The emerging roles of forkhead box (Fox) proteins in cancer

Nature Reviews Cancer

Volumn 7, Issue 11, 2007, Pages 847-859

  Myatt, Stephen S ^a   Lam, Eric W F ^a  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BETA CATENIN; BIOLOGICAL MARKER; CETUXIMAB; GEFITINIB; HEPATOCYTE NUCLEAR FACTOR 3ALPHA; IMATINIB; KP 372 1; PACLITAXEL; PHOSPHOTRANSFERASE INHIBITOR; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FKHR; TRANSCRIPTION FACTOR FKHRL1; TRANSCRIPTION FACTOR FOXL1; TRANSCRIPTION FACTOR FOXM1; TRANSCRIPTION FACTOR FOXO4; TRANSCRIPTION FACTOR FOXP1; TRANSCRIPTION FACTOR FOXP2; TRANSCRIPTION FACTOR FOXP3; TRASTUZUMAB; UNCLASSIFIED DRUG;

ACETYLATION; BREAST CANCER; CANCER GROWTH; DEREGULATION; HUMAN; INTERVENTION STUDY; KIDNEY CANCER; LUNG NON SMALL CELL CANCER; MYELOID LEUKEMIA; NONHUMAN; OVARY CANCER; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION; REVIEW; RNA TRANSLATION; UBIQUITINATION;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL TRANSFORMATION, NEOPLASTIC; DISEASE PROGRESSION; DRUG DESIGN; FEMALE; FORKHEAD TRANSCRIPTION FACTORS; GENE EXPRESSION REGULATION, DEVELOPMENTAL; GENE EXPRESSION REGULATION, NEOPLASTIC; HOMEOSTASIS; HUMANS; IMMUNITY; MALE; MICE; MICE, KNOCKOUT; MULTIGENE FAMILY; NEOPLASM PROTEINS; NEOPLASMS; PHYLOGENY; PROTEIN PROCESSING, POST-TRANSLATIONAL;

EID: 35548930209     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc2223     Document Type: Review

References (147)

1. Lai, E. et al. HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes Dev. 4, 1427-1436 (1990).
2. 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 57, 645-658 (1989).
3. Krupczak-Hollis, K. et al. The mouse Forkhead Box m1 transcription factor is essential for hepatoblast mitosis and development of intrahepatic bile ducts and vessels during liver morphogenesis. Dev. Biol. 276, 74-88 (2004).
4. Kalin, T. V. et al. Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. Cancer Res. 66, 1712-1720 (2006).
5. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868 (1999).
6. Kops, G. J. et al. Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol. Cell Biol. 22, 2025-2036 (2002).
7. Paik, J. H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309-323 (2007). A seminal study examining the role of individual FoxO family members in tumour suppression and identifying functional redundancy between family members for the first time.
8. Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771-775 (2007).
9. Hu, H. et al. Foxp1 is an essential transcriptional regulator of B cell development. Nature Immunol. 7, 819-826 (2006).
10. Shu, W. et al. Foxp2 and Foxp1 cooperatively regulate lung and esophagus development. Development 134, 1991-2000 (2007).
11. Campbell, D. J. & Ziegler, S. F. FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nature Rev. Immunol. 7, 305-310 (2007).
12. Perreault, N., Katz, J. P., Sackett, S. D. & Kaestner, K. H. Foxl1 controls the Wnt/beta-catenin pathway by modulating the expression of proteoglycans in the gut. J. Biol. Chem. 276, 43328-33 (2001).
13. Perreault, N., Sackett, S. D., Katz, J. P., Furth, E. E. & Kaestner, K. H. Foxl1 is a mesenchymal modifier of Min in carcinogenesis of stomach and colon. Genes Dev. 19, 311-315 (2005).
14. Barr, F. G. Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. Oncogene 20, 5736-5746 (2001).
15. Dong, X. Y. et al. FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res. 66, 6998-7006 (2006).
16. Wlodarska, I. et al. FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations. Leukemia 19, 1299-1305 (2005).
17. Barrans, S. L., Fenton, J. A., Banham, A., Owen, R. G. & Jack, A. S. Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Blood 104, 2933-2935 (2004).
