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 (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

s that play important roles in regulating the expression of

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

s involved in

cell growth Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

, proliferation, differentiation, and

longevity Longevity may refer to especially long-lived members of a population, whereas ''life expectancy'' is defined Statistics, statistically as the average number of years remaining at a given age. For example, a population's life expectancy at birth ...

. 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, re ...

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 r ...

during cell differentiation processes. There are 50 different FOX genes encoding FOX proteins in humans that are further divided into 19 subdivisions based on conserved sequence similarity. The defining feature of FOX proteins is the

forkhead box 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 ...

, a sequence of 80 to 100

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

forming a motif that binds to

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. 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. FOX proteins are a subgroup of the

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

class of proteins.

Biological roles

FOX genes are key elements in many developmental and

biological process Biological processes are those processes that are necessary for an organism to live and that shape its capacities for interacting with its environment. Biological processes are made of many chemical reactions or other events that are involved in ...

es, including regulating the cell cycle, metabolism, apoptosis, immune control, and pluripotency of embryonic stem cells. Beginning in

unicellular A unicellular organism, also known as a single-celled organism, is an organism that consists of a single cell, unlike a multicellular organism that consists of multiple cells. Organisms fall into two general categories: prokaryotic organisms and ...

eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

s, FOX genes developed by means of duplication and

divergence In vector calculus, divergence is a vector operator that operates on a vector field, producing a scalar field giving the rate that the vector field alters the volume in an infinitesimal neighborhood of each point. (In 2D this "volume" refers to ...

to acquire specialized roles. By binding to particular

sequences, these proteins control

gene expression Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...

and so affect cellular differentiation and

organogenesis Organogenesis is the phase of embryonic development that starts at the end of gastrulation and continues until birth. During organogenesis, the three germ layers formed from gastrulation (the ectoderm, endoderm, and mesoderm) form the internal org ...

. Many genes encoding FOX proteins have been identified. There are 50 FOX genes in humans, divided into 19 different subclasses from FOXA to FOXS, based on conserved sequences. These subdivisions have diverse functions across different tissues and biological processes and genes within a given subunit often exhibit functional similarities. For example, the FOXM genes encode proteins that are involved in

cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

progression. FOXC genes encode proteins that ensure normal embryonic development and play a key role in the growth and function of different organs. FOX proteins play an important role in apoptosis and function as tumor suppressors, removing damaged cells. This is done via a mitochondria-dependent pathway or a mitochondria-independent pathway. In the mitochondria-independent pathway, FOX proteins increase the expression of death receptor ligands such as Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In the mitochondria-dependent pathway, FOX proteins activate pro-apoptotic Bcl-2 family proteins. FOXM1 is a well-defined transcription factor controlling genes linked to cell cycle development, preserving cellular

homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...

. FOXM1 promotes the entry of a

cell Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

into the

S phase S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S ...

and ensures the cell undergoes

mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...

properly. FOXM1 activity is regulated by proliferation and anti-proliferation signals. FOXM1 is a highly expressed tumour

repressor In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...

in growing cells and contributes to tumorigenesis when dysregulated. Phosphorylation events regulate FOXM1 activity by influencing its localization and transcriptional action. The FOXO1 gene is involved in maintaining the pluripotency of

embryonic stem cell Embryonic stem cells (ESCs) are Cell potency#Pluripotency, pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-Implantation (human embryo), implantation embryo. Human embryos reach the blastocyst stage 4� ...

s. FOXO1 regulates critical pluripotency associated genes such as OCT4, NANOG and SOX2 by occupying and activating their promoters. This function can be inhibited by the ATK protein kinase. The FOXO genes also play a role in the regulation of

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. FOXO proteins translate

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

and growth factor signaling into physiological responses, including suppressing

. FOXO1 is involved in promoting gluconeogenesis in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

by interacting with PGC-1α. This interaction can be inhibited by phosphorylation events, where FOXO1 is removed from the nucleus. 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 A basal cell is a general cell type that is present in many forms of epithelial tissue throughout the body. Basal cells are located between the basement membrane and the remainder of the epithelium, effectively functioning as an anchor for the epi ...

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, mesoder ...

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 In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

, including

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

acetylation : In 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 opposite react ...

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 19 ...

