FOX proteins explained

FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic development.^{[1] [2]} FOX proteins also have pioneering transcription activity by being able to bind condensed chromatin during cell differentiation processes.^[3]

The defining feature of FOX proteins is the forkhead box, a sequence of 80 to 100 amino acids forming a motif that binds to DNA. This forkhead motif is also known as the winged helix, due to the butterfly-like appearance of the loops in the protein structure of the domain.^[4] Forkhead proteins are a subgroup of the helix-turn-helix class of proteins.

Biological roles

Many genes encoding FOX proteins have been identified. For example, the FOXF2 gene encodes forkhead box F2, one of many human homologues of the Drosophila melanogaster transcription factor forkhead. FOXF2 is expressed in the lung and placenta.

Some FOX genes are downstream targets of the hedgehog signaling pathway, which plays a role in the development of basal cell carcinomas. Members of class O (FOXO- proteins) regulate metabolism, cellular proliferation, stress tolerance and possibly lifespan. The activity of FoxO is controlled by post-translational modifications, including phosphorylation, acetylation and ubiquitination.^[5]

Discovery

The founding member and namesake of the FOX family is the fork head transcription factor in Drosophila, discovered by German biologists Detlef Weigel and Herbert Jäckle.^{[6] [7]} Since then a large number of family members have been discovered, especially in vertebrates. Originally, they were given vastly different names (such as HFH, FREAC, and fkh), but in 2000 a unified nomenclature was introduced that grouped the FOX proteins into subclasses (FOXA-FOXS) based on sequence conservation.^[8]

Genes

• FOXA1, FOXA2, FOXA3 (See also Hepatocyte nuclear factors.)
• FOXB1, FOXB2
• FOXC1 (associated with glaucoma), FOXC2 (varicose veins)
• FOXD1, FOXD2, FOXD3 (vitiligo), FOXD4, FOXD4L1, FOXD4L3, FOXD4L4, FOXD4L5, FOXD4L6
• FOXE1 (thyroid), FOXE3 (lens)
• FOXF1 (lung), FOXF2
• FOXG1 (brain)
• FOXH1 (widely expressed)
• FOXI1 (ear), FOXI2, FOXI3
• FOXJ1 (cilia), FOXJ2 (erythroid), FOXJ3
• FOXK1, FOXK2 (HIV, IL-2, adrenal)
• FOXL1 (ovary), FOXL2
• FOXM1 (cell cycle, erythroid, cancer)
• FOXN1 (hair, thymus), FOXN2, FOXN3 (cell cycle checkpoints; widely expressed), FOXN4
• FOXO1 (widely expressed: muscle, liver, pancreas), FOXO3 (apoptosis, erythroid, longevity), FOXO4 (widely expressed), FOXO6 (liver, skeletal muscle, brain)
• FOXP1 (pluripotency then brain, heart and lung), FOXP2 (widely expressed? brain; language), FOXP3 (T cells), FOXP4  - may be ancestrally responsible for motor learning, based on insect studies (where there's only one FoxP)^[9]
• FOXQ1
• FOXR1, FOXR2
• FOXS1^[10]

Cancer

A member of the FOX family, FOXD2, has been detected progressively overexpressed in human-papillomavirus-positive neoplastic keratinocytes derived from uterine cervical preneoplastic lesions at different levels of malignancy.^[11] For this reason, this gene is likely to be associated with tumorigenesis and may be a potential prognostic marker for uterine cervical preneoplastic lesions progression.^[11]

Notes and References

1. Tuteja G, Kaestner KH . SnapShot: forkhead transcription factors I . Cell . 130 . 6 . 1160.e1–1160.e2 . September 2007 . 17889656 . 10.1016/j.cell.2007.09.005 . 38793380 . free .
2. Tuteja G, Kaestner KH . Forkhead transcription factors II . Cell . 131 . 1 . 192–192.e1 . October 2007 . 17923097 . 10.1016/j.cell.2007.09.016 . 322449 . free .
3. Zaret KS, Carroll JS . Pioneer transcription factors: establishing competence for gene expression . Genes Dev. . 25 . 21 . 2227–41 . November 2011 . 22056668 . 3219227 . 10.1101/gad.176826.111 .
4. Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Bhattacharya SS . Fox's in development and disease . Trends in Genetics . 19 . 6 . 339–344 . 2003 . 12801727. 10.1016/S0168-9525(03)00111-2 .
5. van der Horst A, Burgering BM . Stressing the role of FoxO proteins in lifespan and disease . Nat. Rev. Mol. Cell Biol. . 8 . 6 . 440–50 . June 2007 . 17522590 . 10.1038/nrm2190 . 31546098 .
6. Weigel D, Jürgens G, Küttner F, Seifert E, Jäckle H . The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo . Cell . 57 . 4 . 645–658 . 1989 . 2566386 . 10.1016/0092-8674(89)90133-5. 12317967 .
7. Weigel D, Jäckle H . The fork head domain, a novel DNA-binding motif of eucaryotic transcription factors? . Cell . 63 . 3 . 455–456 . 1990 . 2225060 . 10.1016/0092-8674(90)90439-L. 1986657 .
8. Kaestner KH, Knochel W, Martinez DE . Unified nomenclature for the winged helix/forkhead transcription factors . Genes & Development . 14 . 2. 142–146 . 2000 . 10702024 . 10.1101/gad.14.2.142 . 26488600 . free .
9. Mendoza . E . Colomb . J . Rybak . J . Pflüger . HJ . Zars . T . Scharff . C . Brembs . B . Drosophila FoxP mutants are deficient in operant self-learning. . PLOS ONE . 2014 . 9 . 6 . e100648 . 10.1371/journal.pone.0100648 . 24964149 . 4070984 . 2014PLoSO...9j0648M . free.
10. Web site: Gene group: Forkhead boxes (FOX). HUGO Gene Nomenclature Committee at the European Bioinformatics Institute. 6 June 2021.
11. Rotondo JC, Bosi S, Bassi C, Ferracin M, Lanza G, Gafà R, Magri E, Selvatici R, Torresani S, Marci R, Garutti P, Negrini M, Tognon M, Martini F . Gene expression changes in progression of cervical neoplasia revealed by microarray analysis of cervical neoplastic keratinocytes. . J Cell Physiol . 230. 4 . 802–812 . April 2015 . 25205602 . 10.1002/jcp.24808. 11392/2066612 . 24986454 . free .