Document Detail

The AP-2 family of transcription factors.
Jump to Full Text
MedLine Citation:
PMID:  16420676     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The AP-2 family of transcription factors consists of five different proteins in humans and mice: AP-2alpha, AP-2beta, AP-2gamma, AP-2delta and AP-2epsilon. 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-2alpha-/- animals have impairments in neural-crest-derived facial structures. AP-2beta is indispensable for kidney development and AP-2gamma is necessary for the formation of trophectoderm cells shortly after implantation; AP-2alpha and AP-2gamma 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.
Authors:
Dawid Eckert; Sandra Buhl; Susanne Weber; Richard Jäger; Hubert Schorle
Related Documents :
16420676 - The ap-2 family of transcription factors.
11165496 - Qbrn-2, a pou iii gene in quail: distinct developmental expression revealed by a specif...
15582776 - Hedgehog and retinoid signalling confines nkx2.2b expression to the lateral floor plate...
7589816 - Expression of snail2, a second member of the zebrafish snail family, in cephalic mesend...
24347226 - Expression of far upstream element (fuse) binding protein 1 in human glioma is correlat...
16972096 - Over-expression of a flower-specific transcription factor gene atmyb24 causes aberrant ...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review     Date:  2005-12-28
Journal Detail:
Title:  Genome biology     Volume:  6     ISSN:  1465-6914     ISO Abbreviation:  Genome Biol.     Publication Date:  2005  
Date Detail:
Created Date:  2006-01-19     Completed Date:  2006-07-24     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  100960660     Medline TA:  Genome Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  246     Citation Subset:  IM    
Affiliation:
Department of Developmental Pathology, Institute of Pathology, Sigmund-Freud Strasse 25, 53125 Bonn, Germany.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Evolution
Humans
Multigene Family*
Phylogeny
Protein Binding
Transcription Factor AP-2 / chemistry,  metabolism*
Chemical
Reg. No./Substance:
0/Transcription Factor AP-2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Genome Biol
ISSN: 1465-6906
ISSN: 1465-6914
Publisher: BioMed Central, London
Article Information
Download PDF
Copyright © 2005 BioMed Central Ltd
Print publication date: Year: 2005
Electronic publication date: Day: 28 Month: 12 Year: 2005
Volume: 6 Issue: 13
First Page: 246 Last Page: 246
ID: 1414101
Publisher Id: gb-2005-6-13-246
PubMed Id: 16420676
DOI: 10.1186/gb-2005-6-13-246

The AP-2 family of transcription factors
Dawid Eckert1
Sandra Buhl1
Susanne Weber1
Richard Jäger1
Hubert Schorle1 Email: Hubert.Schorle@ukb.uni-bonn.de
1Department of Developmental Pathology, Institute of Pathology, Sigmund-Freud Strasse 25, 53125 Bonn, Germany

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%.

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.

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].

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 [17-19] 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.

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 [7,31-33]. 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 [2,39-41]. 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 [19,54-60]. 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.


Frontiers

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 [61-63]. 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.


Acknowledgements

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.


