FOX (forkhead box) proteins are a family of

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

s that play important roles in regulating the expression of

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

s 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 Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

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 Helix-turn-helix is a DNA-binding protein (DBP). The helix-turn-helix (HTH) is a major structural motif capable of binding DNA. Each monomer incorporates two α helices, joined by a short strand of amino acids, that bind to the major groove of ...

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''

forkhead. FOXF2 is expressed in the lung and placenta. Some FOX genes are downstream targets of the

hedgehog signaling pathway The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathwa ...

, 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.

Discovery

The founding member and namesake of the FOX family is the ''fork head'' transcription factor in

Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...

, discovered by German biologists Detlef Weigel and Herbert Jäckle. Since then a large number of family members have been discovered, especially in

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...

s. 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 Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the ''FOXA1'' gene. Function FOXA1 is a member of the forkhead class of DNA-binding proteins. These hepatocy ...

FOXA2 Forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3B), is a transcription factor that plays an important role during development, in mature tissues and, when dysregulated or mutated, also in cancer. Structure ...

, FOXA3 (See also

Hepatocyte nuclear factors Hepatocyte nuclear factors (HNFs) are a group of phylogenetically unrelated transcription factors that regulate the transcription of a diverse group of genes into proteins. These proteins include blood clotting factors and in addition, enzymes a ...

.) *

FOXB1 Forkhead box B1 is a protein that in humans is encoded by the FOXB1 gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...

, FOXB2 * FOXC1 (associated with glaucoma), FOXC2 (varicose veins) *

FOXD1 Forkhead box D1 is a protein that in humans is encoded by the FOXD1 gene. Forkhead d1 is a kidney expressed transcription factor maps at the chromosome 5 at position 5q12—q13, identified in ''Drosophila forkhead'' protein and mammalian HNF3 tra ...

, FOXD2, FOXD3 (

vitiligo Vitiligo is a disorder that causes the skin to lose its color. Specific causes are unknown but studies suggest a link to immune system changes. Signs and symptoms The only sign of vitiligo is the presence of pale patchy areas of depigmen ...

FOXD4 Forkhead box protein D4 is a protein that in humans is encoded by the ''FOXD4'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ...

, FOXD4L1, FOXD4L3, FOXD4L4, FOXD4L5, FOXD4L6 * FOXE1 (thyroid), FOXE3 (lens) * FOXF1 (lung), FOXF2 *

FOXG1 Forkhead box protein G1 is a protein that in humans is encoded by the ''FOXG1'' gene. Function This gene belongs to the forkhead family of transcription factors that is characterized by a distinct forkhead domain. The complete function of thi ...

(brain) * FOXH1 (widely expressed) *

FOXI1 Forkhead box I1 is a protein that in humans is encoded by the ''FOXI1'' gene. This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. The specific function of this gene has not y ...

(ear), FOXI2,

FOXI3 Forkead box I3 (FOXI3) is a protein that in humans is encoded by the ''FOXI3'' gene. FOXI3 is a forkhead box transcription factor that is expressed in the development of hair and teeth. One of its mutations is a dominant allele responsible for t ...

* FOXJ1 (cilia), FOXJ2 (erythroid), FOXJ3 *

FOXK1 Forkhead box protein K1 is a transcription factor of the Forkhead transcription factors, forkhead box family that in humans is encoded by the ''FOXK1'' gene. During starvation, in type 2 diabetes, in rapidly dividing cells during Embryonic develo ...

, FOXK2 (HIV, IL-2, adrenal) * FOXL1 (ovary), FOXL2 * FOXM1 (cell cycle, erythroid, cancer) * FOXN1 (hair, thymus), FOXN2,

FOXN3 Forkhead box protein N3 is a protein that in humans is encoded by the ''FOXN3'' gene. This gene is a member of the forkhead/winged helix transcription factor family. Checkpoints are eukaryotic DNA damage-inducible cell cycle arrests at G1 and G2. ...

(cell cycle checkpoints; widely expressed), FOXN4 * FOXO1 (widely expressed: muscle, liver, pancreas),

FOXO3 Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the ''FOXO3'' gene. Function FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA-bi ...

(apoptosis, erythroid, longevity),

FOXO4 Forkhead box protein O4 is a protein that in humans is encoded by the ''FOXO4'' gene. Structure and function FOXO4 is a member of the forkhead family transcription factors O subclass, which is characterized by a winged helix domain used for DN ...

(widely expressed),

FOXO6 Forkhead box O6 is a protein that in humans is encoded by the FOXO6 gene. FoxO6 is expressed in the liver, skeletal muscle, and the hippocampus of the brain. In the liver, FoxO6 normally promotes gluconeogenesis in the fasted state, but insulin b ...

(liver, skeletal muscle, brain) * FOXP1 (pluripotency then brain, heart and lung),

FOXP2 Forkhead box protein P2 (FOXP2) is a protein that, in humans, is encoded by the ''FOXP2'' gene. FOXP2 is a member of the forkhead box family of transcription factors, proteins that regulate gene expression by binding to DNA. It is expressed ...

(widely expressed? brain; language),

FOXP3 FOXP3 ( forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of ...

(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

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.

References

External links

* {{DEFAULTSORT:Fox Proteins * Aging-related proteins