“FOXO3”的意思、由来-开放百科全书

Function

FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA-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).^[2] Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.

This protein likely functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA,^[3] or downregulation of anti-apoptotic proteins such as FLIP.^[4]

Gopinath et al.(2014)^[5] demonstrate a functional requirement for FOXO3 as a regulator of Notch signaling pathway (an essential regulator of quiescence in adult stem cells) in the self-renewal of stem cells during muscle regeneration.

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.

Clinical significance

Deregulation of FOXO3a is involved in tumorigenesis,^[6] 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.^[7]

Association with longevity

A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world.^[8]^[9] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms.

See also

References

1. ^{{cite journal | vauthors = Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC | title = Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily | journal = Genomics | volume = 47 | issue = 2 | pages = 187–99 | date = Jan 1998 | pmid = 9479491 | doi = 10.1006/geno.1997.5122 }}
2. ^{{cite journal | vauthors = Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME |author-link3 = Michael J. Zigmond | title = Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor | journal = Cell | volume = 96 | issue = 6 | pages = 857–68 | date = Mar 1999 | pmid = 10102273 | doi = 10.1016/S0092-8674(00)80595-4 }}
3. ^{{cite journal | vauthors = Ekoff M, Kaufmann T, Engström M, Motoyama N, Villunger A, Jönsson JI, Strasser A, Nilsson G | title = The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells | journal = Blood | volume = 110 | issue = 9 | pages = 3209–17 | date = Nov 2007 | pmid = 17634411 | pmc = 2200922 | doi = 10.1182/blood-2007-02-073957 }}
4. ^{{cite journal | vauthors = Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC, Walsh K | title = The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP | journal = The Journal of Biological Chemistry | volume = 279 | issue = 2 | pages = 1513–25 | date = Jan 2004 | pmid = 14551207 | doi = 10.1074/jbc.M304736200 }}
5. ^{{cite journal | vauthors = Gopinath SD, Webb AE, Brunet A, Rando TA | title = FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal | journal = Stem Cell Reports | volume = 2 | issue = 4 | date = Apr 2014 | pmid = 24749067 | doi = 10.1016/j.stemcr.2014.02.002 | pages=414–26 | pmc=3986584}}
6. ^{{cite journal | vauthors = Myatt SS, Lam EW | title = The emerging roles of forkhead box (Fox) proteins in cancer | journal = Nature Reviews. Cancer | volume = 7 | issue = 11 | pages = 847–59 | date = Nov 2007 | pmid = 17943136 | doi = 10.1038/nrc2223 }}
7. ^{{cite web | title = Entrez Gene: FOXO3A forkhead box O3A| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2309| accessdate = }}
8. ^{{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 = 13987–92 | date = Sep 2008 | pmid = 18765803 | pmc = 2544566 | doi = 10.1073/pnas.0801030105 }}
9. ^{{cite journal | vauthors = Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A | title = Association of FOXO3A variation with human longevity confirmed in German centenarians | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 8 | pages = 2700–5 | date = Feb 2009 | pmid = 19196970 | pmc = 2650329 | doi = 10.1073/pnas.0809594106 }}

Function

Clinical significance

Association with longevity

See also

References

Further reading

External links