Existing users Log In New users Sign up


Critical physiological and pathological functions of
Forkhead Box O tumor suppressors

DISCOVERIES (ISSN 2359-7232),2013, October-December

CITATION:
Dumitrascu GR, Bucur O. Critical physiological and pathological functions of Forkhead Box O tumor suppressors. Discoveries 2013, Oct-Dec; 1(1): e5.
DOI: 10.15190/d.2013.5

GO BACK to 2013, Oct-Dec issue
GO BACK to DISCOVERIES

Critical physiological and pathological functions of Forkhead Box O tumor suppressors


MD (1) and MD (2)*


Affiliation:
(1) “Victor Babes” National Institute of Pathology and Biomedical Sciences, Bucharest, Romania;
(2) Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA;

Correspondence to: Dr. Octavian Bucur, Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA. E-mail: obucur@bidmc.harvard.edu.


Abstract

The Forkhead box, subclass O (FOXO) proteins are critical transcription factors, ubiquitously expressed in the human body. These proteins are characterized by a remarkable functional diversity, being involved in cell cycle arrest, apoptosis, oxidative detoxification, DNA damage repair, stem cell maintenance, cell differentiation, cell metabolism, angiogenesis, cardiac development, aging and others. In addition, FOXO have critical implications in both normal and cancer stem cell biology. New strategies to modulate FOXO expression and activity may now be developed since the discovery of novel FOXO regulators and non-coding RNAs (such as microRNAs) targeting FOXO transcription factors. This review focuses on physiological and pathological functions of FOXO proteins and on their action as fine regulators of cell fate and context-dependent cell decisions. A better understanding of the structure and critical functions of FOXO transcription factors and tumor suppressors may contribute to the development of novel therapies for cancer and other diseases.

Access full text of the manuscript here:

