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FLASH GENE

Symbol

FOXC2

contributors: mct/npt - updated : 28-06-2014

HGNC name	forkhead box C2 (MFH-1, mesenchyme forkhead 1)
HGNC id	3801

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine pancreas         Nervous nerve cranial nerve       Reproductive female system uterus       Respiratory lung       moderately Urinary kidney nephron renal capsule glomerulus   Visual eye retina

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	embryonic mesoderm
	anterior rhombomeres, in the developing lymphatic vessels

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a forkhead with (FH, winged helix) domain and DNA-binding motif
	two loops-wings on the C-terminal side of an helix-turn-helix homeo domain

HOMOLOGY

interspecies	homolog to murine mesenchyme forkhead 1 (MFH-1)
	homolog to Drosophila homeo forkhead
	homolog to murine Foxc2

Homologene

FAMILY

HNF-3 FKH family of transcriptional activators

CATEGORY

DNA associated , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	embryonic transcriptional regulator, playing a role in adipocyte metabolism by increasing the sensitivity of the beta-adremergic CAMP protein kinase A
	involved in the specification of the lymphatic capillary versus collecting lymphatic vessel
	playing a central role in promoting invasion and metastasis and that it may prove to be a highly specific molecular marker for human basal-like breast cancers
	common transcriptional activator of insulin and TGF-beta signaling to directly regulate SERPINE1 expression via 2 distinct target sites, an insulin response element (IRE) and a novel forkhead-binding element (FBE), adjacent to a SMAD-binding site
	controls the expression of a distinct set of podocyte genes involved in podocyte differentiation and glomerular basement membrane maturation
	important regulator of the chemotactic motility of endothelial cells through the induction of CXCR4 expression
	playing an important role for the normal development and maintenance of venous and lymphatic valves (Mellor 2007)
	plays a role in conditions such as obesity, dyslipidemia, and type 2 diabetes
	essential regulator of the cardiovascular system in development and disease
	regulates angiogenesis via multiple signaling pathways, including ITGB3, CXCR4, and DLL4
	implicated in cancer progression through its induction of epithelial-to-mesenchymal transition
	important metabo-regulator of mitochondrial morphology and metabolism
	plays an important role in regulation of metabolism, arterial specification, and vascular sprouting
	plays an important role in osteoblastogenesis by promoting osteoblast proliferation, survival and differentiation through up-regulation of ITGB1 in response to stimuli which induce bone formation
	FOXC1 and FOXC2 are forkhead transcription factors that play essential roles during development and physiology
	new role in regulating proliferation and preventing premature differentiation of activated muscle satellite cells
	forkhead transcription factor that plays an essential role in lymphatic vascular development
	pivotal role of phosphorylation in the regulation of FOXC2-mediated transcription in lymphatic endothelial cells and importance of FOXC2 phosphorylation in vascular development
	required for the maintenance of the mesenchymal phenotype after TGFB1 induced EMT in human ovarian cancer cells

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

lipid/lipoprotein

signaling

sensory transduction/vision

mesenchymal development

a component

INTERACTION

DNA

binding

RNA

small molecule

protein	interacting with ANGPT2 (controls ANGPT2 expression by direct activation of its promoter in adipocytes, promoter that alters vascular patterning, remodeling, maturation, and functions)
	key molecule to regulate SERPINE1 gene expression
	interacting with ITGB3 (directly induces ITGB3 expression and regulates angiogenesis by ITGB3-mediated endothelial cell adhesion and migration)
	induces WNT signaling by direct interaction with the WNT4 (wingless-type MMTV integration site family member-4) promoter region
	enhanced the expression of CTNNB1, an important modulator of osteoblastogenesis
	requirement of FOXC2 for inorganic phosphate (Pi)-induced osteopontin (SPP1) expression and secretion from cancer cells as necessary for the angiogenic response

cell & other

REGULATION

induced by	high fat diet and counteracting most of the symptoms associated with obesity,hypertriglyceridemia and diet-induced insulin resistance
		during the course of tumor progression and that it might play a causal role in enabling metastatic dissemination

ASSOCIATED DISORDERS

corresponding disease(s)

LPDD , YNS

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in metastatic cancer cells tumoral     --over   in invasive ovarian cancer cell lines and tissues constitutional     --over   in bone marrow mesenchymal stem cells (BMSCs), may promote osteogenic differentiation and inhibit adipogenic differentiation, and this effect can be mediated via activating the canonical Wnt-CTNNB1signaling pathway (PMId: 24122419) tumoral     --over   in esophageal squamous cell carcinoma with advanced tumor stage, lymph node metastasis, and lymphatic invasion

Susceptibility

to varicose veins and hemorrhoids

Variant & Polymorphism other	mutations strongly associated with primary venous valve failure in both the superficial and deep veins in the lower limb (Mellor 2007)

Candidate gene
Marker
Therapy target	functional interference with FOXC2 or ANGPT2 might provide a therapeutic approach for prevention and treatment of obesity or its related disorders

ANIMAL & CELL MODELS

FOXC2 knockout mouse displaying anterior segment abnormalities,craniofacial,cardiovascular and vertebrate anomalies