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FLASH GENE

Symbol

ZFHX3

contributors: mct/npt - updated : 27-02-2024

HGNC name	zinc finger homeobox 3
HGNC id	777

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	ubiquitous

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 Digestive salivary gland       highly Hearing/Equilibrium ear       highly Nervous brain       highly Homo sapiens Fetal   brain basal nuclei striatum     Homo sapiens Fetal   brain diencephalon thalamus     Homo sapiens Fetal Reproductive female system breast mammary gland   highly Homo sapiens Visual eye       highly Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Visual amacrine cell Homo sapiens Visual ganglion cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo, neonatal, pregnancy

Text

brain

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	four helix-turn-helix (homeo) domains, suggesting dynamic functions in diverse biological processes
	23 zinc finger motifs
	multiple putative nuclear receptor boxes, including one consensus LXXLL motif and 31 of its variants LXXXL
	one DEAD and one DEAH boxes (Asp-Glu-Ala-Asp/His)
	a RNA and an ATP binding sites
	two large RS domains and many phosphorylation sites

HOMOLOGY

interspecies	homolog to Drosophila ZFH-2
	homolog to murine Atbf1
	ortholog to C.elegans zc123.3

Homologene

FAMILY

giant, multiple-homeodomain and zinc finger family

CATEGORY

transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm,nuclear bodies
	intracellular,nucleus,chromatin/chromosome
text	normally localized in nuclei, and its mislocalization to cytoplasm was reported in multiple cancers
	in an estrogen receptor (ER)-positive breast cancer cell line (MCF7), estrogen induced ZFHX3 translocation from cytoplasm to nuclei in an ER dependent pathway

basic FUNCTION	AT-binding transcription factor 1 and DNA/RNA dependent ATPase activity, maybe involved in neuronal differentiation (ATBF1-A)
	regulatory factor for STAT3-mediated signal transduction through its interaction with PIAS3
	regulating myoblastic differentiation
	plays a role in both the maintenance of breast epithelial homeostasis and breast tumorigenesis caused by elevated estrogen levels
	inhibits estrogen-mediated cell proliferation and gene regulation in ER-positive breast cancer cells by selectively competing for binding to the ESR1 with NCOA3
	may have an autoregulatory feedback loop with estrogen-ESR1 signaling
	appears to be the first gene that has an autoregulatory negative feedback loop with estrogen-ESR1 signaling
	transcription factor that regulates genes responsible for repairing tissues and the protection of cells from oxidative stress
	plays a role in the development of pubertal mammary gland likely by modulating the function of estrogen-ER signaling in luminal cells and by modulating gene expression in basal cells
	nuclear localization and SUMOylation are important for the transcription factor function of ZFHX3, and ZFHX3 could cooperate with promyelocytic leukemia (PML)-nuclear body to regulate protein SUMOylation in different biological processes
	is a transcription factor that regulates multiple cellular processes including cell proliferation, differentiation and neoplastic development
	modulates retinal sensitivity and circadian responses to light
	important role for ZFHX3 in the control of cardiac genes and signaling pathways essential for normal atrial function
	functions in neuronal development and differentiation in both the central and peripheral nervous system
	is implied in cerebellar neurons’ responses to oxidative stress, plausibly linking variation in this gene to a cerebellar disorder
	is the first known mammalian mediator of CO2 effects on immune gene expression
	is a zinc-finger homeodomain transcription factor involved in various biological processes, including cell differentiation and tumorigenesis
	ZFHX3 is an important regulator in neuronal differentiation
	key role for ZFHX3 in neuron and axon development

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA	an AT-rich motif in the alpha-fetoprotein gene enhancer

RNA

small molecule	metal binding, nucleotide,
	Zn2+
	ATP

protein	interacting with v-Myb in regulation of its transactivation
	interacting with PIAS3
	required for the PIT1 gene early activation
	associates with RUNX3 and translocates to the nucleus in response to TGF-beta signal transduction and might function in the nucleus as tumor suppressor and transcriptional regulator
	estrogen induces the binding of the ESR1 onto the promoter of ZFHX3 and ZFHX3 is an ESR1 target gene
	TRIM25 is an E3 ubiquitin ligase mediating oestrogen-induced ZFHX3 protein degradation
	because of its ability to suppress AFP gene transcription in hepatic cells, ZFHX3 is a factor associated with differentiation of the hepatocyte
	phosphorylation of ZFHX3 was an important regulatory mechanism protecting it from digestion by CAPN1
	is a transcriptional target of Progesterone-PGR signaling in mammary epithelial cells
	plays an essential role in proper lactogenic development in mammary glands, at least in part by maintaining PRLR expression and PRLR-JAK2-STAT5 signaling activity
	ZFHX3 is an integral transcription factor of PGR signaling in driving side-branching and alveologenesis during mammary gland development
	ZFHX3 plays likely an important role in intracellular calcium homeostasis in mammary epithelial cells, at least in part, by regulating TRPV6
	ZFHX3 is an angiogenic transcription factor that is integral to the HIF1A/VEGFA signaling axis in hepatocellular carcinoma (HCC) cells
	interact with the chromatin remodeling SMARCA4 and the cleavage and polyadenylation complex, suggesting a function in chromatin remodeling and mRNA processing

cell & other

REGULATION

activated by

progesterone (PG)(its expression is upregulated by PG via the binding of PGR to the ZFHX3 promoter, and ZFHX3 is necessary for PG to induce the expression of stem cell markers and the expansion of progenitor cells

Other	higher levels of estrogen cause the degradation of ZFHX3 protein by the proteasome system
	phosphorylation of ZFHX3 is a key mechanism for the protection of ZFHX3 from degradation

ASSOCIATED DISORDERS

corresponding disease(s)

SCA4 , ATFB8 , IDASDB

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral somatic mutation       in prostate cancer tumoral     --low   in breast cancers with poor prognosis tumoral     --over   and this up-regulation correlated with both HIF1A up-regulation and worse patient survival, confirming a functional association between ZFHX3 and HIF1A in human hepatocellular carcinoma (HCC)

Susceptibility

to atrial fibrillation (AF) to Kawasaki disease (KD)

Variant & Polymorphism SNP	rs7193343-T, associated significantly with AF
	rs7199343 significantly associated to KS (Burgner 2009)
	rs2106261 in ZFHX3 confers a significant risk of AF in a Chinese Han population

Candidate gene	ZFHX3, MACF1, RBM15, and SETD2 are Orofacial cleft candidate risk genes
Marker
Therapy target
	System Type Disorder Pubmed respiratory lung chr.Bronchopathy obstructive therapeutic targets to interrupt hypercapnic immunosuppression in patients with advanced lung disease

ANIMAL & CELL MODELS

in mouse mammary tissue, knock-out of Zfhx3 interrupted lactogenesis, resulting in underdeveloped glands with much smaller and fewer alveoli