Forkhead box protein O3

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Forkhead box protein O3
Properties of human protein
Mass / length primary structure 673 amino acids
Identifier
Gene name FOXO3
External IDs
Occurrence
Parent taxon Animals, mushrooms

The forkhead box protein O3 ( FOXO3 , older names include FOXO3A , FKHRL1 or AF6q21 ) is a transcription factor in animals and fungi that is encoded by the FOXO3 gene in humans . The FOXO3 gene is often referred to in popular or non-scientific publications as the age gene , the greisen gene or the Methuselah gene .

Location, structure and function

The gene product of FOXO3 belongs to the family of fox proteins . It is a transcription factor that attaches to certain parts of the DNA in the cell nucleus and thus influences the transcription of genes. In humans, the FOXO family also includes FOXO1, FOXO4 and FOXO6.

The FOXO3 gene is located on chromosome 6 gene locus q21 in humans . A pseudogene is on chromosome 17 gene locus p11. FOXO3 consists of at least three exons and two introns . It occupies at least 90 kb . The gene product consists of 673 amino acids .

Acute food deprivation causes increased expression of sirtuin-1 and FOXO3 in mice . This increases the resistance of the cells to oxidative stress . Switching off the FOXO3 gene ( gene knockout ) ensures that the enzyme sirtuin-1 is not expressed excessively when food is deprived. The stimulation of sirtuin-1 transcription by FOXO3 is mediated by two p53 binding sites in the sirtuin-1 promoter .

FOXO3 and aging

Stress-activated protein kinases such as JNK and p38 can stimulate the expression of FOXO3. This in turn leads to reduced cell growth and reduced cell division , among other things through inhibition of Akt / PKB . The cell goes into a state of quiescence . FOXO3 also increases the expression of the antioxidant enzymes manganese superoxide dismutase (MnSOD) and iron superoxide dismutase (FeSOD), as well as catalase . However, FOXO3 can also set apoptosis (programmed cell death) in motion.

In 2009, a study by a Kiel research group led by Friederike Flachsbart , Almut Nebel and Stefan Schreiber caused a stir , in which DNA samples from 388 centenarian Germans were compared with 731 younger people. It was noticeable that a certain allele of the FOXO3 gene is particularly common in centenarians.

In the press, terms such as longevity gene , age gene , old man's gene or methuselah gene were used. As early as September 2008, a US research group had found that the FOXO3 genotype has a significant influence on a person's life expectancy. Studies in other countries came to the same conclusion.

In 2012, researchers from the Christian-Albrechts-Universität zu Kiel (CAU) again identified the FoxO gene as the potential cause of immortality in freshwater polyps . This shows that FOXO proteins with their function as important transcription factors were preserved in the evolution of animals, the effect of which is particularly noticeable in long-lived humans.

Non-scientific reports sometimes misrepresent the facts about FOXO3. Therefore it should be made clear: every person has this gene in their genome . In the particularly long-lived people, however, two single nucleotide variants of this gene were found and their function was confirmed in experiments. Only these variants of the FOXO3 gene contribute to the noticeably longer lifespan of this group of people.

literature

  • Brian J Morris, Donald Craig Willcox, Timothy A Donlon, Bradley J Willcox: FOXO3: A major gene for human longevity - A mini-review. In: Gerontology 61 (6) / 2015: 515-525. doi: 10.1159 / 000375235 .

Web links

Individual evidence

  1. ↑ Homologues at inParanoid
  2. ↑ News from the Greisen gene. In: Spiegel-Online from February 3, 2009
  3. ↑ "Methuselah gene" identified. In: scinexx from February 4, 2009
  4. ↑ Gene discovered for longevity. In: Die Welt from February 2, 2009
  5. ↑ MJ Anderson et al .: Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. In: Genomics 47, 1998, pp. 187-199. PMID 9479491
  6. ^ Forkhead box protein O3.  In: Online Mendelian Inheritance in Man . (English)
  7. ^ S. Nemoto et al.: Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. In: Science 306, 2004, pp. 2105-2108. PMID 15604409
  8. ↑ L. Rensing: Which cellular factors determine aging? The limits of service life. In: Biol Unserer Zeit 3, 2007, pp. 190–199. doi: 10.1002 / biuz.200610337
  9. ↑ BM Burgering and RH Medema: Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB / Akt is off duty. In: J Leukoc Biol 73, 2003, pp. 689-701. PMID 12773501 (Review)
  10. ^ F. Flachsbart et al .: Association of FOXO3A variation with human longevity confirmed in German centenarians. In: PNAS 106/2009: pp. 2700–2705. PMID 19196970
  11. ↑ Live longer with the "longevity gene". Press release of the Christian-Albrechts-Universität zu Kiel from February 2nd, 2009
  12. ↑ On the trail of the Methuselah gene. In: Der Stern from February 3, 2009
  13. ↑ The 100-year-old gene. In: Focus from February 3, 2009
  14. ↑ G. Schütte: In search of the Methuselah genes. In: Die Welt of August 24, 2009
  15. ↑ BJ Willcox, TA Donlon, Q. He, R. Chen, JS Grove, K. Yano, KH Masaki, DC Willcox, B. Rodriguez, JD Curb: FOXO3A genotype is strongly associated with human longevity. In: Proceedings of the National Academy of Sciences . Volume 105, number 37, September 2008, pp. 13987-13992, doi: 10.1073 / pnas.0801030105 , PMID 18765803 , PMC 2544566 (free full text).
  16. ↑ CV Anselmi: Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. In: Rejuvenation Res 12, 2009, pp. 95-104. PMID 19415983
  17. ↑ Anna-Marei Boehm, Konstantin Khalturin, Friederike Anton-Erxleben, another 7 authors and Thomas CG Bosch : FoxO is a critical regulator of stem cell maintenance in immortal Hydra. In: Proceedings of the National Academy of Sciences . Volume 109, number 48, November 2012, pp. 19697-19702, doi : 10.1073 / pnas.1209714109 , PMID 23150562 , PMC 3511741 (free full text).
  18. ↑ FOCUS Online: Has the secret of eternal youth been revealed? German researchers discover immortality gene
  19. ↑ Friederike Flachsbart, Janina Dose, Liljana Gentschew, Claudia Geismann, another 29 authors and Almut Nebel: Identification and characterization of two functional variants in the human longevity gene FOXO3. In: Nature Communication 8/2017: 2063, 1–12. DOI: 10.1038 / s41467-017-02183-y .
  20. ↑ Martina Drexler: On the trail of centenarians. In: Kieler Nachrichten January 15, 2018: p. 11.