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FLASH GENE
Symbol ZFHX3 contributors: mct/npt - updated : 27-02-2024
HGNC name zinc finger homeobox 3
HGNC id 777
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestivesalivary gland   highly
Hearing/Equilibriumear   highly
Nervousbrain   highly Homo sapiensFetal
Reproductivefemale systembreastmammary gland highly Homo sapiens
Visualeye   highly Homo sapiens
cells
SystemCellPubmedSpeciesStageRna symbol
Visualamacrine cell Homo sapiens
Visualganglion 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
  • 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
  • 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
  • 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
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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
    SystemTypeDisorderPubmed
    respiratorylungchr.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