References

1. Yang JY, Hung MC. Deciphering the role of forkhead transcription factors in cancer therapy. Curr Drug Targets. 2011; 12(9):1284-1290. PMID: 21443462.
2. Jagani Z, Singh A, Khosravi-Far R. FoxO tumor suppressors and BCR-ABL-induced leukemia: a matter of evasion of apoptosis. Biochim Biophys Acta. 2008; 1785(1):63-84. PMID: 17980712.
3. Tuteja G, Kaestner KH. SnapShot: forkhead transcription factors I. Cell. 2007; 130(6):1160. PMID: 17889656.
4. Maiese K, Chong ZZ, Shang YC. "Sly as a FOXO": new paths with Forkhead signaling in the brain. Curr Neurovasc Res. 2007; 4(4):295-302. PMID: 18045156.
5. Weigel D, Jürgens G, Küttner F, Seifert E, Jäckle 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):645-58. PMID: 2566386.
6. Weigel D, Jäckle H. The fork head domain: a novel DNA binding motif of eukaryotic transcription factors? Cell. 1990; 63(3):455-6. PMID: 2225060.
7. Kaestner KH, Knochel W, Martinez DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 2000; 14(2):142-6. PMID: 10702024.
8. Wotton KR, Shimeld SM. Comparative genomics of vertebrate Fox cluster loci. BMC Genomics. 2006; 7:271. PMID: 17062144.
9. Jackson BC, Carpenter C, Nebert DW, Vasiliou V. Update of human and mouse forkhead box (FOX) gene families. Hum Genomics. 2010; 4(5):345-52. PMID: 20650821.
10. Mazet F, Yu JK, Liberles DA, Holland LZ, Shimeld SM. Phylogenetic relationships of the Fox (Forkhead) gene family in the Bilateria. Gene. 2003; 316:79-89. PMID: 14563554.
11. Heglind M, Cederberg A, Aquino J, Lucas G, Ernfors P, et al. Lack of the central nervous system- and neural crest-expressed forkhead gene Foxs1 affects motor function and body weight. Mol Cell Biol. 2005; 25(13):5616-25. PMID: 15964817.
12. Katoh M, Katoh M. Germ-line mutation of Foxn5 gene in mouse lineage. Int J Mol Med. 2004; 14(3):463-7. PMID: 15289901.
13. Katoh M, Katoh M. Identification and characterization of human FOXN6, mouse Foxn6, and rat Foxn6 genes in silico. Int J Oncol. 2004;25(1):219-23. PMID: 15202009.
14. Wang F, Marshall CB, Yamamoto K, Li GY, Plevin MJ, et al. Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. J Mol Biol. 2008; 384(3):590-603. PMID: 18824006.
15. Glauser DA, Schlegel W. The emerging role of FOXO transcription factors in pancreatic beta cells. J Endocrinol. 2007; 193(2):195-207. PMID: 17470511.
16. 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):2869-72. PMID: 8187070.
17. Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet. 1993; 5(3):230-5. PMID: 8275086.
18. 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 Jan 15;47(2):187-99. PMID: 9479491.
19. Borkhardt A, Repp R, Haas OA, Leis T, Harbott J, 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 Jan 16;14(2):195-202. PMID: 9010221.
20. Maiese K, Chong ZZ, Hou J, Shang YC. The “O” class: crafting clinical care with FoxO transcription factors. Adv Exp Med Biol. 2009; 665:242-60. PMID – 20429429.
21. NCBI Protein Database. Forkhead box protein O1 [Homo sapiens]. Accession: NP_002006.2 GI: 9257222. Available at: http://www.ncbi.nlm.nih.gov/protein/NP_002006.2
22. NCBI Protein Database. Forkhead box protein O3 [Homo sapiens]. Accession: NP_963853.1 GI: 42519916. Available at: http://www.ncbi.nlm.nih.gov/protein/NP_963853.1
23. NCBI Protein Database. Forkhead box protein O4 [Homo sapiens]. Accession: AAI06762.1 GI: 76827750 Available at: http://www.ncbi.nlm.nih.gov/protein/AAI06762.1
24. NCBI Protein Database. Forkhead box protein O6 [Homo sapiens]. Accession: A8MYZ6.1 GI: 166988458 Available at: http://www.ncbi.nlm.nih.gov/protein/A8MYZ6.1
25. Obsil T, Obsilova V. Structure/function relationships underlying regulation of FOXO transcription factors. Oncogene. 2008; 27(16): 2263-75. PMID: 18391969.
26. Maiese K, Chong ZZ, Shang YC, Hou J. A “FOXO” in sight: targeting Foxo proteins from conception to cancer. Med Res Rev. 2009;29(3):395-418. PMID: 18985696.
27. Van der Vos KE, Coffer PJ. The extending network of FOXO transcriptional target genes. Antioxid Redox Signal. 2011; 14(4):579-92. PMID: 20673124.
28. Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, et al. Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of posttranslational modification. Nucleic Acids Res. 2007;35(20):6984-94. PMID: 17940099.
29. Weigelt J, Climent I, Dahlman-Wright K, Wikström M. Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4).Biochemistry. 2001; 40(20): 5861-9. PMID: 11352721.
30. Fu Z, Tindall DJ. FOXOs, cancer and regulation of apoptosis. Oncogene. 2008; 27(16):2312-9. PMID: 18391973.
31. Calnan DR, Brunet A. The FoxO code. Oncogene. 2008; 27(16):2276-88. PMID: 18391970.
32. 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):412-20. PMID: 8332212.
33. 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):1294-303. PMID: 19671690.
