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Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
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FOXO1, also known as FOXO1a (and originally as FKHR), is a member of the Forkhead family proteins of the O subclass. FOXOs have overlapping expression profiles and activities, but FOXO1 is particularly known to be an important downstream target of the insulin/IGF-1/PI3-K signalling pathway and has a role in cell cycle control and apoptosis, fertility, stress response and longevity [1][2][3]. It has a widespread distribution in the body, although expression levels are not equal throughout tissues. FOXO1 is expressed at high levels in insulin-responsive tissues (eg. adipose tissue and muscle) and insulin-production tissues (eg. pancreatic beta cells) [4].

It contains a characteristic Forkhead box DNA binding domain (DBD), and is able to up- and downregulate expression of a variety of genes via binding of its consensus Forkhead Recognition Element, or similar sequences (including Insulin Response Elements). DNA recognition is performed by helix 3 of the DBD, although other parts of the DBD also contact the DNA to increase binding stability.

FOXO1 is a human orthologue of C. elegans's daf-16, a gene required for the long-lived phenotype of daf-2-null nematodes. FOXO1’s involvement in longevity, ageing and senescence may be linked to its roles in oxidative stress, as reactive oxygen species (ROS) are known to induce cellular senescence. FOXO1 is activated and upregulated in response to oxidative stress, where it upregulates the expression of antioxidants such as catalase, MnSOD or sestrin 3. In response to DNA damage, FOXO1 contributes to cell cycle arrest [5] and if necessary, helps bring about apoptosis by upregulating/downregulating pro/anti-apoptotic genes such as Bim, PUMA and FLIP [6]. FOXO proteins are considered tumour suppressors; FOXO1 is very broadly anti-proliferative, and pro-apoptotic [7]. FOXO proteins, in particular FOXO1, have a critical role in the regulation of metabolism [4].

FOXO1 contains both nuclear export and nuclear import signals, allowing it to be localised in different subcellular areas, and sequestered in the cytoplasm. It is regulated via a complex set of post-translational modifications including phosphorylation, methylation, acetylation and polyubiquitination. These covalent modifications affect stability, subcellular localisation, gene target specificity, and DNA binding activity [8]. One of the most famous and important FOXO1 regulators is the serine/threonine kinase Akt (PKB), downstream of PI-3-kinase, which inhibits FOXO1 activity by phosphorylating it at three sites throughout the protein. Regulation by acetylation includes SIRT (sirtuin) activity, removing acetyl groups added by proteins including p300 and CBP. In adipocytes, SIRT2 activity on FOXO1 apparently suppresses adipogenesis through repression of adipogenic differentiation genes, including C/EBPalpha and PPARγ [9].

As well as post-translational modifications, FOXO1 transcriptional activity is thought to be modulated by physical interactions with proteins such as HOX5 and nuclear receptors, including estrogen receptor, androgen receptor, progesterone receptor, and PPARγ.

In mice, Foxo1 deletion is embryonic lethal and Foxo1-deficient mice die on embryonic day 10.5 due to a lack of vascular system development [10]. Despite the functional redundancy between the FoxO members, FoxO1 has an indispensable role in regulating insulin production in pancreatic beta cells, glucose and lipid production in liver, food intake and body weight in hypothalamus, and differentiation of preadipocytes, myoblasts and vascular endothelium.

  1. Maiese K et al. A "FOXO" in sight: targeting Foxo proteins from conception to cancer. Med Res Rev, 29(3):395-418. (PMID 18985696)
  2. Huang H and Tindall DJ. Dynamic FoxO transcription factors. J. Cell. Sci., 120(Pt 15):2479-87. (PMID 17646672)
  3. Maiese K et al. OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. , 14(5):219-27. (PMID 18403263)
  4. Gross DN et al. The role of FoxO in the regulation of metabolism. Oncogene, 27(16):2320-36. (PMID 18391974)
  5. Ho KK et al. Many forks in the path: cycling with FoxO. Oncogene, 27(16):2300-11. (PMID 18391972)
  1. Cornforth AN et al. FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells. Oncogene, 27(32):4422-33. (PMID 18391984)
  2. Dansen TB and Burgering BM. Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol., 18(9):421-9. (PMID 18715783)
  3. Calnan DR and Brunet A. The FoxO code. Oncogene, 27(16):2276-88. (PMID 18391970)
  4. Jing E et al. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab., 6(2):105-14. (PMID 17681146)
  5. Hosaka T et al. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc. Natl. Acad. Sci. U.S.A., 101(9):2975-80. (PMID 14978268)
FIGURE 1 Phosphorylation and other modifications of FOXO1
Schematic figure showing confirmed sites of covalent modification in FOXO1, and the kinases, acetyl transferase and methylase involved. Phosphorylation by MST increases FOXO1 activity, while Akt, and SGK are inhibitors. DBD = forkhead DNA binding domain, NLS = nuclear localisation sequence, NES = nuclear export signal, TAD = transactivation domain.
P = phosphorylation, Me = methylation, Ac = acetylation. Numbers refer to amino acid number.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.