FOXO4

FOXO4 is a member of the forkhead family of transcription factors in O subclass, which is characterized by a winged helix domain used for DNA binding.{{cite journal | vauthors = Weigel D, Jäckle H | title = The fork head domain: a novel DNA binding motif of eukaryotic transcription factors? | journal = Cell | volume = 63 | issue = 3 | pages = 455–456 | date = Nov 1990 | pmid = 2225060 | doi=10.1016/0092-8674(90)90439-l| s2cid = 1986657 }}{{cite journal | vauthors = Kaestner KH, Knochel W, Martinez DE | title = Unified nomenclature for the winged helix/forkhead transcription factors | journal = Genes & Development | volume = 14 | issue = 2 | pages = 142–146 | date = Jan 2000 | pmid = 10702024 | doi=10.1101/gad.14.2.142| s2cid = 26488600 | doi-access = free }} There are 4 members of the FOXO family, including FOXO1, FOXO3, and FOXO6. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation.{{cite journal | vauthors = van der Horst A, Burgering BM | title = Stressing the role of FoxO proteins in lifespan and disease | journal = Nature Reviews Molecular Cell Biology | volume = 8 | issue = 6 | pages = 440–450 | date = Jun 2007 | pmid = 17522590 | doi = 10.1038/nrm2190 | s2cid = 31546098 }} Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis.{{cite journal | vauthors = van der Heide LP, Jacobs FM, Burbach JP, Hoekman MF, Smidt MP | title = FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling | journal = The Biochemical Journal | volume = 391 | issue = Pt 3 | pages = 623–629 | date = Nov 2005 | pmid = 15987244 | doi = 10.1042/BJ20050525 | pmc=1276963}}{{cite journal | vauthors = Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A | title = Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 32 | pages = 11278–11283 | date = Aug 2005 | pmid = 16076959 | doi = 10.1073/pnas.0502738102 | pmc=1183558| bibcode = 2005PNAS..10211278M | doi-access = free }}{{cite journal | vauthors = Boura E, Silhan J, Herman P, Vecer J, Sulc M, Teisinger J, Obsilova V, Obsil T | title = Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding | journal = The Journal of Biological Chemistry | volume = 282 | issue = 11 | pages = 8265–8275 | date = Mar 2007 | pmid = 17244620 | doi = 10.1074/jbc.M605682200 | s2cid = 22561455 | doi-access = free }}{{cite journal | vauthors = Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD |author5-link=Mien-Chie Hung | title = Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification | journal = Nucleic Acids Research | volume = 35 | issue = 20 | pages = 6984–6994 | pmid = 17940099 | doi = 10.1093/nar/gkm703 | year=2007 | pmc=2175300}}{{cite journal | vauthors = Brent MM, Anand R, Marmorstein R | title = Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification | journal = Structure | volume = 16 | issue = 9 | pages = 1407–16 | date = Sep 2008 | pmid = 18786403 | doi = 10.1016/j.str.2008.06.013 | pmc=2597217}} Two of the main upstream regulators of FOXO4 activity are phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB.{{cite journal | vauthors = Manning BD, Cantley LC | title = AKT/PKB signaling: navigating downstream | journal = Cell | volume = 129 | issue = 7 | pages = 261–1274 | date = Jun 2007 | pmid = 17604717 | doi = 10.1016/j.cell.2007.06.009 | pmc=2756685}}{{cite journal | vauthors = Calnan DR, Brunet A | title = The FoxO code | journal = Oncogene | volume = 27 | issue = 16 | pages = 2276–2288 | date = Apr 2008 | pmid = 18391970 | doi = 10.1038/onc.2008.21 | s2cid = 35743203 }} Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.

