TFAP2A: Wikis


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Transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)
Symbols TFAP2A; AP-2; AP-2alpha; AP2TF; TFAP2
External IDs OMIM107580 MGI104671 HomoloGene2421 GeneCards: TFAP2A Gene
RNA expression pattern
PBB GE TFAP2A 204653 at tn.png
PBB GE TFAP2A 204654 s at tn.png
PBB GE TFAP2A 210669 at tn.png
More reference expression data
Species Human Mouse
Entrez 7020 21418
Ensembl ENSG00000137203 ENSMUSG00000021359
UniProt P05549 Q3UL09
RefSeq (mRNA) NM_001032280 NM_011547
RefSeq (protein) NP_001027451 NP_035677
Location (UCSC) Chr 6:
10.5 - 10.53 Mb
Chr 13:
40.73 - 40.75 Mb
PubMed search [1] [2]

Transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha), also known as TFAP2A, is a protein which in humans is encoded by the TFAP2A gene.[1]



AP2-alpha is a 52-kD retinoic acid-inducible and developmentally regulated activator of transcription that binds to a consensus DNA-binding sequence CCCCAGGC in the SV40 and metallothionein (MIM 156350) promoters.[1]

In melanocytic cells TFAP2A gene expression may be regulated by MITF.[2]

The transcription factor AP-2alpha is a sequence-specific DNA-binding protein expressed in neural crest lineages with the highest levels of expression corresponding to early neural crest cells suggesting that AP-2alpha 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.[3][4][5][6]

The AP-2alpha protein acts as a sequence specific DNA-binding transcription factor recognizing and binding to the specific DNA sequence and recruiting the 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]

To study the role of AP-2 alpha during embryogenesis, Schorle et al.[7] created AP-2alpha knockout mice. They reported that Ap2 -/- mice died perinatally with cranioabdominoschisis and severe dysmorphogenesis of the face, skull, sensory organs, and cranial ganglia. Homozygous knockout mice were also showed by Zhang et al. (1996)[8] to have neural tube defects followed by craniofacial and body wall abnormalities.

Recently, Milunsky et al. (2008)[9] reported a family with branchiooculofacial syndrome (BOFS)[10] and detected a 3.2-Mb deletion at chromosome 6p24.3. 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. Rahimov et al. (2008)[11] reported that the disruption of an AP-2alphaa binding site in an IRF6 enhancer is associated with cleft lip.

Mutations in IRF6 gene cause Van der Woude syndrome (VWS)[12] that is a rare mendelian clefting autossomal dominant disorder with lower lip pits in 85% of affected individuals.[13]

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[14] and was independently replicated.[15][16][17][18]

A recent study Rahimov et al. [11] involving NSCL/P cases searched for potential regulatory elements for IRF6 gene aligning genomic sequences to a 500 Kb region encompassing IRF6 from 17 vertebrate species. They used human sequence as reference and searched for multispecies conserved sequences (MCSs). The 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-2alpha.

Mutations on AP-2alpha cause branchio-oculo-facial syndrome,[9] 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-2alpha are in the same developmental pathway and identify a variant in a regulatory region that contributes substantially to a common complex disorder.


TFAP2A has been shown to interact with APC,[19] DEK,[20] EP300,[21] CITED2,[21][22] Myc[23] and P53.[24]

