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The AP-2 family of transcription factors


The AP-2 family of transcription factors consists of five different proteins in humans and mice: AP-2α, AP-2β, AP-2γ, AP-2δ and AP-2ε. Frogs and fish have known orthologs of some but not all of these proteins, and homologs of the family are also found in protochordates, insects and nematodes. The proteins have a characteristic helix-span-helix motif at the carboxyl terminus, which, together with a central basic region, mediates dimerization and DNA binding. The amino terminus contains the transactivation domain. AP-2 proteins are first expressed in primitive ectoderm of invertebrates and vertebrates; in vertebrates, they are also expressed in the emerging neural-crest cells, and AP-2α -/- animals have impairments in neural-crest-derived facial structures. AP-2β is indispensable for kidney development and AP-2γ is necessary for the formation of trophectoderm cells shortly after implantation; AP-2α and AP-2γ levels are elevated in human mammary carcinoma and seminoma. The general functions of the family appear to be the cell-type-specific stimulation of proliferation and the suppression of terminal differentiation during embryonic development.

Gene organization and evolutionary history

The AP-2 family of transcription factors (Ensembl Family ENSF00000001105) consists in humans and mice of five members, AP-2α, AP-2β, AP-2γ, AP-2δ and AP-2ε; frogs and fish have some of these proteins, and homologs are also known in invertebrates. The chromosomal locations and accession numbers of the family are given in Tables 1 and 2, respectively. All mammalian AP-2 proteins except AP-2δ are encoded by seven exons and share a characteristic domain structure (reviewed in [1]; for AP-2δ see [2] and for AP-2ε see [3, 4]). Orthologs show a similarity between 60 and 99% at the amino-acid level, whereas paralogs show a similarity between 56 and 78%.

Table 1 Chromosomal locations of AP-2 genes from selected species
Table 2 Accession numbers for AP-2 proteins from selected species

Analysis of the phylogenetic tree (Figure 1) reveals that the vertebrate AP-2 proteins are grouped together and are divided into five groups. The single Xenopus AP-2 is most closely related to mammalian AP-2α proteins. As the genes AP-2β and AP-2δ are found on the same chromosome in chickens, rodents and humans (Table 1), it is likely that they are the result of an internal duplication. According to the phylogenetic tree, AP-2δ genes appear to have separated from the rest of the family early in the vertebrate clade and to have evolved separately (Figure 1). A BLAST search of the puffer fish Fugu rubripes fourth genome assembly database [5] suggests that there are orthologs of AP-2α, AP-2β, AP-2γ and AP-2ε but not AP-2δ genes in bony fish, although only orthologs of AP-2α and AP-2β have been found in zebrafish.

Figure 1

Phylogenetic tree of the AP-2 family. Amino-acid sequence alignments were performed using ClustalW implemented in Sequence Data Explorer of the MEGA3 software [67]. The phylogenetic tree was created using the neighbor-joining method (gaps setting: pairwise deletion; distance method: number of differences). Numbers at selected nodes indicate the percentage frequencies of branch association on the basis of 1,000 bootstrap repetitions. The scale bar indicates the number of residue changes. Asterisks indicate predicted proteins; brackets denote subfamilies in vertebrates. Species: Caenorhabditis elegans (nematode); Ciona intestinalis (sea squirt); Drosophila melanogaster (fruit fly); Danio rerio (zebrafish); Gallus gallus (chicken); Homo sapiens (human); Mus musculus (mouse); Pan troglodytes (chimpanzee); Rattus norvegicus (rat); Xenopus laevis and Xenopus tropicalis (frog).

In the genome of the protochordate Ciona intestinalis a single AP-2 gene has been predicted; the phylogenetic tree shows that the protein evolved before the split of the AP-2α, AP-2β, AP-2γ and AP-2ε proteins, with the highest sequence similarity with the AP-2α group, suggesting that AP-2α might be most similar to the ancestor of AP-2 proteins. This hypothesis is further supported by the conserved epithelial expression patterns of murine AP-2α[6], Xenopus AP-2 [7] and the amphioxus and lamprey AP-2[8] genes. As expected, the two Caenorhabditis elegans and the single Drosophila melanogaster AP-2 proteins show the weakest phylogenetic relationship with vertebrate and protochordate AP-2 transcription factors; they form an outgroup to the other AP-2 family members (Figure 1). Given that no AP-2 gene has been identified in yeast, the family probably originated late in evolution and expanded considerably in the vertebrates.

