TFAP2A

TFAP2A
Identifiers
Aliases	TFAP2A, AP-2, AP-2alpha, AP2TF, BOFS, TFAP2, transcription factor AP-2 alpha
External IDs	MGI: 104671 HomoloGene: 2421 GeneCards: TFAP2A
Genetically Related Diseases
amyotrophic lateral sclerosis[1]
Gene ontology Molecular function • DNA binding • protein dimerization activity • protein homodimerization activity • transcription factor activity, sequence-specific DNA binding • transcription coactivator activity • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • chromatin binding • core promoter proximal region sequence-specific DNA binding • transcription regulatory region sequence-specific DNA binding • RNA polymerase II core promoter proximal region sequence-specific DNA binding • transcription factor activity, RNA polymerase II core promoter proximal region sequence-specific binding • transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding • protein binding • transcription regulatory region DNA binding • RNA polymerase II transcription factor activity, sequence-specific DNA binding • RNA polymerase II core promoter sequence-specific DNA binding • sequence-specific DNA binding Cellular component • cytoplasm • centrosome • Golgi apparatus • intracellular membrane-bounded organelle • nucleoplasm • nucleus Biological process • palate development • cellular response to iron ion • regulation of transcription, DNA-templated • retina layer formation • kidney development • positive regulation of bone mineralization • trigeminal nerve development • negative regulation of transcription by competitive promoter binding • optic vesicle morphogenesis • bone morphogenesis • negative regulation of apoptotic process • negative regulation of transcription from RNA polymerase II promoter • sensory perception of sound • eyelid development in camera-type eye • transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of neuron apoptotic process • positive regulation of gene expression • inner ear morphogenesis • optic cup structural organization • regulation of cell differentiation • embryonic cranial skeleton morphogenesis • negative regulation of reactive oxygen species metabolic process • negative regulation of transcription, DNA-templated • embryonic forelimb morphogenesis • oculomotor nerve formation • negative regulation of cell proliferation • positive regulation of tooth mineralization • transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7020	21418
Ensembl	ENSG00000137203	ENSMUSG00000021359
UniProt	P05549 Q96SH1	P34056
RefSeq (mRNA)	NM_001032280 NM_001042425 NM_003220	NM_001122948 NM_001301674 NM_011547
RefSeq (protein)	NP_001027451.1 NP_001035890.1 NP_003211.1	NP_001288603.1 NP_035677.2
Location (UCSC)	Chr 6: 10.39 – 10.42 Mb	Chr 13: 40.72 – 40.73 Mb
PubMed search	[2]	[3]
Wikidata

Transcription factor AP-2 alpha (Activating enhancer binding Protein 2 alpha), also known as TFAP2A, is a protein that in humans is encoded by the TFAP2A gene.^[4]

Function

The AP-2 alpha protein acts as a sequence-specific DNA-binding transcription factor recognizing and binding to the specific DNA sequence and recruiting transcription machinery. Its binding site is a GC-rich sequence that is present in the cis-regulatory regions of several viral and cellular genes.^[5] AP2-alpha is a 52-kD retinoic acid-inducible and developmentally regulated activator of transcription that binds to a consensus DNA-binding sequence GCCNNNGGC in the SV40 and metallothionein promoters.^[4]

AP-2 alpha is expressed in neural crest cell lineages with the highest levels of expression corresponding to early neural crest cells, suggesting that AP-2 alpha plays a role in their differentiation and development. Transcription factor AP-2 alpha is expressed in ectoderm and in neural-crest cells migrating from the cranial folds during closure of the neural tube in the mouse. Cranial neural crest cell provides patterning information for craniofacial morphogenesis and generate most of the skull bones and the cranial ganglia.^[5][6][7][8]

AP-2 alpha knockout mice die perinatally with cranio-abdominoschisis and severe dysmorphogenesis of the face, skull, sensory organs, and cranial ganglia.^[9] Homozygous knockout mice also have neural tube defects followed by craniofacial and body wall abnormalities.^[10] In vivo gene delivery of AP-2 alpha suppressed spontaneous intestinal polyps in the Apc(Min/+) mouse.^[11] AP-2 alpha also functions as a master regulator of multiple transcription factors in the mouse liver.^[12]

In melanocytic cells TFAP2A gene expression may be regulated by MITF.^[13]

Clinical significance

Mutations in the TFAP2A gene cause Branchio-oculo-facial syndrome often with a midline cleft lip.^[14] In a family with branchio-oculo-facial syndrome (BOFS),^[15] a 3.2-Mb deletion at chromosome 6p24.3 was detected.^[16] Sequencing of candidate genes in that region in 4 additional unrelated BOFS patients revealed 4 different de novo missense mutations in the exons 4 and 5 of the TFAP2A gene.

A disruption of an AP-2 alpha binding site in an IRF6 enhancer is associated with cleft lip.^[17] Mutations in IRF6 gene cause Van der Woude syndrome (VWS)^[18] that is a rare mendelian clefting autossomal dominant disorder with lower lip pits in 85% of affected individuals.^[19] The remaining 15% of individuals with Van der Woude syndrome show only cleft lip and/or cleft palate (CL/P) and are clinically indistinguishable from the common non syndromic CL/P. NSCL/P occur in approximately 1/700 live births and is one of the most common form of congenital abnormalities. A previous association study between SNPs in and around IRF6 and NSCL/P have shown significant results in different populations^[20] and was independently replicated.^{[21][22][23][24]}

A search of NSCL/P cases for potential regulatory elements for IRF6 gene was made aligning genomic sequences to a 500 Kb region encompassing IRF6 from 17 vertebrate species. Human sequence as reference and searched for multispecies conserved sequences (MCSs). Regions contained in introns 5’ and 3’ flanking IRF6 were screened by direct sequencing for potential causative variants in 184 NSCL/P cases. The rare allele of the SNP rs642961 showed a significant association with cleft lip cases. Analysis of transcription factor binding site analysis showed that the risk allele disrupt a binding site for AP-2 alpha.^[17]

Mutations in the AP-2 alpha gene also cause branchio-oculo-facial syndrome,^[16] which has overlapping features with Van der Woude syndrome such as orofacial clefting and occasional lip pits what make rs642961 a good candidate for an etiological variant. These findings show that IRF6 and AP-2 alpha are in the same developmental pathway and identify a variant in a regulatory region that contributes substantially to a common complex disorder.

Interactions

TFAP2A has been shown to interact with:

• APC^[25]
• CITED2^[26][27]
• DEK^[28]
• EP300^[26]
• Myc^[29] and
• P53.^[30]

See also

• Activating protein 2
• Branchio-oculo-facial syndrome

References

Further reading

External links

• GeneReviews/NCBI/NIH/UW entry on Branchiooculofacial Syndrome
• TFAP2A protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook AP-2alpha
• TFAP2A human gene location in the UCSC Genome Browser.
• TFAP2A human gene details in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.