34. Ai J, Duan J, Lv X, Chen M, Yang Q, et al. Overexpression of FoxO1 causes proliferation of cultured pancreatic beta cells exposed to low nutrition. Biochemistry. 2010; 49(1):218-25. PMID: 19938874.
35. Hess Michelini R, Doedens AL, Goldrath AW, Hedrick SM. Differentiation of CD8 memory T cells depends on Foxo1. J Exp Med. 2013; 210(6):1189-200. PMID: 23712431.
36. Potente M, Urbich C, Sasaki K, Hofmann WK, Heeschen C, et al, Involvement of Foxo transcriptional factors in angiogenesis and postnatal neovascularization. J Clin Invest. 2005 Sep;115(9):2382-92. Epub 2005 Aug 11. PMID: 16100571.
37. Zhang W, Patil S, Chauhan B, Guo S, Powell DR, et al. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem. 2006; 281(15):10105-17. PMID: 16492665.
38. Boehm AM, Khalturin K, Anton-Erxleben F, Hemmrich G, Klostermeier UC, et al. FoxO is a critical regulator of stem cell maintenance in immortal Hydra. Proc Natl Acad Sci U S A. 2012; 109(48):19697-702. PMID: 23150562.
39. Sisci D, Maris P, Cesario MG, Anselmo W, Coroniti R, et al. The estrogen receptor a is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness. Cell Cycle. 2013; 12(21): 3405-20. PMID: 24047697.
40. Pino E, Amamoto R, Zheng L, Cacquevel M, Sarria JC, et al. FOXO3 determines the accumulation of a-synuclein and controls the fate of dopaminergic neurons in the substantia nigra. Hum Mol Genet. 2013 Nov 6. (Epub ahead of print). PMID: 24158851.
41. Hong YK, Lee S, Park SH, Lee JH, Han SY, et al. Inhibition of JNK/dFOXO pathway and caspases rescues neurological impairments in Drosophila Alzheimer's disease model. Biochem Biophys Res Commun. 2012; 419(1):49-53. PMID: 22326868.
42. Del Guerra S, Lupi R, Marselli L, Masini M, Bugliani M, et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes. 2005; 54(3): 727-35. PMID:15734849.
43. Galasso G, De Rosa R, Piscione F, Iaccarino G, Vosa C, et al. Myocardial expression of FOXO3a-Atrogin-1 pathway in human heart failure. Eur J Heart Fail. 2010; 12(12):1290-6. MID: 21098579.
44. Tsuchiya K, Tanaka J, Shuiqing Y, Welch CL, DePinho RA, et al. FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis. Cell Metab. 2012; 15(3):372-81. PMID: 22405072.
45. Goettsch W, Gryczka C, Korff T, Ernst E, Goettsch C, et al. Flow-dependent regulation of angiopoietin-2. J Cell Physiol. 2008; 214(2):491-503. PMID: 17960565.
46. Liu L, Rajareddy S, Reddy P, Du C, Jagarlamudi K, et al. Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a. Development. 2007; 134(1):199-209. PMID:17164425.
47. Singh A, Ye M, Bucur O, Zhu S, Tanya Santos M, et al. Protein phosphatase 2A reactivates FOXO3a through a dynamic interplay with 14-3-3 and AKT. Mol Biol Cell. 2010; 21(6):1140-52. PMID: 20110348.
48. You H, Pellegrini M, Tsuchihara K, Yamamoto K, Hacker G, et al. FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Med. 2006; 203(7):1657-63. PMID: 16801400.
49. Yang JY, Xia W, Hu MC. Ionizing radiation activates expression of FOXO3a, Fas ligand, and Bim, and induces cell apoptosis. Int J Oncol. 2006; 29(3):643-8. PMID: 16865280.
50. Valis K, Prochazka L, Boura E, Chladova J, Obsil T, et al. Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner. Cancer Res. 2011; 71(3):946-54. PMID: 21245099.
51. Lin A, Yao J, Zhuang L, Wang D, Han J, Lam EW; et al. The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress. Oncogene. 2013 Jul 15. (Epub ahead of print). PMID: 23851496.
52. Tang TT, Dowbenko D, Jackson A, Toney L, Lewin DA, et al. The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. J Biol Chem. 2002; 277(16):14255-65. PMID: 11777915.
53. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009; 122(Pt 4):437-41. PMID: 19193868.
54. Chen M, Guerrero AD, Huang L, Shabier Z, Pan M, et al. Caspase-9 -induced mitochondrial disruption through cleavage of anti-apoptotic BCL-2 family members. J Biol Chem. 2007; 282(46): 33888-95. PMID:17893147.
55. Plati J, Bucur O, Khosravi-Far R (2008) Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities. J Cell Biochem 104(4): 1124-1149. PubMed: 18459149.
56. Marfè G, Tafani M, Fiorito F, Pagnini U, Iovane G, et al. Involvement of FOXO transcription factors, TRAIL-FasL/Fas, and sirtuin proteins family in canine coronavirus type II-induced apoptosis. PLoS One. 2011; 6(11):e27313. PMID: 22087287.
57. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96(6):857-68. PMID: 10102273.
58. 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):47928-37. PMID: 12351634.
59. Knight MJ, Riffkin CD, Muscat AM, Ashley DM, Hawkins CJ. Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells. Oncogene. 2001; 20(41):5789-98. PMID: 11593384.
60. Rokudai S, Fujita N, Kitahara O, Nakamura Y, Tsuruo T. Involvement of FKHR-dependent TRADD expression in chemotherapeutic druginduced apoptosis. Mol Cell Biol. 2002; 22(24):8695-708. PMID:12446787.
