TFAP2A explained

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.^[1]

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 regions of a variety of cellular genes.^[2]

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.^{[3] [4] [5]}

During embryonic development, AP-2 alpha is expressed in neural crest 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.^[6] Cranial neural crest cells populate the developing face and provide patterning information for craniofacial morphogenesis and generate most of the skull bones and the cranial ganglia.^[7]

AP-2 alpha knockout mice die perinatally with cranio-abdominoschisis and severe dysmorphogenesis of the face, skull, sensory organs, and cranial ganglia.^[8] Homozygous knockout mice also have neural tube defects followed by craniofacial and body wall abnormalities.^[9] In vivo gene delivery of AP-2 alpha suppressed spontaneous intestinal polyps in the Apc(Min/+) mouse.^[10] AP-2 alpha also functions as a master regulator of multiple transcription factors in the mouse liver.^[11]

In melanocytic cells TFAP2A gene expression may be regulated by MITF.^[12]

Clinical significance

Mutations in the TFAP2A gene cause Branchio-oculo-facial syndrome often with a midline cleft lip.^[13] In a family with branchio-oculo-facial syndrome (BOFS), a 3.2-Mb deletion at chromosome 6p24.3 was detected.^[14] 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.^[15] 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.^[16] 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^[17] and was independently replicated.^{[18] [19] [20] [21]}

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^[22]
• CITED2^[23]
• DEK^[24]
• EP300^[25]
• Myc^[26] and
• P53.^[27]