Characteristic structural features

All AP-2 proteins share a highly conserved helix-span-helix dimerization motif at the carboxyl terminus, followed by a central basic region and a less conserved domain rich in proline and glutamine at the amino terminus (Figure 2). The proteins are able to form hetero- as well as homodimers. The helix-span-helix motif together with the basic region mediates DNA binding [9, 10], and the proline- and glutamine-rich region is responsible for transactivation. AP-2 has been shown to bind to the palindromic consensus sequence 5'-GCCN3GGC-3', found in various cellular and viral enhancers (reviewed in [1]); a binding-site selection assay in vitro also revealed the additional binding motifs 5'-GCCN3GGC-3', 5'-GCCN4GGC-3' and 5'-GCCN3/4GGG-3' [11]. Other binding sites differing from these sequence motifs, for example, the SV40 enhancer element 5'-CCCCAGGC-3' [12], indicate that AP-2 proteins may bind to a range of G/C-rich elements with variable affinities. Target genes with AP-2-binding sites in their promoter sequences are involved in biological processes such as cell growth and differentiation and include, for example, those encoding insulin-like growth factor binding protein 5 (IGF-BP5) with the binding site 5'-GCCAGGGGC-3' [13], prothymosin-α (5'-GCCGGTGGGC-3') [14] and the estrogen receptor (5'-GCCTGCGGGG-3') [15].

Figure 2

A schematic representation of the protein structure of an AP-2α dimer, showing the proline- and glutamine (P/Q)-rich transactivation domain (89 amino acids, red), the PY motif within this domain (5 amino acids, green), the basic domain (20 amino acids, yellow) and the helix-span-helix motif (131 amino acids, blue). The helix-span-helix motif is responsible for dimerization of the proteins and mediates DNA binding together with the basic domain. Modified from SwissProt, ID: P34056 [68].

Most AP-2 proteins have a PY motif (XPPXY) and other highly conserved critical residues in the transactivation domain; by contrast, the PY motif is missing in AP-2δ but the amino- and carboxy-terminal ends of the core sequence of the transactivation domain are still conserved. In addition, the binding affinity of AP-2δ to conserved AP-2-binding sites is much lower than that of other AP-2 proteins [2]. This suggests that AP-2δ might transactivate genes in vivo by a different mechanism from that used by other AP-2 proteins, probably through interactions with a novel group of coactivators and through a different affinity for AP-2-binding sites. Alternatively, AP-2δ might act as a negative regulator, inhibiting or modulating the transactivation capability or DNA-binding affinity of the other AP-2 family members. The crystal structure of the AP-2 proteins has not yet been solved.

Localization and function

AP-2 transcription factors are localized predominantly in the nucleus, where they bind to target sequences and regulate transcription of target genes. AP-2 proteins have also been shown to interfere with other signal transduction pathways; for example, it has been proposed that they modulate the pathway downstream of the developmental signaling molecule Wnt by associating with the Adenomatous polyposis coli (APC) tumor suppressor protein in the nucleus [16].

The activity of AP-2 proteins can be controlled at multiple levels: their transactivation potential, their DNA binding, their subcellular localization [1719] and their degradation [20, 21] can all be modified. Mechanisms of regulation include post-translational modifications, such as protein kinase A-mediated phosphorylation [22, 23], sumoylation [24] and redox regulation [25, 26], as well as physical interaction with various proteins (see Table 3 for a comprehensive list). Interacting proteins either modulate the activity of AP-2 proteins or are influenced in their function by binding to AP-2 proteins.

Table 3 Proteins that physically interact with AP-2 transcription factors

The tissue distribution and developmental functions of AP-2 transcription factors have been studied extensively in several species. Drosophila AP-2 (dAP-2) is expressed in the maxillary segment and neural structures during embryogenesis, and in the central nervous system (CNS) and the leg, antennal and labial imaginal disks during larval development [27, 28]. Mutation of the dAP-2 gene leads to defects in proboscis development and leg-joint formation [29, 30].

