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 Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater th ...

, proliferation, differentiation, and

longevity The word " longevity" is sometimes used as a synonym for " life expectancy" in demography. However, the term ''longevity'' is sometimes meant to refer only to especially long-lived members of a population, whereas ''life expectancy'' is always ...

. Many FOX

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

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 eukaryote, 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 ...

during cell differentiation processes. The defining feature of FOX proteins is the forkhead box, a sequence of 80 to 100

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

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

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 ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...

forkhead. FOXF2 is expressed in the lung and

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

. 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

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoderm ...

s. 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 Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribo ...

, including

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppos ...

and

ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

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 Detlef Weigel (born 1961 in Lower Saxony, Germany) is a German American scientist working at the interface of developmental and evolutionary biology. Education Weigel was an undergraduate in biology and chemistry at the universities of Biele ...

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 ...

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, FOXA2,

FOXA3 Hepatocyte nuclear factor 3-gamma (HNF-3G), also known as forkhead box protein A3 (FOXA3) or transcription factor 3G (TCF-3G) is a protein that in humans is encoded by the ''FOXA3'' gene. Function HNF-3G is a member of the forkhead class of ...

(See also Hepatocyte nuclear factors.) * FOXB1, FOXB2 *

FOXC1 Forkhead box C1, also known as FOXC1, is a protein which in humans is encoded by the ''FOXC1'' gene. Function This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding fork head dom ...

(associated with glaucoma),

FOXC2 Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the ''FOXC2'' gene. FOXC2 is a member of the ...

(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 Forkhead box D3 also known as FOXD3 is a forkhead protein that in humans is encoded by the ''FOXD3'' gene. Function This gene belongs to the forkhead protein family of transcription factors which is characterized by a DNA-binding forkhead do ...

(

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, FOXD4L1, FOXD4L3, FOXD4L4, FOXD4L5, FOXD4L6 *

FOXE1 Forkhead box protein E1 is a protein that in humans is encoded by the ''FOXE1'' gene. Location The FOXE1 gene is located on the long (q) arm of chromosome 9 at position 22 Function This intronless gene belongs to the forkhead family of tra ...

(thyroid),

FOXE3 Forkhead box protein E3 (FOXE3) also known as forkhead-related transcription factor 8 (FREAC-8) is a protein that in humans is encoded by the ''FOXE3'' gene located on the short arm of chromosome 1. Function FOXE3 is a forkhead-box transcrip ...

(lens) * FOXF1 (lung), FOXF2 * FOXG1 (brain) *

FOXH1 Forkhead box protein H1 is a protein that in humans is encoded by the ''FOXH1'' gene. Function FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element ...

(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 Forkhead box protein J1 is a protein that in humans is encoded by the ''FOXJ1'' gene. It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis. FOXJ1 is expressed in ciliated cells of the ...

(cilia), FOXJ2 (erythroid), FOXJ3 * FOXK1,

FOXK2 Forkhead box protein K2 is a protein that in humans is encoded by the ''FOXK2'' gene. The protein encoded by this gene contains a fork head DNA binding domain. This protein can bind to the purine-rich motifs of the HIV long terminal repeat (LT ...

(HIV, IL-2, adrenal) * FOXL1 (ovary),

FOXL2 Forkhead box protein L2 is a protein that in humans is encoded by the ''FOXL2'' gene. Function FOXL2 (OMIM 605597) is a transcription factor belonging to the forkhead box (FOX) superfamily, characterized by the forkhead box/winged-helix DNA-b ...

* FOXM1 (cell cycle, erythroid, cancer) *

FOXN1 Forkhead box protein N1 is a protein that in humans is encoded by the ''FOXN1'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ...

(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 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