61. Bender LM, Morgan MJ, Thomas LR, Liu ZG, Thorburn A. The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm. Cell Death Differ. 2005; 12(5):473-81. PMID:15761471.
62. Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013; 140(15):3079-93. PMID: 23861057.
63. de Keizer PL, Packer LM, Szypowska AA, Riedl-Polderman PE, van den Broek NJ, et al. Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Res. 2010; 70(21):8526-36. PMID: 20959475.
64. Rathbone CR, Booth FW, Lees SJ. FoxO3a preferentially induces p27Kip1 expression while impairing muscle precursor cell-cycle progression. Muscle Nerve. 2008; 37(1):84-9. PMID:17894357.
65. Huang H, Tindall DJ. CDK2 and FOXO1: a fork in the road for cell fate decisions. Cell Cycle. 2007; 6(8):902-6. PMID: 17457058.
66. Huang H, Tindall DJ. Dynamic FoxO transcription factors. J Cell Sci. 2007; 120(Pt 15):2479-87. PMID: 17646672.
67. Alvarez B, Martínez-A C, Burgering BM, Carrera AC.Forkhead transcription factors contribute to execution of the mitotic programme in mammals. Nature. 2001 Oct 18; 413(6857): 744-7. PMID: 11607034.
68. Jonsson H, Allen P, Peng SL. Inflammatory arthritis requires Foxo3a to prevent Fas ligandinduced neutrophil apoptosis. Nat Med. 2005; 11(6): 666-71. PMID: 15895074.
69. Tothova Z, Gilliland DG. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell. 2007; 1(2):140-52. PMID: 18371346.
70. Iyer S, Ambrogini E, Bartell SM, Han L, Roberson PK, et al. FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Invest. 2013; 123(8): 3409-19. PMID: 23867625.
71. Zhang X, Yalcin S, Lee DF, Yeh TY, Lee SM, et al. FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol. 2011; 13(9):1092-9. PMID: 21804543.
72. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 1997; 389(6654):994-9. PMID: 9353126.
73. Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, et al. Insulin regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003; 423(6939):550-5. PMID: 12754525.
74. Kitamura T, Nakae J, Kitamura Y, Kido Y, et al. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest. 2002; 110(12):1839-47. PMID: 12488434.
75. Nakae J, Cao Y, Oki M, Orba Y, Sawa H, et al. Forkhead transcription factor FoxO1 in adipose tissue tissue regulates energy storage and expenditure. Diabetes. 2008; 57(3):563-76. PMID: 18162510.
76. Kitamura T, Feng Y, Kitamura YI, Chua SC Jr, Xu AW, et al. Forkhead protein FoxO1 mediates Agrpdependent effects of leptin on food intake. Nat Med. 2006; 12(5):534-40. PMID: 16604086.
77. Xiong X, Tao R, DePinho RA, Dong XC. Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis. PLoS One. 2013;8(8):e74340. PMID: 24015318.
78. Altomonte J, Cong L, Harbaran S, Richter A, Xu J, et al. Foxo1 mediates insulin action on apoCIII and triglyceride metabolism. J Clin Invest. 2004;114(10): 1493-503. PMID: 15546000.
79. Tao R, Wei D, Gao H, Liu Y, DePinho RA, et al. Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene. J Biol Chem. 2011;286(16):14681-90. PMID: 21388966.
80. Hong SH, Lee KS, Kwak SJ, Kim AK, Bai H, Jung MS, et al. Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals. PLoS Genet. 2012;8(8):e1002857. PMID: 22876196.
81. Ren H, Orozco IJ, Su Y, Suyama S, Gutiérrez-Juárez R, et al. FoxO1 target Grp17 activates AgRP neurons to regulate food intake. Cell. 2012; 149(6):1314-26. PMID: 22682251.
82. Chiribau CB, Cheng L, Cucoranu IC, Yu YS, Clempus RE, et al. FOXO3 regulates peroxiredoxin III expression in human cardiac fibro blasts. J Biol Chem. 2008; 283(13):8211-7. PMID: 18195003.
83. Dansen TB, Kops GJ, Denis S, Jelluma N, Wanders RJ, et al. Regulation of sterol carrier protein gene expression by the forkhead transcription factor FOXO3a. J Lipid Res. 2004; 45(1):81-8. PMID: 14563822.
84. Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ Jr, et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science. 2002; 296(5567):530-4. PMID: 11964479.
85. Tullet JM, Araiz C, Sanders MJ, Benedetto A, Papatheodorou I, et al. DAF-16/FoxO Directly Regulates an Atypical AMP-Activated Protein Kinase Gamma Isoform to Mediate the Effects of Insulin/IGF-1 Signaling on Aging in Caenorhabditis elegans. PLoS Genet. 2014; 10(2):e1004109. PMID: 24516399.
86. Kyoung Kim H, Kyoung Kim Y, Song IH, Baek SH, Lee SR, et al. Down-regulation of a forkhead transcription factor, FOXO3a, accelerates cellular senescence in human dermal fibroblasts. J Gerontol A Biol Sci Med Sci. 2005; 60(1):4-9. PMID: 15741276.
87. Li M, Chiu JF, Mossman BT, Fukagawa NK. Down-regulation of manganese-superoxide dismutase through phosphorylation of FOXO3a by Akt in explanted vascular smooth muscle cells from old rats. J Biol Chem. 2006; 281(52):40429–40439. PubMed: 17079231.
88. Miyauchi H, Minamino T, Tateno K, Kunieda T, Toko H, Komuro I. Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. EMBO J. 2004;23(1):212-20. PMID: 14713953.
