TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha))

2009-09-01   Francesca Orso , Daniela Taverna 

Identity

HGNC
LOCATION
6p24.3
IMAGE
Atlas Image
LEGEND
Figure 1 : TFAP2A human gene including promoter, 7 exons and 6 introns.
LEGEND
Modified from Entrez Gene (Genomic DNA).
LOCUSID
ALIAS
AP-2,AP-2alpha,AP2TF,BOFS,TFAP2
FUSION GENES

DNA/RNA

Atlas Image
Figure 2 : Three main transcripts are shown. Exons: red and green. Red: protein-coding sequences; Green: 5 and 3 Untranslated (UTR) regions. Black lines: introns.
Modified from Entrez Gene (Transcripts).

Description

The gene encompasses 22.882 kb of DNA; 7 exons.

Transcription

mRNA, NM_001042425; NM_003220; NM_001032280.

Proteins

Atlas Image
Figure 3.
Modified from Williams and Tjian, 1991.

Description

The main TFAP2A isoform consists of 437 amino acids and has a molecular weight of 52 kDa. TFAP2A proteins contain a unique, highly conserved helix-span-helix dimerization motif at the C-terminal half of the protein, a central basic region and a less conserved proline- and glutamine-rich domain at the amino terminus. The helix-span-helix motif and the basic region mediate DNA binding and dimerization while the proline- and glutamine-rich region is responsible for transcriptional transactivation (see figure 3).

Expression

Ubiquitous. Abnormal expression is found in a variety of human tumours.

Localisation

Located predominantly in the nucleus.

Function

The TFAP2A proteins are able to form hetero- as well as homo-dimers and bind to GC-rich DNA sequences within regulatory regions of their target genes, mediating both activation and repression of gene transcription. Functional TFAP2 binding sites, such as 5-GCCN3GGC-3 or 5-GCCN4GGC-3 or 5-GCCN3/4GGG-3 or 5-CCCCAGGC-3 have been identified and regulate genes involved in physiological or pathological processes such as development, cell growth, differentiation, apoptosis and tumorigenesis. Examples of activated genes are CDKN1A, TGFA, estrogen receptor, keratinocyte-specific genes, KIT, ERBB2 and IGFBP5 while MCAM/MUC18, C/EBPA, MYC and DCBLD2/ESDN/CLCP1 are repressed by TFAP2A. TFAP2A protein expression is highly cell-type specific, showing different spatial and temporal expression during development and in various tissues. The TFAP2A proteins are essential during embryogenesis as demonstrated by mouse genetic studies. Loss of TFAP2A impairs cranial closure and leads to severe dismorphogenesis of different organs and death at birth. Loss of TFAP2A activity in general alters proliferation and induces premature differentiation and/or apoptosis in various cell types as demonstrated by in vivo and in vitro studies. Because of their involvement in these fundamental cellular processes TFAP2A proteins are essential for maintaining cellular homeostasis. Deregulation of TFAP2A protein levels alter the cell functions in such a drastic way that it can eventually lead to cancer formation and/or progression. In fact, several studies have associated aberrant TFAP2A activity with tumorigenesis (see below).

Homology

With the other members of the TFAP2 family: TFAP2B, TFAP2C, TFAP2D, TFAP2E.

Mutations

Note

Found in branchio-oculo-facial syndrome (BOFS).
A de novo 10529A-G transition in exon 4 of the TFAP2A human gene was found in an 18-year-old man with branchio-oculo-facial syndrome (BOFS), a rare autosomal-dominant cleft palate-craniofacial disorder with variable expressivity. The mutation leads to arg255-to-gly (R255G) substitution in a highly conserved residue in the basic region of the DNA-binding domain, a change that replaces a charged polar side chain with a nonpolar side chain with a predicted conformational space change. Four additional BOFS patients were found to have de novo missense mutations in the highly conserved exons 4 and 5. No mutations were found in more than 300 controls. (Milunsky et al., 2008).
A de novo deletion of 18 and insertion of 6 nucleotides, resulting in LPGARR deletion and RI insertion between amino acids 276 and 281, was found within the basic DNA binding and dimerization domains of TFAP2A in a 4-year-old girl with congenital sensorineural deafness associated with inner ear malformation. The girl also had pseudocleft lips, skin defects, auricle abnormalities, and unilateral multicystic dysplastic kidney, leading to the diagnosis of branchio-oculo-facial (BOF) syndrome. (Tekin et al., 2009).