References
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. [pmid: 11137286] [doi: 10.1016/S0378-1119(00)00454-6]
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. [pmid: 11522791] [doi: 10.1074/jbc.M106284200]
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. [pmid: 15305293] [doi: 10.1002/dvdy.20119]
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. [pmid: 14572467] [doi: 10.1016/S1044-7431(03)00209-4]
IMCB - Fugu Genome Project
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. [pmid: 1989904]
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. [pmid: 1722450]
Meulemans D,Bronner-Fraser M. Amphioxus and lamprey AP-2 genes: implications for neural crest evolution and migration patterns.Development 2002;129:4953–4962. [pmid: 12397104]
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. [pmid: 2010091]
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. [pmid: 1998122]
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. [pmid: 10373594] [doi: 10.1093/nar/27.13.2760]
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. [pmid: 3040262] [doi: 10.1016/0092-8674(87)90512-5]
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. [pmid: 7559606] [doi: 10.1074/jbc.270.42.24844]
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. [pmid: 7729426]
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. [pmid: 10698518] [doi: 10.1038/sj.onc.1203416]
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. [pmid: 15331612] [doi: 10.1074/jbc.M405025200]
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. [pmid: 15548692] [doi: 10.1158/0008-5472.CAN-04-2055]
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. [pmid: 11676824] [doi: 10.1046/j.0022-202x.2001.01472.x]
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. [pmid: 15196531] [doi: 10.1016/j.ejca.2004.02.020]
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.
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. [pmid: 11438643] [doi: 10.1128/MCB.21.15.4856-4867.2001]
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. [pmid: 10037142] [doi: 10.1016/S0014-5793(99)00021-6]
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. [pmid: 8102369]
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. [pmid: 14597399] [doi: 10.1016/S0378-1119(03)00823-0]
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. [pmid: 12952965] [doi: 10.1074/jbc.M309511200]
Huang Y,Domann FE. Redox modulation of AP-2 DNA binding activity in vitro.Biochem Biophys Res Commun 1998;249:307–312. [pmid: 9712692] [doi: 10.1006/bbrc.1998.9139]
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. [pmid: 9788434] [doi: 10.1038/sj.onc.1202114]
Monge I,Mitchell PJ. DAP-2, the Drosophila homolog of transcription factor AP-2.Mech Dev 1998;76:191–195. [pmid: 9867351] [doi: 10.1016/S0925-4773(98)00125-7]
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. [pmid: 11262225]
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. [pmid: 11262226]
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. [pmid: 11969261] [doi: 10.1006/dbio.2002.0621]
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. [pmid: 1852613]
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. [pmid: 12511599] [doi: 10.1073/pnas.0237226100]
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. [pmid: 15944192] [doi: 10.1242/dev.01879]
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. [pmid: 14534139] [doi: 10.1242/dev.00816]
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. [pmid: 14534133] [doi: 10.1242/dev.00575]
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. [pmid: 14985255] [doi: 10.1242/dev.01033]
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. [pmid: 14699580] [doi: 10.1002/dvdy.10494]
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. [pmid: 12711551] [doi: 10.1016/S1567-133X(02)00067-4]
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. [pmid: 8989526] [doi: 10.1002/(SICI)1097-0177(199701)208:1<115::AID-AJA11>3.0.CO;2-5]
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. [pmid: 8808408] [doi: 10.1016/0925-4773(95)00463-7]
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. [pmid: 8622765] [doi: 10.1038/381235a0]
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. [pmid: 8622766] [doi: 10.1038/381238a0]
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. [pmid: 12695560]
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. [pmid: 9271117]
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. [pmid: 12015300]
Werling U,Schorle H. Transcription factor gene AP-2 gamma essential for early murine development.Mol Cell Biol 2002;22:3149–3156. [pmid: 11940672] [doi: 10.1128/MCB.22.9.3149-3156.2002]
OMIM - Online Mendelian Inheritance in Man
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. [pmid: 11505339] [doi: 10.1086/323410]
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. [pmid: 10802654] [doi: 10.1038/75578]
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. [pmid: 11741941] [doi: 10.1074/jbc.M108578200]
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. [pmid: 12654297] [doi: 10.1016/S0012-1606(02)00119-7]
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. [pmid: 14573793]
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. [pmid: 15700319] [doi: 10.1002/ijc.20913]
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. [pmid: 15830141] [doi: 10.1007/s10549-004-4815-x]
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. [pmid: 15623634] [doi: 10.1158/1078-0432.CCR-04-1285]
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. [pmid: 11737892] [doi: 10.1186/bcr329]
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. [pmid: 11485026] [doi: 10.1007/s001090100211]
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. [pmid: 9850080]
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. [pmid: 8895516]
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. [pmid: 14975718] [doi: 10.1016/j.ydbio.2003.10.033]
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. [pmid: 14975722] [doi: 10.1016/j.ydbio.2003.10.039]
Werling U,Schorle H. Conditional inactivation of transcription factor AP-2gamma by using the Cre/loxP recombination system.Genesis 2002;32:127–129. [pmid: 11857798] [doi: 10.1002/gene.10057]
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. [pmid: 16109038] [doi: 10.1111/j.1440-169X.2005.00809.x]
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. [pmid: 15467710] [doi: 10.1038/modpathol.3800292]
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. [pmid: 15123780] [doi: 10.1093/molehr/gah059]
Kumar S,Tamura K,Nei M. MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment.Brief Bioinform 2004;5:150–163. [pmid: 15260895] [doi: 10.1186/1471-2105-5-150]
Swiss-Prot
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. [pmid: 12586840] [doi: 10.1074/jbc.M208144200]
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. [pmid: 11744733] [doi: 10.1074/jbc.M110850200]
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. [pmid: 11835395] [doi: 10.1002/jcb.10094]
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. [pmid: 12595566] [doi: 10.1093/nar/gkg247]
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. [pmid: 8610173] [doi: 10.1073/pnas.93.7.3088]
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. [pmid: 9889285] [doi: 10.1093/nar/27.3.866]
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. [pmid: 14673159] [doi: 10.1128/MCB.24.1.245-257.2004]
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. [pmid: 12226108] [doi: 10.1074/jbc.M208924200]
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. [pmid: 9776742] [doi: 10.1093/nar/26.21.4837]
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. [pmid: 9632747]
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. [pmid: 10446912] [doi: 10.1210/me.13.8.1402]
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. [pmid: 12072434] [doi: 10.1074/jbc.M202780200]
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. [pmid: 9830047] [doi: 10.1074/jbc.273.49.32957]
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. [pmid: 11018030] [doi: 10.1074/jbc.M006074200]