89. Ferrara N, Rinaldi B, Corbi G, Conti V, Stiuso P, Boccuti S, et al. Exercise training promotes SIRT1 activity in aged rats. Rejuvenation Res. 2008; 11(1):139-50. PMID: 18069916.
90. Haftmann C, Stittrich AB, Sgouroudis E, Matz M, Chang HD, et al. Lymphocyte signaling: regulation of FoxO transcription factors by microRNAs. Ann N Y Acad Sci. 2012; 1247:46-55. PMID: 22236474.
91. Ouyang W, Beckett O, Flavell RA, Li MO. An essential role of the Forkhead-box transcription factor Foxo1 in control of T cellhomeostasis and tolerance. Immunity. 2009; 30(3):358-71. PMID: 19285438.
92. Venieratos PD, Drossopoulou GI, Kapodistria KD, Tsilibary EC, Kitsiou PV. High glucose induces suppression of insulin signalling and apoptosis via upregulation of endogenous IL-1beta and suppressor of cytokine signalling-1 in mouse pancreatic beta cells. Cell Signal. 2010; 22(5):791-800. PMID: 20067833.
93. Peng C, Ma J, Gao X, Tian P, Li W, Zhang L. High glucose induced oxidative stress and apoptosis in cardiac microvascular endothelial cells are regulated by FoxO3a. PLoS One. 2013; 8(11). PMID: 24260294.
94. Bucur O, Ray S, Bucur MC, Almasan A (2006) APO2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in prostate cancer therapy. Front Biosci 11: 1549-1568. PubMed: 16368536.
95. So CW, Cleary ML. Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood. 2003; 101(2):633-9. PMID: 12393557.
96. Ying Zhao, Yachen Wang, and Wei-Guo Zhu. Applications of post-translational modifications of FoxO family proteins in biological functions. J Mol Cell Biol. 2011; 0:1–7. PMID: 21669942.
97. Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 2007; 128(2): 309-23. PMID: 17254969.
98. Yang XB, Zhao JJ, Huang CY, Wang QJ, Pan K, Wang DD, et al. Decreased expression of the FOXO3a gene is associated with poor prognosis in primary gastric adenocarcinoma patients. PLoS One. 2013; 8(10):e78158. PMID: 24194912.
99. Brenkman AB, van den Broek NJ, de Keizer PL, van Gent DC, Burgering BM. The DNA damage repair protein Ku70 interacts with FOXO4 to coordinate a conserved cellular stress response. FASEB J. 2010; 24(11):4271-80. PMID: 20570964.
100. Ausserlechner MJ, Salvador C, Deutschmann A, Bodner M, Viola G, et al. Therapy-resistant acute lymphoblastic leukemia (ALL) cells inactivate FOXO3 to escape apoptosis induction by TRAIL and Noxa. Oncotarget. 2013; 4(7):995-1007. PMID:23828551.
101. Delpuech O, Griffiths B, East P, Essafi A, Lam EW, et al. Induction of Mxi1-SR alpha by FOXO3a contributes to repression of Myc-dependent gene expression. Mol Cell Biol. 2007; 27(13):4917-30. PMID: 17452451.
102. Bucur O, Stancu AL, Goganau I, Petrescu SM, Pennarun B, et al. Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells. PLoS One. 2013; 8(10):e77390. PMID: 24155950.
103. Ito Y, Daitoku H, Fukamizu A. Foxo1 increased pro-inflammatory gene expression by inducing C/EBPbeta in TNF-alpha-treated adipocytes. Biochem Biophys Res Commun. 2009; 378(2):290-5. PMID: 19026986.
104. Su D, Coudriet GM, Hyun Kim D, Lu Y, Perdomo G, et al, FoxO1 links insulin resistance to proinflammatory cytokine IL 1beta production in macrophages. Diabetes. 2009; 58(11):2624-33. PMID: 19651810.
105. Reed SA, Sandesara PB, Senf SM, Judge AR. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. FASEB J. 2012; 26(3):987-1000. PMID: 22102632.
106. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007; 6(6): 458-71. PMID: 18054315.
107. Zhao J, Brault JJ, Schild A, Cao P, Sandri M, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007; 6(6):472-83. PMID:18054316.
108. Chiacchiera F, Simone C. Inhibition of p38alpha unveils an AMPK-FoxO3A axis linking autophagy to cancer-specific metabolism. Autophagy. 2009; 5(7):1030-3. PMID: 19587525.
109. Tan WQ, Wang K, Lv DY, Li PF. Foxo3a inhibits cardiomyocyte hypertrophy through transactivating catalase. J Biol Chem. 2008; 283(44):29730-9. PMID:18772130.
110. Allen DL, Unterman TG. Regulation of myostatin expression and myoblast differentiation by FoxO and SMADtranscription factors. Am J Physiol Cell Physiol. 2007; 292(1):C188-99. PMID:16885393.
111. Altomonte J, Richter A, Harbaran S, Suriawinata J, Nakae J, et al. Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab. 2003;285(4):E718-28. PMID:12783775.
112. Ni YG, Wang N, Cao DJ, Sachan N, Morris 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):20517-22. PMID: 18077353.
113. Kuningas M, Mägi R, Westendorp RG, Slagboom PE, Remm M, van Heemst D. Haplotypes in the human Foxo1a and Foxo3a genes; impact on disease and mortality at old age. Eur J Hum Genet. 2007; 15(3):294-301. PMID:17245409.
114. Furuyama T, Kitayama K, Shimoda Y, Ogawa M, Sone K, Yoshida-Araki K, Hisatsune H, et al. Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J Biol Chem. 2004; 279(33):34741-9. PMID: 15184386.