The multiple overlapping and diverging expression patterns of AP-2 family proteins suggest that, following the expansion of the family during vertebrate evolution, redundant and non-redundant functions of the individual AP-2 family members evolved. Although the single AP-2 protein in the cephalochordate amphioxus is expressed mainly in non-neuronal ectoderm, in the lamprey, a primitive vertebrate, AP-2 has co-opted a second expression domain, the neural crest [8]. The single AP-2 homolog described so far in Xenopus is expressed in the epidermis and neural crest and has been shown to be critical for the development of these structures [7, 3133]. In zebrafish, the two AP-2 family members, tfap2a and tfap2b [34], are coexpressed in the neural tube, the ectoderm and the pronephric ducts of the developing kidney, but only tfap2a is expressed in neural crest cells [35, 36]. Positional cloning revealed that the zebrafish point mutants named mont blanc [35] and lockjaw [36] encode tfap2a; the mutant animals display impaired development of neural-crest derivatives, such as the facial skeleton, the peripheral nervous system and pigment cells [37, 38]. It is also interesting to note that AP-2 proteins are expressed in the primitive ectoderm of both invertebrates and vertebrates, suggesting an evolutionarily conserved role for the family in the formation of this tissue.

In mice, three of the five AP-2 family members (AP-2α, AP-2β and AP-2γ) are coexpressed in neural-crest cells, the peripheral nervous system, facial and limb mesenchyme, various epithelia of the developing embryo and the extraembryonic trophectoderm [2, 3941]. AP-2δ expression is restricted mainly to the developing heart, CNS and retina [39], whereas AP-2ε expression is detected in cells of the olfactory bulb [3, 4]. Despite the overlapping expression patterns of AP-2α, AP-2β and AP-2γ, disruption of these AP-2 genes reveals non-redundant roles during development. Mutation of AP-2α predominantly affects the cranial neural crest and the limb mesenchyme, leading to disturbances of facial and limb development in a manner reminiscent of the defects described in dAP2 mutant flies [42, 43]. AP-2β and AP-2γ, on the other hand, are essential for kidney development [44, 45] or placentation of the embryo [46, 47], respectively. In humans, mutations generating a dominant negative allele of AP-2β have been shown to be the cause of Char syndrome (Online Mendelian Inheritance in Man (OMIM) ID 169100 [48]); the hallmarks of this syndrome are patent ductus arteriosus (abnormal persistence of a normal fetal heart structure after birth) with facial dysmorphism and abnormal fifth digits [49, 50].

Comparing all mutant phenotypes, it can be seen that loss of AP-2 transcription factor activity generally impairs proliferation and induces premature differentiation and/or apoptosis in various cell types during development. This conclusion is further substantiated by results from a screen for AP-2α target genes [51] and supported by gain-of-function studies in Xenopus and mice [31, 52, 53]. As uncontrolled proliferation leads to malignancies, AP-2 transcription factors are not only implicated in normal development, but also seem to be involved in cellular neoplasia, and enhanced AP-2 levels have been reported in various types of cancer [19, 5460]. In a murine breast-cancer model, tumor progression is enhanced after transgenic overexpression of AP-2γ [55]. Thus, AP-2 proteins can be viewed as gatekeepers controlling the balance between proliferation and differentiation during embryogenesis.


The lethal phenotypes of the AP-2 mutants generated so far have precluded an analysis of the roles of AP-2 transcription factors in adult tissues. We and others are currently exploiting the power of conditional mouse mutants to overcome these restrictions [6163]. Such approaches will not only shed light on normal AP-2 functions but will probably also lead to unique insights into human disorders.

Complementary approaches currently include the identification of AP-2 target genes; this might give a better understanding of developmental disturbances and pave the way to novel treatment options [51, 64]. At the molecular level, one major challenge will be the identification of specific AP-2 homo- or hetero-dimeric complexes bound to a particular promoter and the identification of the specific properties of each complex with respect to gene regulation. Also, the signaling pathways responsible for induction of AP-2 genes are currently under investigation. A cross-species comparison of the various AP-2 promoters may give insights into the evolution of tissue specificity and help to determine important enhancer elements. Moreover, given that CpG islands are present in AP-2 promoters, epigenetic regulation such as DNA methylation also needs to be considered.

AP-2 transcription factors are currently being studied extensively in human cancer, and they may be of diagnostic value, as has been demonstrated for mammary or testicular carcinoma [19, 54, 56, 65, 66]. It is tempting to speculate that AP-2 transcription factors might not only be molecular markers for certain types of cancer, but could also be causally involved in their etiologies and would therefore represent a potential target for therapeutic intervention.