Post-Translational Modifications

Control of FOX protein activity, localization, and stability depends critically on

post-translational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

s (PTMs). These modifications, including phosphorylation,

methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...

and acetylation, help FOX proteins respond to various cellular signals, thereby enabling them to mediate essential biological processes such as

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

, cell survival, and cell cycle progression. Among the primary PTMs influencing FOX proteins is

. For instance, phosphorylation of FOXO

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s can drive their nuclear translocation in response to stress signals, which is necessary for starting apoptotic

. This change allows FOXO proteins to mediate the stress reaction and control cell survival. Additionally, under control by phosphorylation is

FOXM1 Forkhead box protein M1 is a protein that in humans is encoded by the ''FOXM1'' gene. The protein encoded by this gene is a member of the FOX family of transcription factors. Its potential as a target for future cancer treatments led to it being ...

, a necessary component of cell cycle progression. Specifically, phosphorylation increases the transcriptional activity of FOXM1, so advancing cell cycle progression during

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...

and

, which is a process essential for appropriate cellular growth. Particularly in relation to the development of

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

and the way cells traverse their growth cycle,

is particularly crucial in determining the function of FOXM1. Enzymes such as p300/CBP add

acetyl group In organic chemistry, an acetyl group is a functional group denoted by the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, an acetyl grou ...

s to specific sites on the FOXM1 protein, thus this process occurs. Particularly, this happens at particular lysine residues, including K63, K422, K440, K603, and K614. FOXM1 is able to greatly increase its capacity to activate genes linked with DNA copying and

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

by means of acetylation. Remarkably, the degree of acetylation of FOXM1 varies during the cell cycle rather than being constant. It peaks in the S, G2, and M phases of the

—the times when cells are actively getting ready for division. During these phases, the acetylated form of FOXM1 can more readily attach to its target genes, helping the cell to move through the cell cycle. On the other hand, FOXM1 becomes less active in the

G1 phase The G1 phase, gap 1 phase, or growth 1 phase, is the first of four phases of the cell cycle that takes place in eukaryotic cell division. In this part of interphase, the cell synthesizes Messenger RNA, mRNA and proteins in preparation for subsequ ...

, and the degree of acetylation also falls here. This variation in acetylation serves as a timing mechanism to guarantee that FOXM1 only acts when the cell needs it. Regarding cancer, the stakes are even higher. Acetylation improves FOXM1's capacity to activate genes, helping cancer cells grow, survive, and repair their DNA. When FOXM1 cannot be acetylated, as is the case when

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s stop the process from happening, its capacity to activate genes reduces, as well as its capacity to cause the development of tumours. This is why

scientist A scientist is a person who Scientific method, researches to advance knowledge in an Branches of science, area of the natural sciences. In classical antiquity, there was no real ancient analog of a modern scientist. Instead, philosophers engag ...

s are looking at several approaches to interfere with FOXM1's acetylation in order to either stop or slow down cancer's spread. The focus of this process could create fresh paths for the evolution of the next treatments. Another post translational modification of the FOX protein involves adding

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...

groups to specific amino acids. These modifications play a crucial role in

immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...

, cancer progression, and aging by altering FOX protein functions through protein-level changes.

Discovery

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

Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...

, 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 Bielefel ...

and Herbert Jäckle. Since then a large number of family members have been discovered, especially in

vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...

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. The discovery of the FOX gene family and its evolutionary significance was outlined in a 2009 study by Hannenhalli and Kaestner. The researchers detailed how FOX genes, originating in unicellular

s, evolved through

gene duplication Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene ...

and loss events to form a complex family in mammals. This study also highlighted the diverse biological roles of FOX genes, including contributions to developmental processes such as

and

speech acquisition Speech acquisition focuses on the development of vocal, acoustic and oral language by a child. This includes motor planning and execution, pronunciation, phonological and articulation patterns (as opposed to content and grammar which is language). ...

, and their association with various diseases, including

and

language disorder Language disorders or language impairments are disorders that involve the processing of linguistic information. Problems that may be experienced can involve grammar (syntax and/or morphology (linguistics), morphology), semantics (meaning), or o ...

Genes

* FOXA1,

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 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 D ...

(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 an ...

.) * 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 domain. ...

(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 tr ...

, 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 d ...

(

vitiligo Vitiligo (, ) is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure, and susceptibili ...