Implicated in

Entity name
Various cancers
Note
TFAP2A has been implicated in various cancers, first of all in melanoma and breast tumors. However several evidences link deregulation of TFAP2A to prostate and ovarian carcinomas as well as gliomas.
Entity name
Melanoma
Note
Malignant melanoma follows the transformation and proliferation of melanocytes, normally present in the basal cell layer of the epidermis. Tumor growth consists of a horizontal or radial initial growth phase (RGP) followed by a subsequent vertical growth phase (VGP) corresponding to the infiltration of the dermis and hypodermis (biphasic growth). Alternatively the growth pattern can be only vertical (monophasic growth). When the lesion enters the vertical growth phase, the expression of adhesion molecules changes as the tumor enters the dermis and acquires the capacity to metastasize. Deregulated expression or activity of a number of transcription factors and their downstream target genes (including those involved in invasion and motility) has been found and TFAP2A is one of them. In fact, in cutaneous malignant melanoma, reduced nuclear TFAP2A expression has been associated with aggressive clinicopathological outcomes. Moreover low TFAP2A levels predict shorter recurrence-free survival. In melanoma cell lines, loss of TFAP2A associates with enhanced invasion, metastasis formation as well as angiogenesis as tested in mouse models, due to events such as overexpression of the cell adhesion molecule MCAM/MUC18, protease protease-activated receptor 1 (F2R/PAR1), MMP2 as well as downregulation of the tyrosine kinase receptor KIT. On the other hand TFAP2A re-expression in melanoma cells suppresses tumorigenicity and metastatic potential.
Entity name
Breast cancer
Note
TFAP2A nuclear or total expression is significantly reduced in invasive carcinomas compared to benign breast epithelium (BBE) or ductal carcinoma in situ (DCIS) and associates with adverse clinicopathological parameters suggesting a tumor suppressor function for this transcription factor. However, there are reports showing increased TFAP2A expression in breast tumors. Discrepancies could be related to the low specificity of the tools (mostly antibodies) used to analyze TFAP2A expression. In fact, other TFAP2-family members with biological or pathological functions, could have been identified in those experiments. One possible mechanism by which TFAP2A could function as a tumor suppressor is by inducing growth arrest and apoptosis via induction of p21WAF1 expression, inhibition of MYC-related transactivation and BCL2 expression. TFAP2A expression in breast cancer has also been related to high sensitiveness to chemotherapeutic drugs due to massive induction of apoptosis in TFAP2A highly expressing cells.
Entity name
Prostate cancer
Note
TFAP2A expression is associated with luminal differentiation of normal prostate tissues but its expression is lost early when prostate adenocarcinomas develop. Increase cell proliferation has been observed in prostate tumors with low cytoplasmic TFAP2A expression. In TFAP2A-negative prostate cancer cells, TFAP2A expression inhibits tumorigenicity and leads to deregulation of relevant genes such as VEGF.
Entity name
Ovarian cancer
Note
Reduced cytoplasmic TFAP2A expression predicts poor overall survival of epithelial ovarian tumors and in ovarian cancer cells this transcription factor suppresses cell proliferation and invasion parallel to decreased phosphorylation of HER2, AKT and ERK pathways, reduced pro-MMP2 levels and increased CDH1/ECAD expression.
Entity name
Gliomas
Note
High nuclear levels of TFAP2A associate with better differentiation of human gliomas, absence of MMP2 and VEGF expression and offer some survival advantage to the patients.