  1. 1.

    Hilger-Eversheim K, Moser M, Schorle H, Buettner R: Regulatory roles of AP-2 transcription factors in vertebrate development, apoptosis and cell-cycle control. Gene. 2000, 260: 1-12. 10.1016/S0378-1119(00)00454-6.

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Zhao F, Satoda M, Licht JD, Hayashizaki Y, Gelb BD: Cloning and characterization of a novel mouse AP-2 transcription factor, AP-2delta, with unique DNA binding and transactivation properties. J Biol Chem. 2001, 276: 40755-40760. 10.1074/jbc.M106284200.

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Wang HV, Vaupel K, Buettner R, Bosserhoff AK, Moser M: Identification and embryonic expression of a new AP-2 transcription factor, AP-2 epsilon. Dev Dyn. 2004, 231: 128-135. 10.1002/dvdy.20119.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Feng W, Williams T: Cloning and characterization of the mouse AP-2 epsilon gene: a novel family member expressed in the developing olfactory bulb. Mol Cell Neurosci. 2003, 24: 460-475. 10.1016/S1044-7431(03)00209-4.

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    IMCB - Fugu Genome Project. []

  6. 6.

    Mitchell PJ, Timmons PM, Hebert JM, Rigby PW, Tjian R: Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis. Genes Dev. 1991, 5: 105-119.

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Snape AM, Winning RS, Sargent TD: Transcription factor AP-2 is tissue-specific in Xenopus and is closely related or identical to keratin transcription factor 1 (KTF-1). Development. 1991, 113: 283-293.

    PubMed  CAS  Google Scholar 

  8. 8.

    Meulemans D, Bronner-Fraser M: Amphioxus and lamprey AP-2 genes: implications for neural crest evolution and migration patterns. Development. 2002, 129: 4953-4962.

    PubMed  CAS  Google Scholar 

  9. 9.

    Williams T, Tjian R: Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. Genes Dev. 1991, 5: 670-682.

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Williams T, Tjian R: Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins. Science. 1991, 251: 1067-1071.

    PubMed  CAS  Article  Google Scholar 

  11. 11.

    Mohibullah N, Donner A, Ippolito JA, Williams T: SELEX and missing phosphate contact analyses reveal flexibility within the AP-2[alpha] protein: DNA binding complex. Nucleic Acids Res. 1999, 27: 2760-2769. 10.1093/nar/27.13.2760.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  12. 12.

    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. 1987, 50: 847-861. 10.1016/0092-8674(87)90512-5.

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Duan C, Clemmons DR: Transcription factor AP-2 regulates human insulin-like growth factor binding protein-5 gene expression. J Biol Chem. 1995, 270: 24844-24851. 10.1074/jbc.270.42.24844.

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    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. EMBO J. 1995, 14: 1508-1519.

    PubMed  CAS  PubMed Central  Google Scholar 

  15. 15.

    Newman SP, Bates NP, Vernimmen D, Parker MG, Hurst HC: Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer. Oncogene. 2000, 19: 490-497. 10.1038/sj.onc.1203416.

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    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. J Biol Chem. 2004, 279: 45669-45675. 10.1074/jbc.M405025200.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  17. 17.

    Aqeilan RI, Palamarchuk A, Weigel RJ, Herrero JJ, Pekarsky Y, Croce CM: Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor. Cancer Res. 2004, 64: 8256-8261. 10.1158/0008-5472.CAN-04-2055.

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Mazina OM, Phillips MA, Williams T, Vines CA, Cherr GN, Rice RH: Redistribution of transcription factor AP-2alpha in differentiating cultured human epidermal cells. J Invest Dermatol. 2001, 117: 864-870. 10.1046/j.0022-202x.2001.01472.x.

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Pellikainen J, Naukkarinen A, Ropponen K, Rummukainen J, Kataja V, Kellokoski J, Eskelinen M, Kosma VM: Expression of HER2 and its association with AP-2 in breast cancer. Eur J Cancer. 2004, 40: 1485-1495. 10.1016/j.ejca.2004.02.020.

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Li M, Wang Y, Hung MC, Kannan P: Inefficient proteasomal-degradation pathway stabilizes AP-2alpha and activates HER-2/neu gene in breast cancer. Int J Cancer. 2005, doi:10.1002/ijc.21426.