115. Sethi G, Shanmugam MK, Ramachandran L, Kumar AP, Tergaonkar V. Multifaceted link between cancer and inflammation. Biosci Rep. 2012; 32(1):1-15. PMID: 21981137.
116. Kim SY, Yoon J, Ko YS, Chang MS, Park JW, Lee HE, et al. Constitutive phosphorylation of the FOXO1 transcription factor in gastric cancer cells correlates with microvessel area and the expressions of angiogenesis - related molecules. BMC Cancer. 2011; 11:264. PMID: 21696576.
117. Sengupta A, Molkentin JD, Paik JH, DePinho RA, Yutzey KE. FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress. J Biol Chem. 2011 Mar 4;286(9):7468-78. PMID: 21159781.
118. Abid MR, Yano K, Guo S, Patel VI, Shrikhande G, et al. Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia. J Biol Chem. 2005; 280(33):29864-73. PMID: 15961397.
119. Tsuchiya K, Westerterp M, Murphy AJ, Subramanian V, Ferrante AW Jr, et al. Expanded granulocyte/monocyte compartment in myeloid-specific triple FoxO knockout increases oxidative stress and accelerates atherosclerosis in mice. Circ Res. 2013; 112(7):992-1003. PMID: 23420833.
120. Watkins WJ, Umbers AJ, Woad KJ, Harris SE, Winship IM, et al. Mutational screening of FOXO3A and FOXO1A in women with premature ovarian failure. Fertil Steril. 2006; 86(5):1518-21. PMID: 16979636.
121. Yilmaz OH, Morrison SJ. The PI-3kinase pathway in hematopoietic stem cells and leukemia-initiating cells: a mechanistic difference between normal and cancer stem cells. Blood Cells Mol Dis. 2008; 41(1):73-6. PMID: 18387833.
122. Martínez DE. Mortality pattern suggest lack of senescence in hydra. Exp Gerontol. 1998; 33(3):217-25. PMID:9615920.
123. Eijkelenboom A, Burgering BM. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 2013; 14(2):83-97. PMID: 23325358.
124. Kwei KA, Baker JB, Pelham RJ. Modulators of sensitivity and resistance to inhibition of PI3K identified in a pharmacogenomic screen of the NCI-60 human tumor cell line collection. PLoS One. 2012; 7(9):e46518. PMID: 23029544.
125. Moghaddas Gholami A, Hahne H, Wu Z, Auer FJ, Meng C, et al. Global proteome analysis of the NCI-60 cell line panel. Cell Rep. 2013; 4(3):609-20. PMID:23933261.
126. Wu C, Orozco C, Boyer J, Leglise M, Goodale J, et al. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol. 2009; 10(11):R130.PMID: 19919682.
127. Wu C, Macleod I, Su AI. BioGPS and MyGene.info: organizing online, gene-centric information. Nucleic Acids Res. 2013; 41(Database issue):D561-5 PMID:23175613.
128. Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A. 2004; 101(16):6062-7. PMID: 15075390.
129. Wondisford AR, Xiong L, Chang E, Meng S, Meyers DJ, et al. Control of Foxo1 Gene Expression by Co-activator P300. J Biol Chem. 2014; 289(7):4326-33. PMID: 24379407.
130. van Roon EH, Boot A, Dihal AA, Ernst RF, van Wezel T, et al. BRAF mutation-specific promoter methylation of FOX genes in colorectal cancer. Clin Epigenetics. 2013; 5(1):2. PMID: 23324568.
131. Albulescu R, Neagu M, Albulescu L, Tanase C.Tissular and soluble miRNAs for diagnostic and therapy improvement in digestive tract cancers. Expert Rev Mol Diagn. 2011 Jan;11(1):101-20. doi: 10.1586/erm.10.106. PMID:21171925.
132. Neagu M, Constantin C, Tanase C. Immune-related biomarkers for diagnosis/prognosis and therapy monitoring of cutaneous melanoma. Expert Rev Mol Diagn. 2010; 10(7): 897-919. PMID: 20964610.
133. Kim KM, Park SJ, Jung SH, Kim EJ, Jogeswar G, et al. miR-182 is a negative regulator of osteoblast proliferation, differentiation, and skeletogenesis through targeting FoxO1. J Bone Miner Res. 2012; 27(8):1669-79. PMID: 22431396.
134. Guo Y, Liu H, Zhang H, Shang C, Song Y.miR-96 regulates FOXO1-mediated cell apoptosis in bladder cancer. Oncol Lett. 2012; 4(3):561-565. PMID: 23741253.
135. Lin H, Dai T, Xiong H, Zhao X, Chen X, et al. Unregulated miR-96 induces cell proliferation in human breast cancer by downregulating transcriptional factor FOXO3a. PLoS One. 2010; 5(12):e15797.
136. Xie L, Ushmorov A, Leithäuser F, Guan H, Steidl C, et al. FOXO1 is a tumor suppressor in classical Hodgkin lymphoma. Blood. 2012; 119(15):3503-11. PMID: 22343918.
137. Wu Z, Sun H, Zeng W, He J, Mao X. Upregulation of MircoRNA-370 induces proliferation in human prostate cancer cells by downregulating the transcription factor FOXO1. PLoS One. 2012; 7(9):e45825. PMID: 23029264.
138. Wu C, Jin B, Chen L, Zhuo D, Zhang Z, et al. MiR-30d induces apoptosis and is regulated by the Akt/FOXO pathway in renal cell carcinoma. Cell Signal. 2013; 25(5):1212-21. PMID: 23416459.
139. Singhal R, Bard JE, Nowak NJ, Buck MJ, Kandel ES. FOXO1 regulates expression of a microRNA cluster on X chromosome. Aging (Albany NY). 2013; 5(5):347-56. PMID: 23748164.
140. Brett JO, Renault VM, Rafalski VA, Webb AE, Brunet A. The microRNA cluster miR-106b~25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiation. Aging (Albany NY). 2011; 3(2):108-24. PMID: 21386132.