Bibliography

Pubmed IDLast YearTitleAuthors
88955161996A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma.Bosher JM et al
78460461995The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma.Bosher JM et al
164206762005The AP-2 family of transcription factors.Eckert D et al
77294261995Transcriptional activation by Myc is under negative control by the transcription factor AP-2.Gaubatz S et al
106295511999Immunohistochemical analysis reveals a tumour suppressor-like role for the transcription factor AP-2 in invasive breast cancer.Gee JM et al
111372862000Regulatory roles of AP-2 transcription factors in vertebrate development, apoptosis and cell-cycle control.Hilger-Eversheim K et al
96875041998Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis.Huang S et al
181812132008Mouse genetic models of cleft lip with or without cleft palate.Juriloff DM et al
98172791998Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma.Karjalainen JM et al
186981652008Transcriptional control of the melanoma malignant phenotype.Melnikova VO et al
184235212008TFAP2A mutations result in branchio-oculo-facial syndrome.Milunsky JM et al
127416832003Transcriptional regulation of metastasis-related genes in human melanoma.Nyormoi O et al
184433662008AP-2alpha and AP-2gamma regulate tumor progression via specific genetic programs.Orso F et al
173302352007Activator protein-2 in carcinogenesis with a special reference to breast cancer--a mini review.Pellikainen JM et al
106450072000AP-2 transcription factors in the regulation of ERBB2 gene transcription by oestrogen.Perissi V et al
86227651996Transcription factor AP-2 essential for cranial closure and craniofacial development.Schorle H et al
192061572009A complex TFAP2A allele is associated with branchio-oculo-facial syndrome and inner ear malformation in a deaf child.Tekin M et al
165338072006Apoptosis induction by activator protein 2alpha involves transcriptional repression of Bcl-2.Wajapeyee N et al
91620571997Transcription factor AP-2 controls transcription of the human transforming growth factor-alpha gene.Wang D et al
19981221991Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins.Williams T et al
89881731997AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression.Zeng YX et al

Other Information

Locus ID:

NCBI: 7020
MIM: 107580
HGNC: 11742
Ensembl: ENSG00000137203

Variants:

dbSNP: 7020
ClinVar: 7020
TCGA: ENSG00000137203
COSMIC: TFAP2A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000137203ENST00000319516P05549
ENSG00000137203ENST00000379608P05549
ENSG00000137203ENST00000379613P05549
ENSG00000137203ENST00000461628H7C4N4
ENSG00000137203ENST00000465858C9J6N8
ENSG00000137203ENST00000466073C1K3N0
ENSG00000137203ENST00000475264H7C5E5
ENSG00000137203ENST00000482890P05549
ENSG00000137203ENST00000488193F8WEX2
ENSG00000137203ENST00000489805F8WDC8
ENSG00000137203ENST00000498450C9JXZ2

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMOylationREACTOMER-HSA-2990846
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
SUMOylation of transcription factorsREACTOMER-HSA-3232118
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factorsREACTOMER-HSA-8864260
Activation of the TFAP2 (AP-2) family of transcription factorsREACTOMER-HSA-8866907
TFAP2 (AP-2) family regulates transcription of growth factors and their receptorsREACTOMER-HSA-8866910
TFAP2 (AP-2) family regulates transcription of other transcription factorsREACTOMER-HSA-8866906
TFAP2 (AP-2) family regulates transcription of cell cycle factorsREACTOMER-HSA-8866911
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiationREACTOMER-HSA-8869496
Negative regulation of activity of TFAP2 (AP-2) family transcription factorsREACTOMER-HSA-8866904

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
188364452008Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip.165
129601472003Effect of clathrin heavy chain- and alpha-adaptin-specific small inhibitory RNAs on endocytic accessory proteins and receptor trafficking in HeLa cells.104
189555042009Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor beta signaling.90
195783712009BCOR regulates mesenchymal stem cell function by epigenetic mechanisms.86
155699942004Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis.85
184235212008TFAP2A mutations result in branchio-oculo-facial syndrome.69
167074882006Type Igamma661 phosphatidylinositol phosphate kinase directly interacts with AP2 and regulates endocytosis.48
175136132007Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation.46
96327471998RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2.42
122261082002Tumor suppressor activity of AP2alpha mediated through a direct interaction with p53.40

Citation

Francesca Orso ; Daniela Taverna

TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha))

Atlas Genet Cytogenet Oncol Haematol. 2009-09-01

Online version: http://atlasgeneticsoncology.org/gene/42526/tfap2a