ZFHX3
Function
Transcriptional regulator which can act as an activator or a repressor. Inhibits the enhancer element of the AFP gene by binding to its AT-rich core sequence. In concert with SMAD-dependent TGF-beta signaling can repress the transcription of AFP via its interaction with SMAD2/3 (PubMed:25105025). Regulates the circadian locomotor rhythms via transcriptional activation of neuropeptidergic genes which are essential for intercellular synchrony and rhythm amplitude in the suprachiasmatic nucleus (SCN) of the brain (By similarity). Regulator of myoblasts differentiation through the binding to the AT-rich sequence of MYF6 promoter and promoter repression (PubMed:11312261). Down-regulates the MUC5AC promoter in gastric cancer (PubMed:17330845). In association with RUNX3, up-regulates CDKN1A promoter activity following TGF-beta stimulation (PubMed:20599712). Inhibits estrogen receptor (ESR1) function by selectively competing with coactivator NCOA3 for binding to ESR1 in ESR1-positive breast cancer cells (PubMed:20720010).
Involvement in disease
Atrial fibrillation, familial, 8
ATFB8
A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.
None
Disease susceptibility is associated with variants affecting the gene represented in this entry. An intronic C-to-A transversion (rs12931021) correlates with decreased ZFHX3 expression and increased risk of atrial fibrillation.
Spinocerebellar ataxia 4
SCA4
A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA4 is characterized by the onset of balance disturbances and gait and limb ataxia usually in the fourth decade, although earlier onset in the teens or twenties has been reported. There is evidence of genetic anticipation within families. Inheritance is autosomal dominant.
None
The disease is caused by variants affecting the gene represented in this entry. SCA4 is caused by heterozygous triplet repeat expansions in the poly-Gly tract. Affected individuals have expansions ranging from 42 to 74 repeats, while the number of repeats ranges from 14 to 26 in the general population (PubMed:38035881, PubMed:38684900). Patient-derived cells have increased ZFHX3 protein levels and show features of abnormal autophagy (PubMed:38684900).
Post-translational modifications
Hyperphosphorylation protects ZFHX3 from calpain/CAPN1-mediated degradation.
Ubiquitinated, leading to its proteasomal degradation.
Nuclear localization is essential for its sumoylation.
Tissue Specificity
Not found in normal gastric mucosa but found in gastric carcinoma cells (at protein level). Expression is higher in ER-positive breast tumors than ER-negative breast tumors (at protein level).
Cellular localization
- Nucleus
- Cytoplasm
- Translocates from the cytoplasm to the nucleus following TGF-beta stimulation. Expressed in nuclear body (NB)-like dots in the nucleus some of which overlap or closely associate with PML body.
Alternative names
ATBF1, C16orf47, ZFHX3, Zinc finger homeobox protein 3, AT motif-binding factor 1, AT-binding transcription factor 1, Alpha-fetoprotein enhancer-binding protein, Zinc finger homeodomain protein 3, ZFH-3