FOXO transcription factors have been shown to be the downstream effector molecules of insulin-like growth factor (IGF) signaling pathway. In the absence of insulin, PI3K is inactive, so the FOXO homolog daf-16 is able to translocate to the nucleus and turn on many genetic pathways associated with longevity in the roundworm Caenorhabditis elegans.{{cite journal | vauthors = Neumann-Haefelin E, Qi W, Finkbeiner E, Walz G, Baumeister R, Hertweck M | title = SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans | journal = Genes & Development | volume = 22 | issue = 19 | pages = 2721–2735 | date = Oct 2008 | pmid = 18832074 | doi = 10.1101/gad.478408 | pmc=2559911}} FOXO's activation of these pathways produces an increase in lifespan for worms, flies, mice; similar variants of FOXO3a have been associated with longer human lives as well.{{cite journal | vauthors = Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R | title = A C. elegans mutant that lives twice as long as wild type | journal = Nature | volume = 366 | issue = 6454 | pages = 461–464 | date = Dec 1993 | pmid = 8247153 | doi = 10.1038/366461a0 | bibcode = 1993Natur.366..461K | s2cid = 4332206 }}{{cite journal | vauthors = Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD | title = FOXO3A genotype is strongly associated with human longevity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 37 | pages = 13987–13992 | date = Sep 2008 | pmid = 18765803 | doi = 10.1073/pnas.0801030105 | pmc=2544566| bibcode = 2008PNAS..10513987W | doi-access = free }}

FOXO4 can bind with p53 protein to induce cellular senescence.{{cite journal | vauthors=Baar MP, Brandt RM, Putavet DA, Klein JD, Derks KW, Bourgeois BR, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RW, Madl T, Hoeijmakers JH, Campisi J, de Keizer PL | title=Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging | journal=Cell | volume=169 | issue=1 | pages=132–147 | year=2017 | doi = 10.1016/j.cell.2017.02.031 | pmc=5556182 | pmid=28340339 }} A peptide competing with FOXO4 can act as a senolytic by excluding p53 from the nucleus.

Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation.{{cite journal | vauthors = Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R | title = PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer | journal = Science | volume = 275 | issue = 5308 | pages = 1943–1947 | date = Mar 1997 | pmid = 9072974 | doi=10.1126/science.275.5308.1943| s2cid = 23093929 }}{{cite journal|author3-link=Alberto Bardelli | vauthors = Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE | title = High frequency of mutations of the PIK3CA gene in human cancers | journal = Science | volume = 304 | issue = 5670 | pages = 554 | date = Apr 2004 | pmid = 15016963 | doi = 10.1126/science.1096502 | s2cid = 10147415 }}{{cite journal | vauthors = Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmström PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R | title = PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma | journal = Cancer Research | volume = 65 | issue = 7 | pages = 2554–2559 | date = Apr 2005 | pmid = 15805248 | doi = 10.1158/0008-5472-CAN-04-3913 }} FOXO4 activates the cell cycle dependent kinase inhibitor, P27, which in turn prevents tumors from progressing into G1.{{cite journal | vauthors = Yang H, Zhao R, Yang HY, Lee MH | title = Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity | journal = Oncogene | volume = 24 | issue = 11 | pages = 1924–35 | date = Mar 2005 | pmid = 15688030 | doi = 10.1038/sj.onc.1208352 | s2cid = 20360440 | doi-access = free }} In HER-2 positive tumor cells, increasing FOXO4 activity reduces tumor size. Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia.{{cite journal | vauthors = Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA | title = FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis | journal = Cell | volume = 128 | issue = 2 | pages = 309–323 | date = Jan 2007 | pmid = 17254969 | doi = 10.1016/j.cell.2006.12.029 | pmc=1855089}} The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.