See also


  1. ^ a b "Entrez Gene: TFAP2A transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)".  
  2. ^ Hoek KS, Schlegel NC, Eichhoff OM, et al. (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.  
  3. ^ Mitchell PJ, Wang C, Tjian R (September 1987). "Positive and negative regulation of transcription in vitro: enhancer-binding protein AP-2 is inhibited by SV40 T antigen". Cell 50 (6): 847–61. doi:10.1016/0092-8674(87)90512-5. PMID 3040262.  
  4. ^ Williams T, Admon A, Lüscher B, Tjian R (December 1988). "Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements". Genes & Development 2 (12A): 1557–69. doi:10.1101/gad.2.12a.1557. PMID 3063603.  
  5. ^ a b Williams T, Tjian R (April 1991). "Analysis of the DNA-binding and activation properties of the human transcription factor AP-2". Genes & Development 5 (4): 670–82. doi:10.1101/gad.5.4.670. PMID 2010091.  
  6. ^ Le Douarin NM, Ziller C, Couly GF (September 1993). "Patterning of neural crest derivatives in the avian embryo: in vivo and in vitro studies". Developmental Biology 159 (1): 24–49. doi:10.1006/dbio.1993.1219. PMID 8365563.  
  7. ^ Schorle H, Meier P, Buchert M, Jaenisch R, Mitchell PJ (May 1996). "Transcription factor AP-2 essential for cranial closure and craniofacial development". Nature 381 (6579): 235–8. doi:10.1038/381235a0. PMID 8622765.  
  8. ^ Zhang J, Hagopian-Donaldson S, Serbedzija G, Elsemore J, Plehn-Dujowich D, McMahon AP, Flavell RA, Williams T (May 1996). "Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2". Nature 381 (6579): 238–41. doi:10.1038/381238a0. PMID 8622766.  
  9. ^ a b Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, Burch MN, Clemens M, Mulliken JB, Smith R, Lin AE (May 2008). "TFAP2A mutations result in branchio-oculo-facial syndrome". American Journal of Human Genetics 82 (5): 1171–7. doi:10.1016/j.ajhg.2008.03.005. PMID 18423521.  
  10. ^ Online 'Mendelian Inheritance in Man' (OMIM) 113620
  11. ^ a b 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 (November 2008). "Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip". Nature Genetics 40 (11): 1341–7. doi:10.1038/ng.242. PMID 18836445.  
  12. ^ Online 'Mendelian Inheritance in Man' (OMIM) 119300
  13. ^ 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 (October 2002). "Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes". Nature Genetics 32 (2): 285–9. doi:10.1038/ng985. PMID 12219090.  
  14. ^ 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 (August 2004). "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. doi:10.1056/NEJMoa032909. PMID 15317890.  
  15. ^ Scapoli L, Palmieri A, Martinelli M, Pezzetti F, Carinci P, Tognon M, Carinci F (January 2005). "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. doi:10.1086/427344. PMID 15558496.  
  16. ^ Blanton SH, Cortez A, Stal S, Mulliken JB, Finnell RH, Hecht JT (September 2005). "Variation in IRF6 contributes to nonsyndromic cleft lip and palate". American Journal of Medical Genetics. Part a 137A (3): 259–62. doi:10.1002/ajmg.a.30887. PMID 16096995.  
  17. ^ Ghassibé M, Bayet B, Revencu N, Verellen-Dumoulin C, Gillerot Y, Vanwijck R, Vikkula M (November 2005). "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 : EJHG 13 (11): 1239–42. doi:10.1038/sj.ejhg.5201486. PMID 16132054.  
  18. ^ 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 (April 2007). "Association between IRF6 and nonsyndromic cleft lip with or without cleft palate in four populations". Genetics in Medicine : Official Journal of the American College of Medical Genetics 9 (4): 219–27. doi:10.1097/GIM.0b013e3180423cca. PMID 17438386.  
  19. ^ Li, Qingjie; Dashwood Roderick H (Oct. 2004). "Activator protein 2alpha associates with adenomatous polyposis coli/beta-catenin and Inhibits beta-catenin/T-cell factor transcriptional activity in colorectal cancer cells". J. Biol. Chem. (United States) 279 (44): 45669–75. doi:10.1074/jbc.M405025200. ISSN 0021-9258. PMID 15331612.  
  20. ^ Campillos, Mónica; García Miguel Angel, Valdivieso Fernando, Vázquez Jesús (Mar. 2003). "Transcriptional activation by AP-2alpha is modulated by the oncogene DEK". Nucleic Acids Res. (England) 31 (5): 1571–5. PMID 12595566.  
  21. ^ a b Bragança, José; Eloranta Jyrki J, Bamforth Simon D, Ibbitt J Claire, Hurst Helen C, Bhattacharya Shoumo (May. 2003). "Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2". J. Biol. Chem. (United States) 278 (18): 16021–9. doi:10.1074/jbc.M208144200. ISSN 0021-9258. PMID 12586840.  
  22. ^ Bragança, José; Swingler Tracey, Marques Fatima I R, Jones Tania, Eloranta Jyrki J, Hurst Helen C, Shioda Toshihiro, Bhattacharya Shoumo (Mar. 2002). "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". J. Biol. Chem. (United States) 277 (10): 8559–65. doi:10.1074/jbc.M110850200. ISSN 0021-9258. PMID 11744733.  
  23. ^ Gaubatz, S; Imhof A, Dosch R, Werner O, Mitchell P, Buettner R, Eilers M (Apr. 1995). "Transcriptional activation by Myc is under negative control by the transcription factor AP-2". EMBO J. (ENGLAND) 14 (7): 1508–19. ISSN 0261-4189. PMID 7729426.  
  24. ^ McPherson, Lisa A; Loktev Alexander V, Weigel Ronald J (Nov. 2002). "Tumor suppressor activity of AP2alpha mediated through a direct interaction with p53". J. Biol. Chem. (United States) 277 (47): 45028–33. doi:10.1074/jbc.M208924200. ISSN 0021-9258. PMID 12226108.  