18. Haralambieva, E. et al. Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation. Leukemia 20, 1300-1303 (2006).
19. Chae, W. J., Henegariu, O., Lee, S. K. & Bothwell, A. L. The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells. Proc. Natl Acad. Sci. USA 103, 9631-9636 (2006).
20. Stroud, J. C. et al. Structure of the forkhead domain of FOXP2 bound to DNA. Structure 14, 159-166 (2006).
21. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942-949 (2004).
22. Korver, W. et al. The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization. Genomics 46, 435-442 (1997).
23. Spirin, K. S. et al. p27/Kip1 mutation found in breast cancer. Cancer Res. 56, 2400-2404 (1996).
24. Singh, B. et al. Molecular cytogenetic characterization of head and neck squamous cell carcinoma and refinement of 3q amplification. Cancer Res. 61, 4506-4513 (2001).
25. Rodriguez, S. et al. Conventional and array-based comparative genomic hybridization analysis of nasopharyngeal carcinomas from the Mediterranean area. Cancer Genet. Cytogenet. 157, 140-147 (2005).
26. Heselmeyer, K. et al. Advanced-stage cervical carcinomas are defined by a recurrent pattern of chromosomal aberrations revealing high genetic instability and a consistent gain of chromosome arm 3q. Genes Chromosomes Cancer 19, 233-240 (1997).
27. Teh, M. T. et al. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res. 62, 4773-4780 (2002).
28. Madureira, P. A. et al. The Forkhead box M1 protein regulates the transcription of the estrogen receptor alpha in breast cancer cells. J. Biol. Chem. 281, 25167-25176 (2006).
29. Liu, M. et al. FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res. 66, 3593-3602 (2006).
30. Kim, I. M. et al. The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. Cancer Res. 66, 2153-2161 (2006).
31. Kalinichenko, V. V. et al. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev. 18, 830-850 (2004).
32. Ruiz i Altaba, A., Sanchez, P. & Dahmane, N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nature Rev. Cancer 2, 361-372 (2002).
33. Kasprzycka, M., Marzec, M., Liu, X., Zhang, Q. & Wasik, M. A. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3. Proc. Natl Acad. Sci. USA 103, 9964-9969 (2006).
34. 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).
35. 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).
36. Hu, M. C. et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225-237 (2004).
37. Bader, A. G., Kang, S., Zhao, L. & Vogt, P. K. Oncogenic PI3K deregulates transcription and translation. Nature Rev. Cancer 5, 921-929 (2005).
38. Heasley, L. E. & Han, S. Y. JNK regulation of oncogenesis. Mol. Cells 21, 167-173 (2006).
39. Perkins, N. D. Integrating cell-signalling pathways with NF-?B and IKK function. Nature Rev. Mol. Cell Biol. 8, 49-62 (2007).
40. Kim, H. J., Hawke, N. & Baldwin, A. S. NF-κB and IKK as therapeutic targets in cancer. Cell Death Differ. 13, 738-747 (2006).
41. Scheijen, B., Ngo, H. T., Kang, H. & Griffin, J. D. FLT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins. Oncogene 23, 3338-3349 (2004).
42. Shore, A. M. et al. Epstein-Barr virus represses the FoxO1 transcription factor through latent membrane protein 1 and latent membrane protein 2A. J. Virol. 80, 11191-11199 (2006).
43. Trotman, L. C. et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523-527 (2006).
44. Jin, G. S. et al. Expression and intracellular localization of FKHRL1 in mammary gland neoplasms. Acta Med. Okayama 58, 197-205 (2004).
45. 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).
46. Coffer, P. J. & Burgering, B. M. Stressed marrow: FoxOs stem tumour growth. Nature Cell Biol. 9, 251-253 (2007).
47. Ali, I. U., Schriml, L. M. & Dean, M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J. Natl Cancer Inst. 91, 1922-1932 (1999).
48. Eng, C. PTEN: one gene, many syndromes. Hum. Mutat. 22, 183-198 (2003).
49. Simpson, L. & Parsons, R. PTEN: life as a tumor suppressor. Exp. Cell Res. 264, 29-41 (2001).
50. Leslie, N. R. & Downes, C. P. PTEN function: how normal cells control it and tumour cells lose it. Biochem. J. 382, 1-11 (2004).
51. Nakamura, N. et al. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol. Cell Biol. 20, 8969-8982 (2000).
52. Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782-787 (2000).
53. Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475-482 (2006).
54. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325-339 (2007). This study demonstrates for the first time that simultaneous depletion of FoxO1, 3 and 4 results in stem cell exhaustion, and that redundancy exists between different FoxO family members in this context.
55. Major, M. L., Lepe, R. & Costa, R. H. Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol. Cell Biol. 24, 2649-2661 (2004).
56. Ma, R. Y. et al. Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c. J. Cell Sci. 118, 795-806 (2005).
57. Wierstra, I. & Alves, J. Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4. Biol. Chem. 387, 949-962 (2006).
58. Chau, B. N. & Wang, J. Y. Coordinated regulation of life and death by RB. Nature Rev. Cancer 3, 130-138 (2003).
59. Sherr, C. J. Cancer cell cycles. Science 274, 1672-1677 (1996).
60. Baylin, S. B., Herman, J. G., Graff, J. R., Vertino, P. M. & Issa, J. P. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv. Cancer Res. 72, 141-196 (1998).
61. Worm, J. et al. Aberrant p27Kip1 promoter methylation in malignant melanoma. Oncogene 19, 5111-5115 (2000).
62. Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501-1512 (1999).
63. Toyoshima, H. & Hunter, T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67-74 (1994).
64. Luscher-Firzlaff, J. M. et al. Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation. Oncogene 18, 5620-5630 (1999).
65. Zukerberg, L. R. et al. Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene. Mod. Pathol. 8, 560-567 (1995).
66. Tan, Y., Raychaudhuri, P. & Costa, R. H. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol. Cell Biol. 27, 1007-1016 (2007).
67. Chen, C. R. et al. Dual induction of apoptosis and senescence in cancer cells by Chk2 activation: checkpoint activation as a strategy against cancer. Cancer Res. 65, 6017-6021 (2005).
68. Matsuoka, S. et al. Reduced expression and impaired kinase activity of a Chk2 mutant identified in human lung cancer. Cancer Res. 61, 5362-5365 (2001).
69. Ghosh, J. C., Dohi, T., Raskett, C. M., Kowalik, T. F. & Altieri, D. C. Activated checkpoint kinase 2 provides a survival signal for tumor cells. Cancer Res. 66, 11576-11579 (2006).
70. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-2015 (2004). The role of SIRT1 (sirtuin) in FOXO3A signalling remains contentious; this article provides the most recent viewpoint and suggests that SIRT1 may differentially affect FOXO3A target gene expression.
71. Lam, E. W., Francis, R. E. & Petkovic, M. FOXO transcription factors: key regulators of cell fate. Biochem Soc. Trans. 34, 722-726 (2006).
72. Li, B. et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc. Natl Acad. Sci. USA 104, 4571-4576 (2007).
73. Ford, J., Jiang, M. & Milner, J. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res. 65, 10457-10463 (2005).
74. 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).
75. van der Horst, A. et al. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature Cell Biol. 8, 1064-1073 (2006).
76. Masuya, D. et al. The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways. J. Pathol. 208, 724-732 (2006).
77. Li, M. et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416, 648-653 (2002).
78. Munoz-Fontela, C. et al. Latent protein LANA2 from Kaposi's sarcoma-associated herpesvirus interacts with 14-3-3 proteins and inhibits FOXO3a transcription factor. J. Virol. 81, 1511-1516 (2007).
79. Laoukili, J. et al. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nature Cell Biol. 7, 126-136 (2005). The first paper to define the role of FOXM in chromosome stability.
80. Wang, X., Kiyokawa, H., Dennewitz, M. B. & Costa, R. H. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proc. Natl Acad. Sci. USA 99, 16881-16886 (2002).
81. Wonsey, D. R. & Follettie, M. T. Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res. 65, 5181-5189 (2005).
82. Wang, I. C. et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol. Cell Biol. 25, 10875-10894 (2005).
83. Kalinichenko, V. V. et al. Ubiquitous expression of the forkhead box M1B transgene accelerates proliferation of distinct pulmonary cell types following lung injury. J. Biol. Chem. 278, 37888-37894 (2003).
84. Wang, X. et al. Increased hepatic Forkhead Box M1B (FoxM1B) levels in old-aged mice stimulated liver regeneration through diminished p27Kip1 protein levels and increased Cdc25B expression. J. Biol. Chem. 277, 44310-44316 (2002).
