FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork headDNA-binding domain. There are three other FoxO family members in humans, FOXO1, FOXO4 and FOXO6. These transcription factors share the ability to be inhibited and translocated out of the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway (aside from FOXO6, which may be constitutively nuclear). Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.
It is thought that FOXO3a is also involved in protection from oxidative stress by upregulating antioxidants such as catalase and MnSOD. Ron DePinho's group generated Foxo3 knockout mice, and showed that female exhibit a dramatic age-dependent infertility, due to premature ovarian failure.
Deregulation of FOXO3a is involved in tumorigenesis, for example translocation of this gene with the MLL gene is associated with secondary acute leukemia. Downregulation of FOXO3a activity is often seen in cancer (e.g. by increase in Akt activity resulting from loss of PTEN). FOXO3 is known as a tumour suppressor.
Alternatively spliced transcript variants encoding the same protein have been observed.
^Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC (Jan 1998). "Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily". Genomics. 47 (2): 187–99. PMID9479491. doi:10.1006/geno.1997.5122.
^Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (Mar 1999). "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor". Cell. 96 (6): 857–68. PMID10102273. doi:10.1016/S0092-8674(00)80595-4.
^Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC, Walsh K (Jan 2004). "The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP". The Journal of Biological Chemistry. 279 (2): 1513–25. PMID14551207. doi:10.1074/jbc.M304736200.
Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM, Medema RH (May 2002). "The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2". Journal of Immunology. 168 (10): 5024–5031. PMID11994454. doi:10.4049/jimmunol.168.10.5024.
Morris BJ, Willcox DC, Donlon TA, Willcox BJ (Mar 2015). "FOXO3: A Major Gene for Human Longevity – A Mini-Review". Gerontology. 61: 515–25. PMID25832544. doi:10.1159/000375235.
Kino T, Chrousos GP (Jun 2004). "Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?". Annals of the New York Academy of Sciences. 1024: 153–67. PMID15265780. doi:10.1196/annals.1321.013.
Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA (Nov 1997). "AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily". Blood. 90 (9): 3714–9. PMID9345057.
Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC (Jan 1998). "Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily". Genomics. 47 (2): 187–99. PMID9479491. doi:10.1006/geno.1997.5122.
DaSilva L, Kirken RA, Taub DD, Evans GA, Duhé RJ, Bailey MA, Farrar WL (Oct 1998). "Molecular cloning of FKHRL1P2, a member of the developmentally regulated fork head domain transcription factor family". Gene. 221 (1): 135–42. PMID9852958. doi:10.1016/S0378-1119(98)00441-7.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (Mar 1999). "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor". Cell. 96 (6): 857–68. PMID10102273. doi:10.1016/S0092-8674(00)80595-4.
Medema RH, Kops GJ, Bos JL, Burgering BM (Apr 2000). "AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1". Nature. 404 (6779): 782–7. PMID10783894. doi:10.1038/35008115.
Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ (Sep 2001). "Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family". The Journal of Biological Chemistry. 276 (36): 33554–60. PMID11435445. doi:10.1074/jbc.M105555200.
Mahmud DL, G-Amlak M, Deb DK, Platanias LC, Uddin S, Wickrema A (Feb 2002). "Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells". Oncogene. 21 (10): 1556–62. PMID11896584. doi:10.1038/sj.onc.1205230.
Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K (Jun 2002). "Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants". Molecular Vision. 8: 205–20. PMID12107410.
Modur V, Nagarajan R, Evers BM, Milbrandt J (Dec 2002). "FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer". The Journal of Biological Chemistry. 277 (49): 47928–37. PMID12351634. doi:10.1074/jbc.M207509200.
Charvet C, Alberti I, Luciano F, Jacquel A, Bernard A, Auberger P, Deckert M (Jul 2003). "Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases". Oncogene. 22 (29): 4557–68. PMID12881712. doi:10.1038/sj.onc.1206778.
Crossley LJ (Oct 2003). "Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1". Journal of Leukocyte Biology. 74 (4): 583–92. PMID12960271. doi:10.1189/jlb.0103020.
Sunters A, Fernández de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA, Coffer PJ, Medema RH, Coombes RC, Lam EW (Dec 2003). "FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines". The Journal of Biological Chemistry. 278 (50): 49795–805. PMID14527951. doi:10.1074/jbc.M309523200.
Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC, Walsh K (Jan 2004). "The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP". The Journal of Biological Chemistry. 279 (2): 1513–25. PMID14551207. doi:10.1074/jbc.M304736200.
Dansen TB, Kops GJ, Denis S, Jelluma N, Wanders RJ, Bos JL, Burgering BM, Wirtz KW (Jan 2004). "Regulation of sterol carrier protein gene expression by the forkhead transcription factor FOXO3a". Journal of Lipid Research. 45 (1): 81–8. PMID14563822. doi:10.1194/jlr.M300111-JLR200.；chih长此人十二厂二