GO BACK to the 2013, Oct-Dec issue
GO BACK to DISCOVERIES
MEET OUR EDITORIAL BOARD
SUBMIT A MANUSCRIPT

Email Email us at info@discoveriesjournals.org if you have any questions.

News & Events Latest news from our journals.

  • 2022| Discoveries Reports

    Access the new website of DISCOVERIES REPORTS at: discoveries-reports.com. 

  • 2022, April| AWARDS!

    2022 Discoveries Award winning articles!

    - Kinal Bhatt et al. 2021 (Larking Health System, FL, USA); Bhatt K, Agolli A, Patel MH, et al. High mortality co-infections of COVID-19 patients: mucormycosis and other fungal infections. Discoveries. 2021;9(1):e126. 
    27 citations in the past 1 year - $1000 prize

    - Hasnain Jan et al. 2020 (Quaid-i-Azam University, Pakistan); Jan H, Faisal S, Khan A, et al. COVID-19: Review of Epidemiology and Potential Treatments Against 2019 Novel Coronavirus. Discoveries. 2020;8(2):e108. 
    23 citations in the past 2 years - $400 prize

    Congratulations! Prizes will be received by the awardees in July, 2022!.

  • 2021, January| AWARDS!

    2022 DISCOVERIES AWARDS! Discoveries will offer $1000 and $400 awards in early 2022, for the most cited (2021 ISI Citations) and visible (Altmetric Score) articles published in 2018-2021.

  • 2020, November| Discoveries on Twitter!

    You can now follow the latest Discoveries news and updates on Twitter! (@DiscoveriesNews) 

  • 2020, August| For Authors!

    Due to a high volume of article submissions, our peer-review process takes more than usual. The pre-screening decision is released in 1-2 days, while the peer-review process lasts between 10 and 20 days.  

  • 2020, April | For Authors!

    WE DO NOT TOLERATE ANY MISCONDUCT! Please be aware that we are testing all received articles with specialized software for PLAGIARISM and WE WILL TAKE MEASURES if your article is already published or in consideration for publication by other journals! This may result in serious professional consequences for the authors. The latest striking case is the following article which is already published and was re-submitted here.  

  • 2020, April | For Authors!

    We are happy to let you know that all articles published in Discoveries are now on PubMedCentral (PMC). New accepted articles will be included in PMC and PubMed within 1-2 weeks after their publication.

  • 2020, January | For Authors!

    Starting in January 2020, Discoveries will also consider articles submitted by Discoveries' Editorial Board members. However, only a small number of such articles (maximum 4 articles/year) will be considered for publication after the peer-review process, and the authors who are also our editors will be clearly disclosed. 