    Google Scholar 

  21. 21.

    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. Mol Cell Biol. 2001, 21: 4856-4867. 10.1128/MCB.21.15.4856-4867.2001.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  22. 22.

    Garcia MA, Campillos M, Marina A, Valdivieso F, Vazquez J: Transcription factor AP-2 activity is modulated by protein kinase A-mediated phosphorylation. FEBS Lett. 1999, 444: 27-31. 10.1016/S0014-5793(99)00021-6.

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Park K, Kim KH: The site of cAMP action in the insulin induction of gene expression of acetyl-CoA carboxylase is AP-2. J Biol Chem. 1993, 268: 17811-17819.

    PubMed  CAS  Google Scholar 

  24. 24.

    Zhong L, Wang Y, Kannan P, Tainsky MA: Functional characterization of the interacting domains of the positive coactivator PC4 with the transcription factor AP-2alpha. Gene. 2003, 320: 155-164. 10.1016/S0378-1119(03)00823-0.

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Grether-Beck S, Felsner I, Brenden H, Krutmann J: Mitochondrial cytochrome c release mediates ceramide-induced activator protein 2 activation and gene expression in keratinocytes. J Biol Chem. 2003, 278: 47498-47507. 10.1074/jbc.M309511200.

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Huang Y, Domann FE: Redox modulation of AP-2 DNA binding activity in vitro. Biochem Biophys Res Commun. 1998, 249: 307-312. 10.1006/bbrc.1998.9139.

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Bauer R, McGuffin ME, Mattox W, Tainsky MA: Cloning and characterization of the Drosophila homologue of the AP-2 transcription factor. Oncogene. 1998, 17: 1911-1922. 10.1038/sj.onc.1202114.

    PubMed  CAS  Article  Google Scholar 

  28. 28.

    Monge I, Mitchell PJ: DAP-2, the Drosophila homolog of transcription factor AP-2. Mech Dev. 1998, 76: 191-195. 10.1016/S0925-4773(98)00125-7.

    PubMed  CAS  Article  Google Scholar 

  29. 29.

    Kerber B, Monge I, Mueller M, Mitchell PJ, Cohen SM: The AP-2 transcription factor is required for joint formation and cell survival in Drosophila leg development. Development. 2001, 128: 1231-1238.

    PubMed  CAS  Google Scholar 

  30. 30.

    Monge I, Krishnamurthy R, Sims D, Hirth F, Spengler M, Kammermeier L, Reichert H, Mitchell PJ: Drosophila transcription factor AP-2 in proboscis, leg and brain central complex development. Development. 2001, 128: 1239-1252.

    PubMed  CAS  Google Scholar 

  31. 31.

    Luo T, Matsuo-Takasaki M, Thomas ML, Weeks DL, Sargent TD: Transcription factor AP-2 is an essential and direct regulator of epidermal development in Xenopus. Dev Biol. 2002, 245: 136-144. 10.1006/dbio.2002.0621.

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Winning RS, Shea LJ, Marcus SJ, Sargent TD: Developmental regulation of transcription factor AP-2 during Xenopus laevis embryogenesis. Nucleic Acids Res. 1991, 19: 3709-3714.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  33. 33.

    Luo T, Lee YH, Saint-Jeannet JP, Sargent TD: Induction of neural crest in Xenopus by transcription factor AP2alpha. Proc Natl Acad Sci USA. 2003, 100: 532-537. 10.1073/pnas.0237226100.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  34. 34.

    Knight RD, Javidan Y, Zhang T, Nelson S, Schilling TF: AP2-dependent signals from the ectoderm regulate craniofacial development in the zebrafish embryo. Development. 2005, 132: 3127-3138. 10.1242/dev.01879.

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Holzschuh J, Barrallo-Gimeno A, Ettl AK, Durr K, Knapik EW, Driever W: Noradrenergic neurons in the zebrafish hindbrain are induced by retinoic acid and require tfap2a for expression of the neurotransmitter phenotype. Development. 2003, 130: 5741-5754. 10.1242/dev.00816.

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Knight RD, Nair S, Nelson SS, Afshar A, Javidan Y, Geisler R, Rauch GJ, Schilling TF: lockjaw encodes a zebrafish tfap2a required for early neural crest development. Development. 2003, 130: 5755-5768. 10.1242/dev.00575.

