ni YG, Wang N, Cao DJ, et al. FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases. Proc Natl Acad Sci U S A 2007; 104(51): 20517-20522.
195. Li L, Ren CH, Tahir SA, Ren C, Thompson TC. Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol 2003; 23(24): 9389-9404.
196. Wolff S, Ma H, Burch D, Maciel GA, Hunter T, Dillin A. SMK-1, an essential regulator of DAF-16-mediated longevity. Cell 2006; 124(5): 1039-1053.
197. Shioda N, Han F, Moriguchi S, Fukunaga K. Constitutively active calcineurin mediates delayed neuronal death through Fas-ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia. J Neurochem 2007; 102(5): 1506-1517.
198. Shiota M, Yokomizo A, Kashiwagi E, et al. Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin. Cancer Sci 2010; 101(5): 1177-1185.
199. Kim SH, Miller FR, Tait L, Zheng J, Novak RF. Proteomic and phosphoproteomic alterations in benign, premalignant and tumor human breast epithelial cells and xenograft lesions: biomarkers of progression. Int J Cancer 2009; 124(12): 2813-2828.
200. Lupertz R, Chovolou Y, Unfried K, Kampkotter A, Watjen W, Kahl R. The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity. Carcinogenesis 2008; 29(11): 2045-2052.
201. Ericson K, Gan C, Cheong I, et al. Genetic inactivation of AKT1, AKT2, and PDPK1 in human colorectal cancer cells clarifies their roles in tumor growth regulation. Proc Natl Acad Sci U S A 2010; 107(6): 2598-2603.
202. Kwon IK, Wang R, Thangaraju M, et al. PKG inhibits TCF signaling in colon cancer cells by blocking beta-catenin expression and activating FOXO4. Oncogene 2010; 29(23): 3423-3434.
203. Lau CJ, Koty Z, Nalbantoglu J. Differential response of glioma cells to FOXO1-directed therapy. Cancer Res 2009; 69(13): 5433-5440.
204. Lu M, Ma J, Xue W, et al. The expression and prognosis of FOXO3a and Skp2 in human hepatocellular carcinoma. Pathol Oncol Res 2009; 15(4): 679-687.
205. Hoekstra AV, Sefton EC, Berry E, et al. Progestins activate the AKT pathway in leiomyoma cells and promote survival. J Clin Endocrinol Metab 2009; 94(5): 1768-1774.
206. Blake DC, Jr., Mikse OR, Freeman WM, Herzog CR. FOXO3a elicits a pro-apoptotic transcription program and cellular response to human lung carcinogen nicotine-derived nitrosaminoketone (NNK). Lung Cancer 2010; 67(1): 37-47.
207. Srivastava VK, Yasruel Z, Nalbantoglu J. Impaired medulloblastoma cell survival following activation of the FOXO1 transcription factor. Int J Oncol 2009; 35(5): 1045-1051.
208. Zanella F, Renner O, Garcia B, et al. Human TRIB2 is a repressor of FOXO that contributes to the malignant phenotype of melanoma cells. Oncogene 2010; 29(20): 2973-2982.
209. Dong XY, Chen C, Sun X, et al. FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res 2006; 66(14): 6998-7006.
210. Hill KM, Kalifa S, Das JR, et al. The role of PI 3-kinase p110beta in AKT signally, cell survival, and proliferation in human prostate cancer cells. Prostate 2010; 70(7): 755-764.
211. Shukla S, Shukla M, Maclennan GT, Fu P, Gupta S. Deregulation of FOXO3A during prostate cancer progression. Int J Oncol 2009; 34(6): 1613-1620.
212. van Duijn PW, Ziel-van der Made AC, van der Korput JA, Trapman J. PTEN-mediated G1 cell-cycle arrest in LNCaP prostate cancer cells is associated with altered expression of cell-cycle regulators. Prostate 2010; 70(2): 135-146.
213. Lynch RL, Konicek BW, McNulty AM, et al. The progression of LNCaP human prostate cancer cells to androgen independence involves decreased FOXO3a expression and reduced p27KIP1 promoter transactivation. Mol Cancer Res 2005; 3(3): 163-169.
214. Fei M, Zhao Y, Wang Y, et al. Low expression of Foxo3a is associated with poor prognosis in ovarian cancer patients. Cancer Invest 2009; 27(1): 52-59.
215. Kornblau SM, Singh N, Qiu Y, Chen W, Zhang N, Coombes KR. Highly phosphorylated FOXO3A is an adverse prognostic factor in acute myeloid leukemia. Clin Cancer Res 2010; 16(6): 1865-1874.
216. Zhao Y, Fei M, Wang Y, Lu M, Cheng C, Shen A. Expression of Foxo3a in non-Hodgkin's lymphomas is correlated with cell cycle inhibitor p27. Eur J Haematol 2008; 81(2): 83-93.
217. Zhang X, Yalcin S, Lee DF, et al., FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol, in press.