), FOXD4, FOXD4L1, FOXD4L3, FOXD4L4, FOXD4L5, FOXD4L6 * FOXE1 (thyroid), FOXE3 (lens) *

FOXF1 Forkhead box protein F1 (FOXF1) is a protein that in humans is encoded by the ''FOXF1'' gene. Function This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. FOX1 protein is imp ...

(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 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 (ear), FOXI2, FOXI3 *

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 (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 ...

(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 has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is ...

(hair, thymus), FOXN2, FOXN3 (cell cycle checkpoints; widely expressed), FOXN4 *

FOXO1 Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...

(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- ...

(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 of transcription factors in O subclass, which is characterized by a winged helix domain used ...

(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 Forkhead box protein P1 is a protein that in humans is encoded by the ''FOXP1'' gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX proteins, FOX family of transcription f ...

(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 Regulation of gene expression, regulate gene expression by DNA- ...

(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 r ...

(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

FOX

s must be under extreme evolutionary supervision in a genomic sequence or cis-acting elements. If not, they can lead to the development of many different types of cancer, including

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

, and

acute lymphocytic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or brui ...

. Depending on the subfamily, the deregulation of FOX proteins is often associated with tumorigenesis and can act as a

tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...

or an

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

. Changes in post-translational modifications, genetic events, or

oncovirus An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term ''oncornaviruses'' was used to denote their RNA virus origin. With the let ...

es are known causes for this deregulation. FOX proteins play critical roles in cellular

as they act as both tumor suppressors and

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

s depending on the context. Dysregulation of FOX proteins may also contribute to diseases such as

neurodevelopmental disorder Neurodevelopmental disorders are a group of mental conditions negatively affecting the development of the nervous system, which includes the brain and spinal cord. According to the American Psychiatric Association Diagnostic and Statistical Manu ...

s and

metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...

s. For example, FOXM1 is essential for cell cycle progression and is frequently over-expressed in tumors while FOXO proteins regulate

and stress responses indicating they often act as tumor suppressors. A member of the FOX family, FOXD2, has been detected progressively over-expressed 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. Additional FOX family members have also been implicated in cancer progression and

metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

. FOXP1 acts as a tumor suppressor in

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

and

prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...

cancers while showing oncogenic traits in certain

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...

s and

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

s. FOXP3 which is crucial for regulatory

T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

function has been shown to repress oncogenic pathways and exhibits tumor suppressive behaviour in breast and prostate cancers. FOXD2-AS1 is a long

non-coding RNA A non-coding RNA (ncRNA) is a functional RNA molecule that is not Translation (genetics), translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally imp ...

related to the FOXD2 gene which serves as a potential

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

in cancer. It is over-expressed in several

malignancies Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not ...

including

colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being rem ...

and gastric cancers and has been associated with poor

prognosis Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) ...

and increased proliferation, invasion, and migration of cancer cells. FOXQ1 is found to promote epithelial-mesenchymal transition which is a process that promotes invasion and metastasis through the repression of

epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

markers such as

E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), is a protein that in humans is encoded by the ''CDH1'' gene (not to be confused with the APC/C activator protein CDH1). Mutations are correlated with Hereditary diffuse gastric cancer, gastric, Here ...

and increases expression of mesenchymal genes. Over-expression of FOXQ1 has been linked to colorectal, gastric, and lung cancers, where it contributes to the tumor progression. FOXK2 has been linked to cancer and can function differently depending on the tissue type and molecular pathway it interacts with. In

non-small-cell lung cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

, FOXK2 suppresses tumor progression by down-regulating

cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lo ...

and CDKs allowing for the inhibition of cell proliferation and invasion. FOXO3a is another member that exhibits tissue-specific behaviour in cancer. In gastric cancer, its over-expression promotes invasion and migration by up-regulating cathepsin L which promotes epithelial-mesenchymal transition. FOXO3a also acts as a tumor suppressor in

nephroblastoma Wilms' tumor or Wilms tumor, also known as nephroblastoma, is a cancer of the kidneys that typically occurs in children (rarely in adults), and occurs most commonly as a renal tumor in child patients. It is named after Max Wilms, the German surg ...

by inhibiting proliferation and invasion while inducing apoptosis. In breast cancer, FOXO3a suppresses metastasis by down-regulating TWIST-1.

References

External links

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