    PubMed  CAS  Article  Google Scholar 

  37. 37.

    Barrallo-Gimeno A, Holzschuh J, Driever W, Knapik EW: Neural crest survival and differentiation in zebrafish depends on mont blanc/tfap2a gene function. Development. 2004, 131: 1463-1477. 10.1242/dev.01033.

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Knight RD, Javidan Y, Nelson S, Zhang T, Schilling T: Skeletal and pigment cell defects in the lockjaw mutant reveal multiple roles for zebrafish tfap2a in neural crest development. Dev Dyn. 2004, 229: 87-98. 10.1002/dvdy.10494.

    PubMed  CAS  Article  Google Scholar 

  39. 39.

    Zhao F, Lufkin T, Gelb BD: Expression of Tfap2d, the gene encoding the transcription factor Ap-2 delta, during mouse embryogenesis. Gene Expr Patterns. 2003, 3: 213-217. 10.1016/S1567-133X(02)00067-4.

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Moser M, Ruschoff J, Buettner R: Comparative analysis of AP-2 alpha and AP-2 beta gene expression during murine embryogenesis. Dev Dyn. 1997, 208: 115-124. 10.1002/(SICI)1097-0177(199701)208:1<115::AID-AJA11>3.0.CO;2-5.

    PubMed  CAS  Article  Google Scholar 

  41. 41.

    Chazaud C, Oulad-Abdelghani M, Bouillet P, Decimo D, Chambon P, Dolle P: AP-2.2, a novel gene related to AP-2, is expressed in the forebrain, limbs and face during mouse embryogenesis. Mech Dev. 1996, 54: 83-94. 10.1016/0925-4773(95)00463-7.

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    Schorle H, Meier P, Buchert M, Jaenisch R, Mitchell PJ: Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature. 1996, 381: 235-238. 10.1038/381235a0.

    PubMed  CAS  Article  Google Scholar 

  43. 43.

    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. 1996, 381: 238-241. 10.1038/381238a0.

    PubMed  CAS  Article  Google Scholar 

  44. 44.

    Moser M, Dahmen S, Kluge R, Grone H, Dahmen J, Kunz D, Schorle H, Buettner R: Terminal renal failure in mice lacking transcription factor AP-2 beta. Lab Invest. 2003, 83: 571-578.

    PubMed  CAS  Article  Google Scholar 

  45. 45.

    Moser M, Pscherer A, Roth C, Becker J, Mucher G, Zerres K, Dixkens C, Weis J, Guay-Woodford L, Buettner R, et al: Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta. Genes Dev. 1997, 11: 1938-1948.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  46. 46.

    Auman HJ, Nottoli T, Lakiza O, Winger Q, Donaldson S, Williams T: Transcription factor AP-2gamma is essential in the extraembryonic lineages for early postimplantation development. Development. 2002, 129: 2733-2747.

    PubMed  CAS  Google Scholar 

  47. 47.

    Werling U, Schorle H: Transcription factor gene AP-2 gamma essential for early murine development. Mol Cell Biol. 2002, 22: 3149-3156. 10.1128/MCB.22.9.3149-3156.2002.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  48. 48.

    OMIM - Online Mendelian Inheritance in Man. []

  49. 49.

    Zhao F, Weismann CG, Satoda M, Pierpont ME, Sweeney E, Thompson EM, Gelb BD: Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation. Am J Hum Genet. 2001, 69: 695-703. 10.1086/323410.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  50. 50.

    Satoda M, Zhao F, Diaz GA, Burn J, Goodship J, Davidson HR, Pierpont ME, Gelb BD: Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat Genet. 2000, 25: 42-46. 10.1038/75578.

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Pfisterer P, Ehlermann J, Hegen M, Schorle H: A subtractive gene expression screen suggests a role of transcription factor AP-2 alpha in control of proliferation and differentiation. J Biol Chem. 2002, 277: 6637-6644. 10.1074/jbc.M108578200.

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Zhang J, Brewer S, Huang J, Williams T: Overexpression of transcription factor AP-2alpha suppresses mammary gland growth and morphogenesis. Dev Biol. 2003, 256: 127-145. 10.1016/S0012-1606(02)00119-7.