Further reading

  • Murphy JE, Keen JH (1992). "Recognition sites for clathrin-associated proteins AP-2 and AP-3 on clathrin triskelia.". J. Biol. Chem. 267 (15): 10850–5. PMID 1587861.  
  • Gaynor RB, Muchardt C, Xia YR, et al. (1991). "Localization of the gene for the DNA-binding protein AP-2 to human chromosome 6p22.3-pter.". Genomics 10 (4): 1100–2. doi:10.1016/0888-7543(91)90209-W. PMID 1916817.  
  • Williams T, Tjian R (1991). "Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins.". Science 251 (4997): 1067–71. doi:10.1126/science.1998122. PMID 1998122.  
  • Williams T, Tjian R (1991). "Analysis of the DNA-binding and activation properties of the human transcription factor AP-2.". Genes Dev. 5 (4): 670–82. doi:10.1101/gad.5.4.670. PMID 2010091.  
  • Williams T, Admon A, Lüscher B, Tjian R (1989). "Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements.". Genes Dev. 2 (12A): 1557–69. doi:10.1101/gad.2.12a.1557. PMID 3063603.  
  • Bauer R, Imhof A, Pscherer A, et al. (1994). "The genomic structure of the human AP-2 transcription factor.". Nucleic Acids Res. 22 (8): 1413–20. doi:10.1093/nar/22.8.1413. PMID 8190633.  
  • Buettner R, Kannan P, Imhof A, et al. (1993). "An alternatively spliced mRNA from the AP-2 gene encodes a negative regulator of transcriptional activation by AP-2.". Mol. Cell. Biol. 13 (7): 4174–85. PMID 8321221.  
  • Williamson JA, Bosher JM, Skinner A, et al. (1996). "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. doi:10.1006/geno.1996.0351. PMID 8661133.  
  • Pirozzi G, McConnell SJ, Uveges AJ, et al. (1997). "Identification of novel human WW domain-containing proteins by cloning of ligand targets.". J. Biol. Chem. 272 (23): 14611–6. doi:10.1074/jbc.272.23.14611. PMID 9169421.  
  • Batsché E, Muchardt C, Behrens J, et al. (1998). "RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2.". Mol. Cell. Biol. 18 (7): 3647–58. PMID 9632747.  
  • Mertens PR, Alfonso-Jaume MA, Steinmann K, Lovett DH (1999). "A synergistic interaction of transcription factors AP2 and YB-1 regulates gelatinase A enhancer-dependent transcription.". J. Biol. Chem. 273 (49): 32957–65. doi:10.1074/jbc.273.49.32957. PMID 9830047.  
  • García MA, Campillos M, Marina A, et al. (1999). "Transcription factor AP-2 activity is modulated by protein kinase A-mediated phosphorylation.". FEBS Lett. 444 (1): 27–31. doi:10.1016/S0014-5793(99)00021-6. PMID 10037142.  
  • Rosenthal JA, Chen H, Slepnev VI, et al. (1999). "The epsins define a family of proteins that interact with components of the clathrin coat and contain a new protein module.". J. Biol. Chem. 274 (48): 33959–65. doi:10.1074/jbc.274.48.33959. PMID 10567358.  
  • Heicklen-Klein A, Ginzburg I (2000). "Tau promoter confers neuronal specificity and binds Sp1 and AP-2.". J. Neurochem. 75 (4): 1408–18. doi:10.1046/j.1471-4159.2000.0751408.x. PMID 10987820.  
  • Nyormoi O, Wang Z, Doan D, et al. (2001). "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.". Mol. Cell. Biol. 21 (15): 4856–67. doi:10.1128/MCB.21.15.4856-4867.2001. PMID 11438643.  
  • Rao DS, Chang JC, Kumar PD, et al. (2001). "Huntingtin interacting protein 1 Is a clathrin coat binding protein required for differentiation of late spermatogenic progenitors.". Mol. Cell. Biol. 21 (22): 7796–806. doi:10.1128/MCB.21.22.7796-7806.2001. PMID 11604514.  
  • Bragança J, Swingler T, Marques FI, et al. (2002). "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.". J. Biol. Chem. 277 (10): 8559–65. doi:10.1074/jbc.M110850200. PMID 11744733.  
  • Mertens PR, Steinmann K, Alfonso-Jaume MA, et al. (2002). "Combinatorial interactions of p53, activating protein-2, and YB-1 with a single enhancer element regulate gelatinase A expression in neoplastic cells.". J. Biol. Chem. 277 (28): 24875–82. doi:10.1074/jbc.M200445200. PMID 11973333.  
  • Eloranta JJ, Hurst HC (2002). "Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo.". J. Biol. Chem. 277 (34): 30798–804. doi:10.1074/jbc.M202780200. PMID 12072434.  
  • Ben-Zimra M, Koler M, Orly J (2003). "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.". Mol. Endocrinol. 16 (8): 1864–80. doi:10.1210/me.2002-0056. PMID 12145340.  

External links

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



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