# FOX proteins

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. FOX proteins also have pioneering transcription activity by being able to bind condensed chromatin during cell differentiation processes.
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. Forkhead proteins are a subgroup of the helix-turn-helix class of proteins.

## Biological roles

Fox genes are key elements in development and many biological processes, including regulating apoptosis. Fox genes must be under extreme evolutionary supervision in a genomic sequence or cis-acting elements. If they are not, they can lead to the development of many different types of cancer. Some of the types of cancer that it can lead to are carcinoma, breast, prostate, and acute lymphocytic leukemia.
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.
FOX proteins act as transcription factors that regulate genes which are associated with the cell cycle. FOX proteins promote the entry of a cell into S-phase and ensures the cell undergoes mitosis properly. The activity of FOX proteins are regulated by proliferation and anti-proliferations signals.

## 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. 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.

## 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)
* FOXQ1
* FOXR1, FOXR2
* FOXS1

## Cancer

Depending on the subfamily, the deregulation of FOX proteins is often associated with tumorigenesis and can act as a tumor suppressor or an oncogene. Changes in post-translational modifications, genetic events, or oncoviruses are known causes for this deregulation.
FOX proteins play critical roles in cellular homeostasis as they act as both tumor suppressors and oncogenes depending on the context. Dysregulation of FOX proteins may also contribute to diseases such as neurodevelopmental disorders and metabolic syndromes. For example, FOXM1 is essential for cell cycle progression and is frequently over-expressed in tumors while FOXO proteins regulate apoptosis and stress responses indicating they often act as tumor suppressors.
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. 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.