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Jager R, Werling U, Rimpf S, Jacob A, Schorle H: Transcription factor AP-2gamma stimulates proliferation and apoptosis and impairs differentiation in a transgenic model. Mol Cancer Res. 2003, 1: 921-929.

    PubMed  Google Scholar 

  54. 54.

    Pauls K, Jager R, Weber S, Wardelmann E, Koch A, Buttner R, Schorle H: Transcription factor AP-2gamma, a novel marker of gonocytes and seminomatous germ cell tumors. Int J Cancer. 2005, 115: 470-477. 10.1002/ijc.20913.

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Jager R, Friedrichs N, Heim I, Buttner R, Schorle H: Dual role of AP-2gamma in ErbB-2-induced mammary tumorigenesis. Breast Cancer Res Treat. 2005, 90: 273-280. 10.1007/s10549-004-4815-x.

    PubMed  Article  Google Scholar 

  56. 56.

    Hoei-Hansen CE, Nielsen JE, Almstrup K, Sonne SB, Graem N, Skakkebaek NE, Leffers H, Meyts ER: Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors. Clin Cancer Res. 2004, 10: 8521-8530. 10.1158/1078-0432.CCR-04-1285.

    PubMed  CAS  Article  Google Scholar 

  57. 57.

    Hurst HC: Update on HER-2 as a target for cancer therapy: the ERBB2 promoter and its exploitation for cancer treatment. Breast Cancer Res. 2001, 3: 395-398. 10.1186/bcr329.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  58. 58.

    Beger M, Butz K, Denk C, Williams T, Hurst HC, Hoppe-Seyler F: Expression pattern of AP-2 transcription factors in cervical cancer cells and analysis of their influence on human papillomavirus oncogene transcription. J Mol Med. 2001, 79: 314-320. 10.1007/s001090100211.

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Turner BC, Zhang J, Gumbs AA, Maher MG, Kaplan L, Carter D, Glazer PM, Hurst HC, Haffty BG, Williams T: Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways. Cancer Res. 1998, 58: 5466-5472.

    PubMed  CAS  Google Scholar 

  60. 60.

    Bosher JM, Totty NF, Hsuan JJ, Williams T, Hurst HC: A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma. Oncogene. 1996, 13: 1701-1707.

    PubMed  CAS  Google Scholar 

  61. 61.

    Nelson DK, Williams T: Frontonasal process-specific disruption of AP-2alpha results in postnatal midfacial hypoplasia, vascular anomalies, and nasal cavity defects. Dev Biol. 2004, 267: 72-92. 10.1016/j.ydbio.2003.10.033.

    PubMed  CAS  Article  Google Scholar 

  62. 62.

    Brewer S, Feng W, Huang J, Sullivan S, Williams T: Wnt1-Cre-mediated deletion of AP-2alpha causes multiple neural crest-related defects. Dev Biol. 2004, 267: 135-152. 10.1016/j.ydbio.2003.10.039.

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Werling U, Schorle H: Conditional inactivation of transcription factor AP-2gamma by using the Cre/loxP recombination system. Genesis. 2002, 32: 127-129. 10.1002/gene.10057.

    PubMed  CAS  Article  Google Scholar 

  64. 64.

    Luo T, Zhang Y, Khadka D, Rangarajan J, Cho KW, Sargent TD: Regulatory targets for transcription factor AP2 in Xenopus embryos. Dev Growth Differ. 2005, 47: 403-413. 10.1111/j.1440-169X.2005.00809.x.

    PubMed  CAS  Article  Google Scholar 

  65. 65.

    Friedrichs N, Jager R, Paggen E, Rudlowski C, Merkelbach-Bruse S, Schorle H, Buettner R: Distinct spatial expression patterns of AP-2alpha and AP-2gamma in non-neoplastic human breast and breast cancer. Mod Pathol. 2005, 18: 431-438. 10.1038/modpathol.3800292.

    PubMed  CAS  Article  Google Scholar 

  66. 66.

    Hoei-Hansen CE, Nielsen JE, Almstrup K, Hansen MA, Skakkebaek NE, Rajpert-DeMeyts E, Leffers H: Identification of genes differentially expressed in testes containing carcinoma in situ. Mol Hum Reprod. 2004, 10: 423-431. 10.1093/molehr/gah059.

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Kumar S, Tamura K, Nei M: MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform. 2004, 5: 150-163. 10.1186/1471-2105-5-150.

