Biology:TFAP2A

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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),[14] a 3.2-Mb deletion at chromosome 6p24.3 was detected.[15] 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.[16] Mutations in IRF6 gene cause Van der Woude syndrome (VWS)[17] that is a rare mendelian clefting autossomal dominant disorder with lower lip pits in 85% of affected individuals.[18] 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[19] and was independently replicated.[20][21][22][23]

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.[16]

Mutations in the AP-2 alpha gene also cause branchio-oculo-facial syndrome,[15] 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:

See also

References

  1. ↑ "Entrez Gene: TFAP2A transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7020. 
  2. ↑ "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. doi:10.1016/0092-8674(87)90512-5. PMID 3040262. 
  3. ↑ "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. doi:10.1101/gad.2.12a.1557. PMID 3063603. 
  4. ↑ "Regulation of transcription factor AP-2 by the morphogen retinoic acid and by second messengers". Genes Dev 3 (10): 1507–17. Oct 1989. doi:10.1101/gad.3.10.1507. PMID 2482225. 
  5. ↑ "Analysis of the DNA-binding and activation properties of the human transcription factor AP-2". Genes & Development 5 (4): 670–82. Apr 1991. doi:10.1101/gad.5.4.670. PMID 2010091. 
  6. ↑ "Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis". Genes Dev 5 (1): 105–19. Jan 1991. doi:10.1101/gad.5.1.105. PMID 1989904. 
  7. ↑ "Patterning of neural crest derivatives in the avian embryo: in vivo and in vitro studies". Developmental Biology 159 (1): 24–49. Sep 1993. doi:10.1006/dbio.1993.1219. PMID 8365563. 
  8. ↑ "Transcription factor AP-2 essential for cranial closure and craniofacial development". Nature 381 (6579): 235–8. May 1996. doi:10.1038/381235a0. PMID 8622765. Bibcode: 1996Natur.381..235S. 
  9. ↑ "Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2". Nature 381 (6579): 238–41. May 1996. doi:10.1038/381238a0. PMID 8622766. Bibcode: 1996Natur.381..238Z. 
  10. ↑ "Activator protein 2alpha suppresses intestinal tumorigenesis in the Apc(min) mouse". Cancer Letters 283 (1): 36–42. Sep 2009. doi:10.1016/j.canlet.2009.03.026. PMID 19376641. 
  11. ↑ "Activator protein-2α functions as a master regulator of multiple transcription factors in the mouse liver". Hepatology Research 41 (8): 776–83. Aug 2011. doi:10.1111/j.1872-034X.2011.00827.x. PMID 21682828. 
  12. ↑ "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research 21 (6): 665–76. Dec 2008. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. 
  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. ↑ Online Mendelian Inheritance in Man (OMIM) 113620
  15. ↑ 15.0 15.1 "TFAP2A mutations result in branchio-oculo-facial syndrome". American Journal of Human Genetics 82 (5): 1171–7. May 2008. doi:10.1016/j.ajhg.2008.03.005. PMID 18423521. 
  16. ↑ 16.0 16.1 "Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip". Nature Genetics 40 (11): 1341–7. Nov 2008. doi:10.1038/ng.242. PMID 18836445. 
  17. ↑ Online Mendelian Inheritance in Man (OMIM) 119300
  18. ↑ "Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes". Nature Genetics 32 (2): 285–9. Oct 2002. doi:10.1038/ng985. PMID 12219090. 
  19. ↑ "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. doi:10.1056/NEJMoa032909. PMID 15317890. http://d-scholarship.pitt.edu/14219/3/nejmoa032909.pdf. 
  20. ↑ "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. doi:10.1086/427344. PMID 15558496. 
  21. ↑ "Variation in IRF6 contributes to nonsyndromic cleft lip and palate". American Journal of Medical Genetics Part A 137A (3): 259–62. Sep 2005. doi:10.1002/ajmg.a.30887. PMID 16096995. 
  22. ↑ "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. doi:10.1038/sj.ejhg.5201486. PMID 16132054. 
  23. ↑ "Association between IRF6 and nonsyndromic cleft lip with or without cleft palate in four populations". Genetics in Medicine 9 (4): 219–27. Apr 2007. doi:10.1097/GIM.0b013e3180423cca. PMID 17438386. 
  24. ↑ "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. doi:10.1074/jbc.M405025200. PMID 15331612. 
  25. ↑ 25.0 25.1 "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. doi:10.1074/jbc.M208144200. PMID 12586840. 
  26. ↑ "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. doi:10.1074/jbc.M110850200. PMID 11744733. 
  27. ↑ "Transcriptional activation by AP-2alpha is modulated by the oncogene DEK". Nucleic Acids Research 31 (5): 1571–5. Mar 2003. doi:10.1093/nar/gkg247. PMID 12595566. 
  28. ↑ "Transcriptional activation by Myc is under negative control by the transcription factor AP-2". The EMBO Journal 14 (7): 1508–19. Apr 1995. doi:10.1002/j.1460-2075.1995.tb07137.x. PMID 7729426. 
  29. ↑ "Tumor suppressor activity of AP2alpha mediated through a direct interaction with p53". The Journal of Biological Chemistry 277 (47): 45028–33. Nov 2002. doi:10.1074/jbc.M208924200. PMID 12226108. 

Further reading

External links

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



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