85. Delpuech, O. et al. Induction of Mxi1-SR? by FOXO3a contributes to repression of Myc dependent gene expression. Mol. Cell Biol. 27, 4917-4930 (2007).
86. Singh, H., Medina, K. L. & Pongubala, J. M. Contingent gene regulatory networks and B cell fate specification. Proc. Natl Acad. Sci. USA 102, 4949-4953 (2005).
87. Carroll, J. S. et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122, 33-43 (2005). A study showing for the first time that ER binding requires FOXA1 at distal sites, revealing a potentially critical role of FOXA1 deregulation in breast cancer progression.
88. Schuur, E. R. et al. Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family. J. Biol. Chem. 276, 33554-33560 (2001).
89. Zhao, H. H. et al. Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions. J. Biol. Chem. 276, 27907-27912 (2001).
90. Kouros-Mehr, H., Slorach, E. M., Sternlicht, M. D. & Werb, Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127, 1041-1055 (2006).
91. Miyamoto, K. et al. Identification of 20 genes aberrantly methylated in human breast cancers. Int. J. Cancer 116, 407-414 (2005).
92. Eeckhoute, J., Carroll, J. S., Geistlinger, T. R., Torres-Arzayus, M. I. & Brown, M. A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer. Genes Dev. 20, 2513-2526 (2006).
93. Williamson, E. A. et al. BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27(Kip1). Oncogene 25, 1391-1399 (2006).
94. Reg-cell function by an interaction between FOXP3 and AML1, leading to repression of AML1 activity.
95. 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).
96. 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 117, 211-223 (2004).
97. Seo, S. et al. The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Dev. Biol. 294, 458-470 (2006).
98. Zhang, H. et al. Transcriptional activation of placental growth factor by the forkhead/winged helix transcription factor FoxD1. Curr. Biol. 13, 1625-1629 (2003).
99. Furuyama, T. et al. Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J. Biol. Chem. 279, 34741-34749 (2004).
100. Potente, M. et al. Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J. Clin. Invest. 115, 2382-2392 (2005).
101. Fosbrink, M., Niculescu, F., Rus, V., Shin, M. L. & Rus, H. C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1. J. Biol. Chem. 281, 19009-19018 (2006).
102. Daly, C. et al. Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells. Proc. Natl Acad. Sci. USA 103, 15491-15496 (2006).
103. Mani, S. A. et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc. Natl Acad. Sci. USA 104, 10069-10074 (2007). The first direct evidence for the role of FOXC2 in tumour progression through promotion of tumour metastasis and invasion.
104. Wolf, I. et al. FOXA1: Growth inhibitor and a favorable prognostic factor in human breast cancer. Int. J. Cancer 120, 1013-1022 (2007).
105. Birkenkamp, K. U. et al. FOXO3a induces differentiation of Bcr-Abl-transformed cells through transcriptional down-regulation of Id1. J. Biol. Chem. 282, 2211-2220 (2007).
106. Fan, W. et al. Insulin-like growth factor 1/insulin signaling activates androgen signaling through direct interactions of Foxo1 with androgen receptor. J. Biol. Chem. 282, 7329-7338 (2007).
107. Li, J., Wang, E., Rinaldo, F. & Datta, K. Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway. Oncogene 24, 5510-5520 (2005).
108. Chen, G. et al. Modulation of androgen receptor transactivation by FoxH1. A newly identified androgen receptor corepressor. J. Biol. Chem. 280, 36355-36363 (2005).
109. Yu, X. et al. Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially. Ann. NY Acad. Sci. 1061, 77-93 (2005).
110. Sunters, A. et al. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J. Biol. Chem. 278, 49795-49805 (2003).
111. Sunters, A. et al. Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Cancer Res. 66, 212-220 (2006).
112. Zeng, Z. et al. Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. Cancer Res. 66, 3737-3746 (2006).
113. Essafi, A. et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 24, 2317-2329 (2005).
114. Reid, A., Vidal, L., Shaw, H. & de Bono, J. Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu). Eur. J. Cancer 43, 481-489 (2007).
115. Real, P. J. et al. Blockade of epidermal growth factor receptors chemosensitizes breast cancer cells through up-regulation of Bnip3L. Cancer Res. 65, 8151-8157 (2005).