    PubMed  CAS  Article  Google Scholar 

  68. 68.

    Swiss-Prot. []

  69. 69.

    Braganca 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. J Biol Chem. 2003, 278: 16021-16029. 10.1074/jbc.M208144200.

    PubMed  CAS  Article  Google Scholar 

  70. 70.

    Braganca 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. J Biol Chem. 2002, 277: 8559-8565. 10.1074/jbc.M110850200.

    PubMed  CAS  Article  Google Scholar 

  71. 71.

    Wu F, Lee AS: CDP and AP-2 mediated repression mechanism of the replication-dependent hamster histone H3.2 promoter. J Cell Biochem. 2002, 84: 699-707. 10.1002/jcb.10094.

    PubMed  Article  Google Scholar 

  72. 72.

    Campillos M, Garcia MA, Valdivieso F, Vazquez J: Transcriptional activation by AP-2alpha is modulated by the oncogene DEK. Nucleic Acids Res. 2003, 31: 1571-1575. 10.1093/nar/gkg247.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  73. 73.

    Somasundaram K, Jayaraman G, Williams T, Moran E, Frisch S, Thimmapaya B: Repression of a matrix metalloprotease gene by E1A correlates with its ability to bind to cell type-specific transcription factor AP-2. Proc Natl Acad Sci USA. 1996, 93: 3088-3093. 10.1073/pnas.93.7.3088.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  74. 74.

    Kannan P, Yu Y, Wankhade S, Tainsky MA: PolyADP-ribose polymerase is a coactivator for AP-2-mediated transcriptional activation. Nucleic Acids Res. 1999, 27: 866-874. 10.1093/nar/27.3.866.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  75. 75.

    Sivak JM, West-Mays JA, Yee A, Williams T, Fini ME: Transcription factors Pax6 and AP-2alpha interact to coordinate corneal epithelial repair by controlling expression of matrix metalloproteinase gelatinase B. Mol Cell Biol. 2004, 24: 245-257. 10.1128/MCB.24.1.245-257.2004.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  76. 76.

    McPherson LA, Loktev AV, Weigel RJ: Tumor suppressor activity of AP2alpha mediated through a direct interaction with p53. J Biol Chem. 2002, 277: 45028-45033. 10.1074/jbc.M208924200.

    PubMed  CAS  Article  Google Scholar 

  77. 77.

    Wu F, Lee AS: Identification of AP-2 as an interactive target of Rb and a regulator of the G1/S control element of the hamster histone H3.2 promoter. Nucleic Acids Res. 1998, 26: 4837-4845. 10.1093/nar/26.21.4837.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  78. 78.

    Batsche E, Muchardt C, Behrens J, Hurst HC, Cremisi C: RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2. Mol Cell Biol. 1998, 18: 3647-3658.

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  79. 79.

    Pena P, Reutens AT, Albanese C, D'Amico M, Watanabe G, Donner A, Shu IW, Williams T, Pestell RG: Activator protein-2 mediates transcriptional activation of the CYP11A1 gene by interaction with Sp1 rather than binding to DNA. Mol Endocrinol. 1999, 13: 1402-1416. 10.1210/me.13.8.1402.

    PubMed  CAS  Article  Google Scholar 

  80. 80.

    Eloranta JJ, Hurst HC: Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo. J Biol Chem. 2002, 277: 30798-30804. 10.1074/jbc.M202780200.

    PubMed  CAS  Article  Google Scholar 

  81. 81.

    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. J Biol Chem. 1998, 273: 32957-32965. 10.1074/jbc.273.49.32957.

    PubMed  CAS  Article  Google Scholar 

  82. 82.

    Wu F, Lee AS: YY1 as a regulator of replication-dependent hamster histone H3.2 promoter and an interactive partner of AP-2. J Biol Chem. 2001, 276: 28-34. 10.1074/jbc.M006074200.

    PubMed  CAS  Article  Google Scholar 

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We thank Roland Dosch and Michael Pankratz for critical reading of the manuscript. This work was supported by funding from the Deutsche Forschungsgemeinschaft (# 503/6 and 503/7) that was awarded to H.S.

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Correspondence to Hubert Schorle.

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Eckert, D., Buhl, S., Weber, S. et al. The AP-2 family of transcription factors. Genome Biol 6, 246 (2005).

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