TFAP2A
Encyclopedia
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
.
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. 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.
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
.
AP-2 alpha knockout mice
die perinatally with cranio-abdominoschisis
and severe dysmorphogenesis of the face, skull, sensory organs, and cranial ganglia. Homozygous knockout mice also have neural tube defects followed by craniofacial and body wall abnormalities.
In melanocytic cells TFAP2A gene expression may be regulated by MITF
.
A disruption of an AP-2 alpha binding site in an IRF6
enhancer is associated with cleft lip. 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 and/or 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 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 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.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the TFAP2A gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
The AP-2 alpha protein acts as a sequence specific DNA-binding transcription factorTranscription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
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
Cis-regulatory element
A cis-regulatory element or cis-element is a region of DNA or RNA that regulates the expression of genes located on that same molecule of DNA . This term is constructed from the Latin word cis, which means "on the same side as". These cis-regulatory elements are often binding sites for one or...
regions of several viral and cellular genes. AP2-alpha is a 52-kD retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
-inducible and developmentally regulated activator of transcription that binds to a consensus DNA-binding sequence GCCNNNGGC in the SV40
SV40
SV40 is an abbreviation for Simian vacuolating virus 40 or Simian virus 40, a polyomavirus that is found in both monkeys and humans...
and metallothionein
Metallothionein
Metallothionein is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus...
promoters.
AP-2 alpha is expressed in neural crest
Neural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
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
Ectoderm
The "ectoderm" is one of the three primary germ cell layers in the very early embryo. The other two layers are the mesoderm and endoderm , with the ectoderm as the most exterior layer...
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
Regional specification
In the field of developmental biology, regional specification is the process by which different areas are identified in the development of the early embryo. The process by which the cells become specified differs between organisms.-Cell fate determination:...
information for craniofacial
Craniofacial
Craniofacial may be used to describe certain congenital malformations, injuries, surgeons who subspecialize in this area, multi-disciplinary medical-surgical teams that treat and do research on disorders affecting this region, and organizations with interest in...
morphogenesis
Morphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
and generate most of the skull bones and the cranial ganglia
Cranial nerve ganglia
In neuroanatomy, the cranial nerve ganglia are sensory ganglia of the cranial nerves. The dorsal root ganglia are the corresponding structures of the spinal nerves....
.
AP-2 alpha knockout mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
die perinatally with cranio-abdominoschisis
Gastroschisis
Gastroschisis represents a congenital defect characterized by a defect in the anterior abdominal wall through which the abdominal contents freely protrude. There is no overlying sac and the size of the defect is usually less than 4 cm...
and severe dysmorphogenesis of the face, skull, sensory organs, and cranial ganglia. Homozygous knockout mice also have neural tube defects followed by craniofacial and body wall abnormalities.
In melanocytic cells TFAP2A gene expression may be regulated by MITF
Microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte and osteoclast development.-Clinical significance:...
.
Clinical significance
In a family with branchiooculofacial 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
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 family...
enhancer is associated with cleft lip. Mutations in IRF6 gene cause Van der Woude syndrome
Van der Woude syndrome
Van Der Woude syndrome is a genetic disorder and congenital malformation. People with VDWS have cleft lip with or without cleft palate, pits or mucous cysts on the lower lip, hypodontia, a hypernasal voice, cleft or bifid uvula, syngnathia, narrow high arched palate, and ankyloglossia...
(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 and/or 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 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 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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- APCAPC (gene)Adenomatous polyposis coli also known as deleted in polyposis 2.5 is a protein that in humans is encoded by the APC gene. Mutations in the APC gene may result in colorectal cancer....
, - CITED2CITED2Cbp/p300-interacting transactivator 2 is a protein that in humans is encoded by the CITED2 gene.-Interactions:CITED2 has been shown to interact with EP300, LHX2 and TFAP2A.-Further reading:...
, - DEKDEK (gene)Protein DEK is a protein that in humans is encoded by the DEK gene.-Interactions:DEK has been shown to interact with TFAP2A.-Further reading:...
, - EP300EP300E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene. This protein regulates the activity of many genes in tissues throughout the body...
, - MycMycMyc is a regulator gene that codes for a transcription factor. In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases...
and - P53P53p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
.