116. Yang, J. Y., Xia, W. & Hu, M. C. Ionizing radiation activates expression of FOXO3a, Fas ligand, and Bim, and induces cell apoptosis. Int. J. Oncol. 29, 643-648 (2006).
117. Matsumoto, M., Han, S., Kitamura, T. & Accili, D. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J. Clin. Invest. 116, 2464-2472 (2006).
118. Puig, O. & Tjian, R. Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev. 19, 2435-2446 (2005).
119. Nair, S., Boczkowski, D., Fassnacht, M., Pisetsky, D. & Gilboa, E. Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res. 67, 371-380 (2007).
120. Radhakrishnan, S. K. et al. Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box m1. Cancer Res. 66, 9731-9735 (2006).
121. Gusarova, G. A. et al. A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment. J. Clin. Invest. 117, 99-111 (2007).
122. Gomez-Gutierrez, J. G. et al. Adenovirus-mediated gene transfer of FKHRL1 triple mutant efficiently induces apoptosis in melanoma cells. Cancer Biol. Ther. 5, 875-883 (2006).
123. Ali, S. & Coombes, R. C. Endocrine-responsive breast cancer and strategies for combating resistance. Nature Rev. Cancer 2, 101-112 (2002).
124. Clark, K. L., Halay, E. D., Lai, E. & Burley, S. K. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 364, 412-420 (1993).
125. Weigelt, J., Climent, I., Dahlman-Wright, K. & Wikstrom, M. Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4). Biochemistry 40, 5861-5869 (2001).
126. Barthel, A., Schmoll, D. & Unterman, T. G. FoxO proteins in insulin action and metabolism. Trends Endocrinol. Metab. 16, 183-189 (2005).
127. Li, S., Weidenfeld, J. & Morrisey, E. E. Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions. Mol. Cell Biol. 24, 809-822 (2004).
128. Rinner, O. et al. An integrated mass spectrometric and computational framework for the analysis of protein interaction networks. Nature Biotechnol. 25, 345-352 (2007).
129. Motta, M. C. et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 116, 551-563 (2004).
130. Luscher-Firzlaff, J. M., Lilischkis, R. & Luscher, B. Regulation of the transcription factor FOXM1c by Cyclin E/CDK2. FEBS Lett. 580, 1716-1722 (2006).
131. Liu, H., Komai-Koma, M., Xu, D. & Liew, F. Y. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc. Natl Acad. Sci. USA 103, 7048-7053 (2006).
132. Kops, G. J. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316-321 (2002).
133. Tran, H. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530-534 (2002).
134. Schmidt, M. et al. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol. Cell Biol. 22, 7842-7852 (2002).
135. Dijkers, P. F., Medema, R. H., Lammers, J. W., Koenderman, L. & Coffer, P. J. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr. Biol. 10, 1201-1204 (2000).
136. Modur, V., Nagarajan, R., Evers, B. M. & Milbrandt, J. FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J. Biol. Chem. 277, 47928-47937 (2002).
137. Nemoto, S. & Finkel, T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295, 2450-2452 (2002).
138. Guo, S. & Sonenshein, G. E. Forkhead box transcription factor FOXO3a regulates estrogen receptor ? expression and is repressed by the Her-2/neu/phosphatidylinositol 3-kinase/Akt signaling pathway. Mol. Cell Biol. 24, 8681-8690 (2004).
139. Liu, J. W. et al. Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS. Oncogene 24, 2020-2031 (2005).
140. Marson, A. et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931-935 (2007).
141. Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375-387 (2006).
142. Liu, V. C. et al. Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-β. J. Immunol. 178, 2883-2892 (2007).
143. Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68-73 (2001).
144. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genet. 27, 20-21 (2001).
145. Streubel, B., Vinatzer, U., Lamprecht, A., Raderer, M. & Chott, A. T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia 19, 652-658 (2005).
146. Lee, C. S., Friedman, J. R., Fulmer, J. T. & Kaestner, K. H. The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944-947 (2005).
147. Halmos, B. et al. A transcriptional profiling study of CCAAT/enhancer binding protein targets identifies hepatocyte nuclear factor 3 beta as a novel tumor suppressor in lung cancer. Cancer Res. 64, 4137-4147 (2004).