Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or
mesenchyme
Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...
fork head protein 1 (MFH1) is a
protein
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 ...
that in humans is encoded by the ''FOXC2''
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 ba ...
.
FOXC2 is a member of the
fork head box (FOX) 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 fu ...
s.
Structure and function
The protein is 501 amino acids in length. The gene has no
introns
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...
; the single
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
is approximately 1.5kb in size.
FOX transcription factors are expressed during development and are associated with a number of cellular and developmental
differentiation processes. FOXC2 is required during early development of the kidneys, including differentiation of
podocyte
Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. Bowman's capsule ...
s and maturation of the
glomerular basement membrane. It is also involved in the early development of the heart.
An increased expression of FOXC2 in adipocytes can increase the amount of brown adipose tissue leading to lower weight and an increased sensitivity to insulin.
Role in disease
Absence of FOXC2 has been shown to lead to the failure of lymphatic valves to form and problems with lymphatic remodelling. A number of mutations in the FOXC2 gene have been associated with
Lymphedema–distichiasis syndrome
Lymphedema–distichiasis syndrome is a medical condition associated with the FOXC2 gene. People with this hereditary condition have a double row of eyelashes, which is called ''distichiasis'', and a risk of swollen limbs due to problems in the ...
,
It has also been suggested that there may be a link between polymorphisms in FOXC2 and varicose veins.
FOXC2 is also involved in
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
metastases
Metastasis is a pathogenic agent's spread 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, then, ...
. In particular, expression of FOXC2 is induced when
epithelial cells
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
undergo an
epithelial-mesenchymal transition (EMT) and become
mesenchymal
Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...
looking cells. EMT can be induced by a number of genes including
Snail
A snail is, in loose terms, a shelled gastropod. The name is most often applied to land snails, terrestrial pulmonate gastropod molluscs. However, the common name ''snail'' is also used for most of the members of the molluscan class Gastro ...
,
Twist
Twist may refer to:
In arts and entertainment Film, television, and stage
* ''Twist'' (2003 film), a 2003 independent film loosely based on Charles Dickens's novel ''Oliver Twist''
* ''Twist'' (2021 film), a 2021 modern rendition of ''Olive ...
,
Goosecoid
Homeobox protein goosecoid (GSC) is a homeobox protein that is encoded in humans by the ''GSC'' gene. Like other homeobox proteins, goosecoid functions as a transcription factor involved in morphogenesis. In ''Xenopus'', ''GSC'' is thought to pla ...
, and
TGF-beta 1
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other si ...
.
Overexpression of FOXC2 has been noted in subtypes of breast cancer which are highly metastatic.
Suppression of FOXC2 expression using
shRNA
A short hairpin RNA or small hairpin RNA (shRNA/Hairpin Vector) is an artificial RNA molecule with a tight hairpin turn that can be used to silence target gene expression via RNA interference (RNAi). Expression of shRNA in cells is typically acco ...
in a highly metastatic
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
model blocks their metastatic ability.
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Lymphedema-Distichiasis Syndrome
{{DEFAULTSORT:Foxc2
Forkhead transcription factors