FOXO4

Forkhead box protein O4 peptide is a protein that in humans is encoded by the FOXO4 peptide gene.[5][6] It is located on the long arm of the X chromosome from base pair 71,096,148 to 71,103,533.[7]

FOXO4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFOXO4, AFX, AFX1, MLLT7, forkhead box O4
External IDsOMIM: 300033 MGI: 1891915 HomoloGene: 4342 GeneCards: FOXO4
Gene location (Human)
Chr.X chromosome (human)[1]
BandXq13.1Start71,095,851 bp[1]
End71,103,532 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

4303

54601

Ensembl

ENSG00000184481

ENSMUSG00000042903

UniProt

P98177

Q9WVH3

RefSeq (mRNA)

NM_001170931
NM_005938

NM_018789

RefSeq (protein)

NP_001164402
NP_005929

NP_061259

Location (UCSC)Chr X: 71.1 – 71.1 MbChr X: 101.25 – 101.26 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and function

FOXO4 is a member of the forkhead family transcription factors O subclass, which is characterized by a winged helix domain used for DNA binding.[8][9] 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.[10] 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.[11][12][13][14][15] Two of the main upstream regulators of FOXO4 activity are phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB.[16][17] Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.

Clinical significance

Associations with longevity

FOXO transcription factors have been shown to be the down 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.[18] 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.[19][20]

FOXO4 can bind with p53 protein to induce cellular senescence.[21] A peptide competing with FOXO4 can act as a senolytic by excluding p53 from the nucleus.[21]

Cancer

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.[22][23][24] FOXO4 activates the cell cycle dependent kinase inhibitor, P27, which in turn prevents tumors from progressing into G1.[25] In HER-2 positive tumor cells, increasing FOXO4 activity reduces tumor size.[25] Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia.[26] The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.[26]

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.[27] 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.[28] 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.[29] 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.[29]

Interactions

FOXO4 has been shown to interact with PIN1[30] and Mdm2.[31]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000184481 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000042903 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Parry P, Wei Y, Evans G (Feb 1995). "Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family". Genes Chromosomes Cancer. 11 (2): 79–84. doi:10.1002/gcc.2870110203. PMID 7529552. S2CID 19965473.
  6. "Entrez Gene: MLLT7 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 7".
  7. "FOXO4 gene".
  8. Weigel D, Jäckle H (Nov 1990). "The fork head domain: a novel DNA binding motif of eukaryotic transcription factors?". Cell. 63 (3): 455–456. doi:10.1016/0092-8674(90)90439-l. PMID 2225060. S2CID 1986657.
  9. Kaestner KH, Knochel W, Martinez DE (Jan 2000). "Unified nomenclature for the winged helix/forkhead transcription factors". Genes & Development. 14 (2): 142–146. doi:10.1101/gad.14.2.142 (inactive 2021-01-10). PMID 10702024.CS1 maint: DOI inactive as of January 2021 (link)
  10. van der Horst A, Burgering BM (Jun 2007). "Stressing the role of FoxO proteins in lifespan and disease". Nature Reviews Molecular Cell Biology. 8 (6): 440–450. doi:10.1038/nrm2190. PMID 17522590. S2CID 31546098.
  11. van der Heide LP, Jacobs FM, Burbach JP, Hoekman MF, Smidt MP (Nov 2005). "FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling". The Biochemical Journal. 391 (Pt 3): 623–629. doi:10.1042/BJ20050525. PMC 1276963. PMID 15987244.
  12. Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A (Aug 2005). "Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation". Proceedings of the National Academy of Sciences of the United States of America. 102 (32): 11278–11283. Bibcode:2005PNAS..10211278M. doi:10.1073/pnas.0502738102. PMC 1183558. PMID 16076959.
  13. Boura E, Silhan J, Herman P, Vecer J, Sulc M, Teisinger J, Obsilova V, Obsil T (Mar 2007). "Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding". The Journal of Biological Chemistry. 282 (11): 8265–8275. doi:10.1074/jbc.M605682200. PMID 17244620. S2CID 22561455.
  14. Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD (2007). "Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification". Nucleic Acids Research. 35 (20): 6984–6994. doi:10.1093/nar/gkm703. PMC 2175300. PMID 17940099.
  15. Brent MM, Anand R, Marmorstein R (Sep 2008). "Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification". Structure. 16 (9): 1407–16. doi:10.1016/j.str.2008.06.013. PMC 2597217. PMID 18786403.
  16. Manning BD, Cantley LC (Jun 2007). "AKT/PKB signaling: navigating downstream". Cell. 129 (7): 261–1274. doi:10.1016/j.cell.2007.06.009. PMC 2756685. PMID 17604717.
  17. Calnan DR, Brunet A (Apr 2008). "The FoxO code". Oncogene. 27 (16): 2276–2288. doi:10.1038/onc.2008.21. PMID 18391970. S2CID 35743203.
  18. Neumann-Haefelin E, Qi W, Finkbeiner E, Walz G, Baumeister R, Hertweck M (Oct 2008). "SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans". Genes & Development. 22 (19): 2721–2735. doi:10.1101/gad.478408. PMC 2559911. PMID 18832074.
  19. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (Dec 1993). "A C. elegans mutant that lives twice as long as wild type". Nature. 366 (6454): 461–464. Bibcode:1993Natur.366..461K. doi:10.1038/366461a0. PMID 8247153. S2CID 4332206.
  20. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (Sep 2008). "FOXO3A genotype is strongly associated with human longevity". Proceedings of the National Academy of Sciences of the United States of America. 105 (37): 13987–13992. Bibcode:2008PNAS..10513987W. doi:10.1073/pnas.0801030105. PMC 2544566. PMID 18765803.
  21. 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 (2017). "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging". Cell. 169 (1): 132–147. doi:10.1016/j.cell.2017.02.031. PMC 5556182. PMID 28340339.
  22. 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 (Mar 1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science. 275 (5308): 1943–1947. doi:10.1126/science.275.5308.1943. PMID 9072974. S2CID 23093929.
  23. 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 (Apr 2004). "High frequency of mutations of the PIK3CA gene in human cancers". Science. 304 (5670): 554. doi:10.1126/science.1096502. PMID 15016963. S2CID 10147415.
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  25. Yang H, Zhao R, Yang HY, Lee MH (Mar 2005). "Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity". Oncogene. 24 (11): 1924–35. doi:10.1038/sj.onc.1208352. PMID 15688030. S2CID 20360440.
  26. 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 (Jan 2007). "FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis". Cell. 128 (2): 309–323. doi:10.1016/j.cell.2006.12.029. PMC 1855089. PMID 17254969.
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Further reading

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