See also

• Activating protein 2
• Branchio-oculo-facial syndrome

Further reading

• Murphy JE, Keen JH . Recognition sites for clathrin-associated proteins AP-2 and AP-3 on clathrin triskelia . The Journal of Biological Chemistry . 267 . 15 . 10850–5 . May 1992 . 10.1016/S0021-9258(19)50096-5 . 1587861 . free .
• Richard Gaynor. Gaynor RB, Muchardt C, Xia YR, Klisak I, Mohandas T, Sparkes RS, Lusis AJ . Localization of the gene for the DNA-binding protein AP-2 to human chromosome 6p22.3-pter . Genomics . 10 . 4 . 1100–2 . Aug 1991 . 1916817 . 10.1016/0888-7543(91)90209-W .
• Williams T, Tjian R . Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins . Science . 251 . 4997 . 1067–71 . Mar 1991 . 1998122 . 10.1126/science.1998122 . 1991Sci...251.1067W .
• Williams T, Tjian R . Analysis of the DNA-binding and activation properties of the human transcription factor AP-2 . Genes & Development . 5 . 4 . 670–82 . Apr 1991 . 2010091 . 10.1101/gad.5.4.670 . free .
• Williams T, Admon A, Lüscher B, Tjian R . Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements . Genes & Development . 2 . 12A . 1557–69 . Dec 1988 . 3063603 . 10.1101/gad.2.12a.1557 . free .
• Bauer R, Imhof A, Pscherer A, Kopp H, Moser M, Seegers S, Kerscher M, Tainsky MA, Hofstaedter F, Buettner R . The genomic structure of the human AP-2 transcription factor . Nucleic Acids Research . 22 . 8 . 1413–20 . Apr 1994 . 8190633 . 307999 . 10.1093/nar/22.8.1413 .
• Buettner R, Kannan P, Imhof A, Bauer R, Yim SO, Glockshuber R, Van Dyke MW, Tainsky MA . An alternatively spliced mRNA from the AP-2 gene encodes a negative regulator of transcriptional activation by AP-2 . Molecular and Cellular Biology . 13 . 7 . 4174–85 . Jul 1993 . 8321221 . 359967 . 10.1128/mcb.13.7.4174.
• Williamson JA, Bosher JM, Skinner A, Sheer D, Williams T, Hurst HC . Chromosomal mapping of the human and mouse homologues of two new members of the AP-2 family of transcription factors . Genomics . 35 . 1 . 262–4 . Jul 1996 . 8661133 . 10.1006/geno.1996.0351 . free .
• Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, Fowlkes DM . Identification of novel human WW domain-containing proteins by cloning of ligand targets . The Journal of Biological Chemistry . 272 . 23 . 14611–6 . Jun 1997 . 9169421 . 10.1074/jbc.272.23.14611 . free .
• Batsché E, Muchardt C, Behrens J, Hurst HC, Crémisi C . RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2 . Molecular and Cellular Biology . 18 . 7 . 3647–58 . Jul 1998 . 9632747 . 108947 . 10.1128/mcb.18.7.3647.
• Mertens PR, Alfonso-Jaume MA, Steinmann K, Lovett DH . A synergistic interaction of transcription factors AP2 and YB-1 regulates gelatinase A enhancer-dependent transcription . The Journal of Biological Chemistry . 273 . 49 . 32957–65 . Dec 1998 . 9830047 . 10.1074/jbc.273.49.32957 . free .
• García MA, Campillos M, Marina A, Valdivieso F, Vázquez J . Transcription factor AP-2 activity is modulated by protein kinase A-mediated phosphorylation . FEBS Letters . 444 . 1 . 27–31 . Feb 1999 . 10037142 . 10.1016/S0014-5793(99)00021-6 . 43874770 .
• Rosenthal JA, Chen H, Slepnev VI, Pellegrini L, Salcini AE, Di Fiore PP, De Camilli P . The epsins define a family of proteins that interact with components of the clathrin coat and contain a new protein module . The Journal of Biological Chemistry . 274 . 48 . 33959–65 . Nov 1999 . 10567358 . 10.1074/jbc.274.48.33959 . free .
• Heicklen-Klein A, Ginzburg I . Tau promoter confers neuronal specificity and binds Sp1 and AP-2 . Journal of Neurochemistry . 75 . 4 . 1408–18 . Oct 2000 . 10987820 . 10.1046/j.1471-4159.2000.0751408.x . 6558429 .
• Nyormoi O, Wang Z, Doan D, Ruiz M, McConkey D, Bar-Eli M . Transcription factor AP-2alpha is preferentially cleaved by caspase 6 and degraded by proteasome during tumor necrosis factor alpha-induced apoptosis in breast cancer cells . Molecular and Cellular Biology . 21 . 15 . 4856–67 . Aug 2001 . 11438643 . 87191 . 10.1128/MCB.21.15.4856-4867.2001 .
• Rao DS, Chang JC, Kumar PD, Mizukami I, Smithson GM, Bradley SV, Parlow AF, Ross TS . Huntingtin interacting protein 1 Is a clathrin coat binding protein required for differentiation of late spermatogenic progenitors . Molecular and Cellular Biology . 21 . 22 . 7796–806 . Nov 2001 . 11604514 . 99949 . 10.1128/MCB.21.22.7796-7806.2001 .
• Bragança J, Swingler T, Marques FI, Jones T, Eloranta JJ, Hurst HC, Shioda T, Bhattacharya S . Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2 . The Journal of Biological Chemistry . 277 . 10 . 8559–65 . Mar 2002 . 11744733 . 10.1074/jbc.M110850200 . free .
• Mertens PR, Steinmann K, Alfonso-Jaume MA, En-Nia A, Sun Y, Lovett DH . Combinatorial interactions of p53, activating protein-2, and YB-1 with a single enhancer element regulate gelatinase A expression in neoplastic cells . The Journal of Biological Chemistry . 277 . 28 . 24875–82 . Jul 2002 . 11973333 . 10.1074/jbc.M200445200 . free .
• Eloranta JJ, Hurst HC . Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo . The Journal of Biological Chemistry . 277 . 34 . 30798–804 . Aug 2002 . 12072434 . 10.1074/jbc.M202780200 . free .
• Ben-Zimra M, Koler M, Orly J . Transcription of cholesterol side-chain cleavage cytochrome P450 in the placenta: activating protein-2 assumes the role of steroidogenic factor-1 by binding to an overlapping promoter element . Molecular Endocrinology . 16 . 8 . 1864–80 . Aug 2002 . 12145340 . 10.1210/me.2002-0056 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Branchiooculofacial Syndrome

