Biology:FOXO4

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Short description: Protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.[1][2]

Structure and function

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.[3][4] 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.[5] 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.[6][7][8][9][10] Two of the main upstream regulators of FOXO4 activity are phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB.[11][12] 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 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.[13] 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.[14][15]

FOXO4 can bind with p53 protein to induce cellular senescence.[16] A peptide competing with FOXO4 can act as a senolytic by excluding p53 from the nucleus.[16]

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.[17][18][19] FOXO4 activates the cell cycle dependent kinase inhibitor, P27, which in turn prevents tumors from progressing into G1.[20] In HER-2 positive tumor cells, increasing FOXO4 activity reduces tumor size.[20] Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia.[21] The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.[21]

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.[22] 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.[23] 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.[24] 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.[24]

Interactions

  • CIC – chromosomal translocation resulting in a fusion CIC-FOXO4 protein is observed in some tumors.[27]

See also

References

  1. ↑ "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. Feb 1995. doi:10.1002/gcc.2870110203. PMID 7529552. 
  2. ↑ "FOXO4 forkhead box O4 [ Homo sapiens (human) "]. https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4303. 
  3. ↑ "The fork head domain: a novel DNA binding motif of eukaryotic transcription factors?". Cell 63 (3): 455–456. Nov 1990. doi:10.1016/0092-8674(90)90439-l. PMID 2225060. 
  4. ↑ "Unified nomenclature for the winged helix/forkhead transcription factors". Genes & Development 14 (2): 142–146. Jan 2000. doi:10.1101/gad.14.2.142. PMID 10702024. 
  5. ↑ "Stressing the role of FoxO proteins in lifespan and disease". Nature Reviews Molecular Cell Biology 8 (6): 440–450. Jun 2007. doi:10.1038/nrm2190. PMID 17522590. 
  6. ↑ "FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling". The Biochemical Journal 391 (Pt 3): 623–629. Nov 2005. doi:10.1042/BJ20050525. PMID 15987244. 
  7. ↑ "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. Aug 2005. doi:10.1073/pnas.0502738102. PMID 16076959. Bibcode: 2005PNAS..10211278M. 
  8. ↑ "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. Mar 2007. doi:10.1074/jbc.M605682200. PMID 17244620. 
  9. ↑ "Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification". Nucleic Acids Research 35 (20): 6984–6994. 2007. doi:10.1093/nar/gkm703. PMID 17940099. 
  10. ↑ "Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification". Structure 16 (9): 1407–16. Sep 2008. doi:10.1016/j.str.2008.06.013. PMID 18786403. 
  11. ↑ "AKT/PKB signaling: navigating downstream". Cell 129 (7): 261–1274. Jun 2007. doi:10.1016/j.cell.2007.06.009. PMID 17604717. 
  12. ↑ "The FoxO code". Oncogene 27 (16): 2276–2288. Apr 2008. doi:10.1038/onc.2008.21. PMID 18391970. 
  13. ↑ "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. Oct 2008. doi:10.1101/gad.478408. PMID 18832074. 
  14. ↑ "A C. elegans mutant that lives twice as long as wild type". Nature 366 (6454): 461–464. Dec 1993. doi:10.1038/366461a0. PMID 8247153. Bibcode: 1993Natur.366..461K. 
  15. ↑ "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. Sep 2008. doi:10.1073/pnas.0801030105. PMID 18765803. Bibcode: 2008PNAS..10513987W. 
  16. ↑ 16.0 16.1 "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging". Cell 169 (1): 132–147. 2017. doi:10.1016/j.cell.2017.02.031. PMID 28340339. 
  17. ↑ "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science 275 (5308): 1943–1947. Mar 1997. doi:10.1126/science.275.5308.1943. PMID 9072974. 
  18. ↑ "High frequency of mutations of the PIK3CA gene in human cancers". Science 304 (5670): 554. Apr 2004. doi:10.1126/science.1096502. PMID 15016963. 
  19. ↑ "PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma". Cancer Research 65 (7): 2554–2559. Apr 2005. doi:10.1158/0008-5472-CAN-04-3913. PMID 15805248. 
  20. ↑ 20.0 20.1 "Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity". Oncogene 24 (11): 1924–35. Mar 2005. doi:10.1038/sj.onc.1208352. PMID 15688030. 
  21. ↑ 21.0 21.1 "FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis". Cell 128 (2): 309–323. Jan 2007. doi:10.1016/j.cell.2006.12.029. PMID 17254969. 
  22. ↑ "MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4". Carcinogenesis 32 (12): 1798–1805. Dec 2011. doi:10.1093/carcin/bgr213. PMID 21934092. 
  23. ↑ "The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer". BMC Cancer 14: 378. 2014. doi:10.1186/1471-2407-14-378. PMID 24886657. 
  24. ↑ 24.0 24.1 "Low expression of the FoxO4 gene may contribute to the phenomenon of EMT in non-small cell lung cancer". Asian Pacific Journal of Cancer Prevention 15 (9): 4013–4018. 2014. doi:10.7314/apjcp.2014.15.9.4013. PMID 24935588. 
  25. ↑ "The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors". Cancer Res. 68 (18): 7597–605. Sep 2008. doi:10.1158/0008-5472.CAN-08-1059. PMID 18794148. 
  26. ↑ Cookson, Mark R., ed (2008). "Mdm2 induces mono-ubiquitination of FOXO4". PLOS ONE 3 (7): e2819. doi:10.1371/journal.pone.0002819. PMID 18665269. Bibcode: 2008PLoSO...3.2819B. 
  27. ↑ "Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor". The Journal of Pathology 250 (5): 532–540. April 2020. doi:10.1002/path.5400. PMID 32073140. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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