In gastric cancers (GC), it has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ.{{cite journal | vauthors = Liu X, Zhang Z, Sun L, Chai N, Tang S, Jin J, Hu H, Nie Y, Wang X, Wu K, Jin H, Fan D | title = MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4 | journal = Carcinogenesis | volume = 32 | issue = 12 | pages = 1798–1805 | date = Dec 2011 | pmid = 21934092 | doi = 10.1093/carcin/bgr213 }} When compared to normal tissue, all GC epithelia had lower levels of FOXO4 located in the nucleus, consistent with less FOXO4 effector activity and FOXO4's function as a suppressor of carcinogenic properties. It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis by downregulating vimentin.{{cite journal | vauthors = Su L, Liu X, Chai N, Lv L, Wang R, Li X, Nie Y, Shi Y, Fan D | title = The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer | journal = BMC Cancer | volume = 14 | pages = 378 | pmid = 24886657 | doi = 10.1186/1471-2407-14-378 | year=2014 | pmc=4063225 | doi-access = free }} These results are consistent with FOXO4 providing a role in inhibiting the epithelia to mesenchymal transition (EMT).

In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4.{{cite journal | vauthors = Xu MM, Mao GX, Liu J, Li JC, Huang H, Liu YF, Liu JH | title = Low expression of the FoxO4 gene may contribute to the phenomenon of EMT in non-small cell lung cancer | journal = Asian Pacific Journal of Cancer Prevention | volume = 15 | issue = 9 | pages = 4013–4018 | pmid = 24935588 | doi=10.7314/apjcp.2014.15.9.4013 | year=2014| doi-access = free }} As with gastric cancer, these cancers with the lowest levels of FOXO4 also had the lowest levels of E-cadherin and highest levels of vimentin, consistent with FOXO4 acting as a suppressor of the EMT phenotype.

• PIN1, Mdm2 – FOXO4 has been shown to interact with PIN1{{cite journal | vauthors = Brenkman AB, de Keizer PL, van den Broek NJ, van der Groep P, van Diest PJ, van der Horst A, Smits AM, Burgering BM | title = The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors | journal = Cancer Res. | volume = 68 | issue = 18 | pages = 7597–605 | date = Sep 2008 | pmid = 18794148 | doi = 10.1158/0008-5472.CAN-08-1059 }} and Mdm2.{{cite journal | vauthors = Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM | title = Mdm2 induces mono-ubiquitination of FOXO4 | journal = PLOS ONE | volume = 3 | issue = 7 | pages = e2819 | year = 2008 | pmid = 18665269 | pmc = 2475507 | doi = 10.1371/journal.pone.0002819 | bibcode = 2008PLoSO...3.2819B | editor1-last = Cookson | editor1-first = Mark R. | doi-access = free }}

• CIC – chromosomal translocation resulting in a fusion CIC-FOXO4 protein is observed in some tumors.{{cite journal | vauthors = Wong D, Yip S | title = Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor | journal = The Journal of Pathology | volume = 250 | issue = 5 | pages = 532–540 | date = April 2020 | pmid = 32073140 | doi = 10.1002/path.5400 | s2cid = 211192274 | url = | doi-access = free }}

• FOX proteins

{{reflist|33em}}

{{refbegin|33em}}

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• {{cite journal | vauthors = So CW, Cleary ML | title = MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function | journal = Mol. Cell. Biol. | volume = 22 | issue = 18 | pages = 6542–52 | year = 2002 | pmid = 12192052 | pmc = 135648 | doi = 10.1128/MCB.22.18.6542-6552.2002 }}
• {{cite journal | vauthors = Tang TT, Lasky LA | title = The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism | journal = J. Biol. Chem. | volume = 278 | issue = 32 | pages = 30125–35 | year = 2003 | pmid = 12761217 | doi = 10.1074/jbc.M302042200 | s2cid = 43919271 | doi-access = free }}
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{{refend}}

• {{MeshName|MLLT7+protein,+human}}
• {{PDBe-KB2|P98177|Forkhead box protein O4}}

{{NLM content}}

{{PDB Gallery|geneid=4303}}

{{Transcription factors|g3}}

Category:Forkhead transcription factors

Category:Aging-related proteins