  • 2019, September | Indexed by PMC

    Discoveries is now indexed by PubMedCentral and Pubmed. The agreement with US National Library of Medicine was signed on September 10, 2019. Our next step is ISI Web of Science indexing. NOTE: previously published articles will be included on PubMed in early 2020.

  • 2019, September | PubMed inclusion!

    We are happy to let you know that Discoveries successfuly passed the last step (Technical Review) required for PubMedCentral and PubMed inclusion!

  • 2019, June | PubMed inclusion News!

    We are happy to receive positive comments from PMC/NLM-NIH regarding Discoveries' last step (Technical Review) required for PubMedCentral and PubMed inclusion. We will let you know once whole indexing process is completed. 

  • 2018-2019 | For Authors!

    From now on and for at least 1 year, we will only accept articles from authors that are NOT members of Discoveries' Editorial Board. All articles submitted by our editors will be immediately rejected until further notice. 

  • 2018 | PubMed inclusion News!

    Discoveries successfully passed the Scientific Quality Review by NLM-NIH for PubMedCentral and PubMed indexing. This is the first and the most important step towards PubMedCentral and PubMed indexing! The second (last) step is the Technical Review.

  • April 2016 | Faster Peer-Review

    Starting on April 13th, all articles selected for a peer-review will receive the post peer-review decision within 10 days. The initial pre-screening time will remain the same (48h from the submission of the manuscript). This decision will significantly accelerate the publication, with no effect on the quality of the peer-review process.

  • February 2016 | Manuscript submission

    Discoveries is commited to excellence, quality and high editorial standards. We are receiving an increasing number of manuscripts for which the identity of the authors/corresponding author can't be verified. Please NOTE that ALL these articles were and will be immediately REJECTED. Indicating an institutional email address is the easiest way to overcome this problem! Moreover, we do not accept any pressure on our editorial board to accept a manuscript. This results in a prompt rejection of the article.

    Editorial Policies
  • January 2016 |Discoveries-AIM

    After reaching all proposed milestones until now (including being indexed by Google Scholar in 2014), Discoveries' next Aim is PubMed indexing of all its articles (already published and upcoming). There will be no charge for the submission or publication of articles in Discoveries before PubMed indexing.

  • August 2015 | Discoveries - on PubMed

    We are happy to announce that our first Discoveries articles were included in PMC and PubMed. More articles (submitted by NIH funded articles) are now processed for being included.

    Discoveries articles now on PubMed
  • April 2015 | Special Issue

    DISCOVERIES publish the SPECIAL ISSUE entitled "INFLAMMATION BETWEEN DEFENSE AND DISEASE: Impact on Tissue Repair and Chronic Sickness".

    Special Issue on "Inflammation"
  • 2015 | Ischemia Collection

    DISCOVERIES launched a call for papers for a Collection of Articles with focus on "ISCHEMIA". If you are interested to submit a manuscript, please contact us at info@discoveriesjournals.org

  • October 2014 | Special Issue

    DISCOVERIES launched a call for papers, for the SPECIAL ISSUE entitled "INFLAMMATION BETWEEN DEFENSE AND DISEASE: Impact on Tissue Repair and Chronic Sickness".

  • September 2014 | Special Issue

    DISCOVERIES just publish the SPECIAL ISSUE entitled "CELL SECRETION & MEMBRANE FUSION" in September 2014. Initially scheduled for publication between October 2014-March 2015, this issue was successfully published earlier than scheduled. 

    Special Issue
  • April 2014 | Indexed by Google Scholar

    All our published articles are now indexed by Google Scholar! Current citations for each individual article published in either Discoveries or Discoveries Reports are also shown. First citations to Discoveries articles are included! Search for the article's title or the authors:

    Google Scholar Search

  • July 2013 | Manuscript Submission

    Submit your manuscript FREE, FAST and EASY ! (in less than 1 minute)
    There are NO fees for the manuscript submission or publishing of the accepted manuscripts.

    Read more

  • July 2013 | DISCOVERIES

    We are now ACCEPTING MANUSCRIPTS for publishing in DISCOVERIES. We aim to publish a small number of high impact experimental articles & reviews (around 40/year) to maintain a high impact factor. Domains of interest: all areas related to Medicine, Biology and Chemistry ...

    Read more

  • July 2013 | DISCOVERIES REPORTS

    We are now ACCEPTING MANUSCRIPTS for DISCOVERIES REPORTS, publishing inovative and important research findings from all areas related to Medicine, Biology and Chemistry. We are also accepting experimental articles that validate/invalidate highly used reagents in current publications (ex. antibodies) and selected articles presenting negative data with impact and of wide scientific interest ...

    Read more

Member Login
Free Registration Click here to sign up
Copyright © 2013 Applied Systems. All Rights Reserved.