TFAP2A
   HOME

TheInfoList



OR:

Transcription factor AP-2 alpha (Activating enhancer binding Protein 2 alpha), also known as TFAP2A, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''TFAP2A''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.


Function

Transcription factor AP-2 alpha is a 52-kD sequence-specific DNA-binding protein that enhances transcription of specific genes by binding to a GC-rich DNA sequence first identified in the cis-regulatory region of SV40 virus DNA and in
cis-regulatory ''Cis''-regulatory elements (CREs) or ''cis''-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morphoge ...
regions of a variety of cellular genes. The TFAP2-alpha gene was isolated and found to be retinoic acid-inducible in NT2 teratocarcinoma cells suggesting a potential role for AP-2 alpha in cellular differentiation. During embryonic development, AP-2 alpha is expressed in
neural crest The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, ...
cells migrating from the cranial neural folds during neural tube closure, and is also expressed in ectoderm, parts of the central nervous system, limb buds, and mesonephric system suggesting that AP-2 alpha plays an important role in the determination and development of these tissues. Cranial neural crest cells populate the developing face and provide patterning information for
craniofacial Craniofacial surgery is a surgical subspecialty that deals with congenital and acquired deformities of the head, skull, face, neck, jaws and associated structures. Although craniofacial treatment often involves manipulation of bone, craniofacial ...
morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...
and generate most of the skull bones and the
cranial ganglia In neuroanatomy, the cranial nerve ganglia are ganglia of certain cranial nerves. They can be parasympathetic or sensory. All cranial nerve ganglia are bilateral. Parasympathetic The four cranial parasympathetic ganglia are: * ciliary ganglion ...
. AP-2 alpha
knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
die perinatally with cranio- abdominoschisis and severe dysmorphogenesis of the face, skull, sensory organs, and cranial ganglia.
Homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
knockout mice also have neural tube defects followed by craniofacial and body wall abnormalities. In vivo gene delivery of AP-2 alpha suppressed spontaneous intestinal polyps in the Apc(Min/+) mouse. AP-2 alpha also functions as a master regulator of multiple transcription factors in the mouse liver. In melanocytic cells TFAP2A gene expression may be regulated by
MITF Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the ''MITF'' gene. MITF is a basic helix-loop-helix leucine zipper transcription factor ...
.


Clinical significance

Mutations in the TFAP2A gene cause Branchio-oculo-facial syndrome often with a midline
cleft lip A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nasal cavi ...
.Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Reviews Genetics (12): 167-178. In a family with branchio-oculo-facial syndrome (BOFS), a 3.2-Mb deletion at chromosome 6p24.3 was detected. 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 Interferon regulatory factor 6 also known as IRF6 is a protein that in humans is encoded by the ''IRF6'' gene. Function This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly c ...
enhancer is associated with
cleft lip A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nasal cavi ...
. Mutations in IRF6 gene cause Van der Woude syndrome (VWS) that is a rare mendelian clefting autossomal dominant disorder with lower lip pits in 85% of affected individuals. The remaining 15% of individuals with Van der Woude syndrome show only
cleft lip A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nasal cavi ...
and/or
cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
(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 and was independently replicated. 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. Mutations in the AP-2 alpha gene also cause branchio-oculo-facial syndrome, 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 * CITED2 * DEK *
EP300 Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
*
Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes r ...
and *
P53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
.


See also

*
Activating protein 2 Activating Protein 2 (AP-2) is a family of closely related transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (geneti ...
*
Branchio-oculo-facial syndrome Branchio-oculo-facial syndrome (BOFS) is a disease that arises from a mutation in the TFAP2A gene. It is a rare autosomal dominant disorder that starts to affect a child's development before birth. Symptoms of this condition include skin abnormal ...


References


Further reading

* * * * * * * * * * * * * * * * * * * *


External links


GeneReviews/NCBI/NIH/UW entry on Branchiooculofacial Syndrome
* * * * {{Transcription factors, g1 Transcription factors