Notes and References

1. Web site: Entrez Gene: TFAP2A transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha).
2. Mitchell PJ, Wang C, Tjian R . Positive and negative regulation of transcription in vitro: enhancer-binding protein AP-2 is inhibited by SV40 T antigen . Cell . 50 . 6 . 847–61 . Sep 1987 . 3040262 . 10.1016/0092-8674(87)90512-5 . 25657738 .
3. Williams T, Admon A, Lüscher B, Tjian R . Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements . Genes & Development . 2 . 12A . 1557–69 . Dec 1988 . 3063603 . 10.1101/gad.2.12a.1557 . free .
4. Lüscher B, Mitchell PJ, Williams T, Tjian R . Regulation of transcription factor AP-2 by the morphogen retinoic acid and by second messengers . Genes Dev . 3 . 10 . 1507–17 . Oct 1989 . 2482225 . 10.1101/gad.3.10.1507 . free .
5. Williams T, Tjian R . Analysis of the DNA-binding and activation properties of the human transcription factor AP-2 . Genes & Development . 5 . 4 . 670–82 . Apr 1991 . 2010091 . 10.1101/gad.5.4.670 . free .
6. Mitchell PJ, Timmons PM, Hébert JM, Rigby PW, Tjian R . Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis . Genes Dev . 5 . 1 . 105–19 . Jan 1991 . 1989904 . 10.1101/gad.5.1.105 . free .
7. Le Douarin NM, Ziller C, Couly GF . Patterning of neural crest derivatives in the avian embryo: in vivo and in vitro studies . Developmental Biology . 159 . 1 . 24–49 . Sep 1993 . 8365563 . 10.1006/dbio.1993.1219 .
8. Schorle H, Meier P, Buchert M, Jaenisch R, Mitchell PJ . Transcription factor AP-2 essential for cranial closure and craniofacial development . Nature . 381 . 6579 . 235–8 . May 1996 . 8622765 . 10.1038/381235a0 . 1996Natur.381..235S . 581362 .
9. Zhang J, Hagopian-Donaldson S, Serbedzija G, Elsemore J, Plehn-Dujowich D, McMahon AP, Flavell RA, Williams T . Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2 . Nature . 381 . 6579 . 238–41 . May 1996 . 8622766 . 10.1038/381238a0 . 1996Natur.381..238Z . 4367622 .
10. Li Q, Löhr CV, Dashwood RH . Activator protein 2alpha suppresses intestinal tumorigenesis in the Apc(min) mouse . Cancer Letters . 283 . 1 . 36–42 . Sep 2009 . 19376641 . 2713803 . 10.1016/j.canlet.2009.03.026 .
11. Li Q, Luo C, Löhr CV, Dashwood RH . Activator protein-2α functions as a master regulator of multiple transcription factors in the mouse liver . Hepatology Research . 41 . 8 . 776–83 . Aug 2011 . 21682828 . 10.1111/j.1872-034X.2011.00827.x . 4139281 .
12. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E . Novel MITF targets identified using a two-step DNA microarray strategy . Pigment Cell & Melanoma Research . 21 . 6 . 665–76 . Dec 2008 . 19067971 . 10.1111/j.1755-148X.2008.00505.x . 24698373 . free .
13. Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Reviews Genetics (12): 167-178.
14. Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, Burch MN, Clemens M, Mulliken JB, Smith R, Lin AE . TFAP2A mutations result in branchio-oculo-facial syndrome . American Journal of Human Genetics . 82 . 5 . 1171–7 . May 2008 . 18423521 . 2427243 . 10.1016/j.ajhg.2008.03.005 .
15. Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubini M, Domann FE, Govil M, Christensen K, Bille C, Melbye M, Jugessur A, Lie RT, Wilcox AJ, Fitzpatrick DR, Green ED, Mossey PA, Little J, Steegers-Theunissen RP, Pennacchio LA, Schutte BC, Murray JC . Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip . Nature Genetics . 40 . 11 . 1341–7 . Nov 2008 . 18836445 . 2691688 . 10.1038/ng.242 .
16. Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, Howard E, de Lima RL, Daack-Hirsch S, Sander A, McDonald-McGinn DM, Zackai EH, Lammer EJ, Aylsworth AS, Ardinger HH, Lidral AC, Pober BR, Moreno L, Arcos-Burgos M, Valencia C, Houdayer C, Bahuau M, Moretti-Ferreira D, Richieri-Costa A, Dixon MJ, Murray JC . Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes . Nature Genetics . 32 . 2 . 285–9 . Oct 2002 . 12219090 . 3169431 . 10.1038/ng985 .
17. Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC . Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate . The New England Journal of Medicine . 351 . 8 . 769–80 . Aug 2004 . 15317890 . 10.1056/NEJMoa032909 . 3324418 .
18. Scapoli L, Palmieri A, Martinelli M, Pezzetti F, Carinci P, Tognon M, Carinci F . Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population . American Journal of Human Genetics . 76 . 1 . 180–3 . Jan 2005 . 15558496 . 1196422 . 10.1086/427344 .
19. Blanton SH, Cortez A, Stal S, Mulliken JB, Finnell RH, Hecht JT . Variation in IRF6 contributes to nonsyndromic cleft lip and palate . American Journal of Medical Genetics Part A . 137A . 3 . 259–62 . Sep 2005 . 16096995 . 10.1002/ajmg.a.30887 . 25084563 . free .
20. Ghassibé M, Bayet B, Revencu N, Verellen-Dumoulin C, Gillerot Y, Vanwijck R, Vikkula M . Interferon regulatory factor-6: a gene predisposing to isolated cleft lip with or without cleft palate in the Belgian population . European Journal of Human Genetics . 13 . 11 . 1239–42 . Nov 2005 . 16132054 . 10.1038/sj.ejhg.5201486 . free .
21. Park JW, McIntosh I, Hetmanski JB, Jabs EW, Vander Kolk CA, Wu-Chou YH, Chen PK, Chong SS, Yeow V, Jee SH, Park BY, Fallin MD, Ingersoll R, Scott AF, Beaty TH . Association between IRF6 and nonsyndromic cleft lip with or without cleft palate in four populations . Genetics in Medicine . 9 . 4 . 219–27 . Apr 2007 . 17438386 . 2846512 . 10.1097/GIM.0b013e3180423cca .
22. Li Q, Dashwood RH . Activator protein 2alpha associates with adenomatous polyposis coli/beta-catenin and Inhibits beta-catenin/T-cell factor transcriptional activity in colorectal cancer cells . The Journal of Biological Chemistry . 279 . 44 . 45669–75 . Oct 2004 . 15331612 . 2276578 . 10.1074/jbc.M405025200 . free .
23. Bragança J, Swingler T, Marques FI, Jones T, Eloranta JJ, Hurst HC, Shioda T, Bhattacharya S . Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2 . The Journal of Biological Chemistry . 277 . 10 . 8559–65 . Mar 2002 . 11744733 . 10.1074/jbc.M110850200 . free .
24. Campillos M, García MA, Valdivieso F, Vázquez J . Transcriptional activation by AP-2alpha is modulated by the oncogene DEK . Nucleic Acids Research . 31 . 5 . 1571–5 . Mar 2003 . 12595566 . 149840 . 10.1093/nar/gkg247 .
25. Bragança J, Eloranta JJ, Bamforth SD, Ibbitt JC, Hurst HC, Bhattacharya S . Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2 . The Journal of Biological Chemistry . 278 . 18 . 16021–9 . May 2003 . 12586840 . 10.1074/jbc.M208144200 . free .
26. Gaubatz S, Imhof A, Dosch R, Werner O, Mitchell P, Buettner R, Eilers M . Transcriptional activation by Myc is under negative control by the transcription factor AP-2 . The EMBO Journal . 14 . 7 . 1508–19 . Apr 1995 . 7729426 . 398238 . 10.1002/j.1460-2075.1995.tb07137.x.
27. McPherson LA, Loktev AV, Weigel RJ . Tumor suppressor activity of AP2alpha mediated through a direct interaction with p53 . The Journal of Biological Chemistry . 277 . 47 . 45028–33 . Nov 2002 . 12226108 . 10.1074/jbc.M208924200 . free .