Figures

[Figure ID: F1]
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).



[Figure ID: F2]
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].



Tables
[TableWrap ID: T1] Table 1 

Chromosomal locations of AP-2 genes from selected species


AP-2α AP-2β AP-2γ AP-2δ AP-2ε Other AP-2 genes*
H. sapiens 6p24 6p12 20q13.2 6p12.1 1p34.3
P. troglodytes 6p22.3 6p12 21 - -
M. musculus 13 A5-B1 1 A2-A4 2 H3-H4 1 A3 4 D2.2
R. norvegicus 17p12 9q13 3q42 9q13 5q36
G. gallus 2 3 - 3 -
X. tropicalis scaffold_278 - - - -
D. rerio 24 20 - - -
C. elegans II
D. melanogaster 3L

*The AP-2 genes of C. elegans and D. melanogaster are not orthologous to any of the five mammalian genes. Data taken from the database entries for the accession numbers given in Table 2. No information on mapping is available for the C. intestinalis AP-2 gene.


[TableWrap ID: T2] Table 2 

Accession numbers for AP-2 proteins from selected species


AP-2α AP-2β AP-2γ AP-2δ AP-2ε Other AP-2 proteins*
H. sapiens NP_003211 NP_003212 NP_003213 NP_758438 NP_848643
P. troglodytes - XP_518532 XP_526337 - -
M. musculus NP_035677 NP_033360 NP_033361 NP_694794 NP_945198
R. norvegicus XP_225238 XP_217356 NP_958823 XP_236975 XP_233526
G. gallus NP_990425 NP_990226 - XP_426224 -
X. tropicalis AAD53289 - - - -
X. laevis AAA49972 - - - -
D. rerio NP_789829 NP_001019836 - - -
C. elegans NP_4951819
D. melanogaster NP_730664
C. intestinalis BAE06307 and BAE06308

*The AP-2 genes of C. elegans, D. melanogaster and C. intestinalis are not orthologous to any of the five mammalian genes.


[TableWrap ID: T3] Table 3 

Proteins that physically interact with AP-2 transcription factors


Protein Description Domain of AP-2 proteins that interacts* Function of interaction Reference
APC Adenomatous polyposis coli tumor suppressor Basic region Inhibition of β-catenin/TCF/LEF-dependent transcription [16]
CITED2 Coactivator DD Transcriptional activation [69]
CITED4 Coactivator n.d. Transcriptional activation [70]
CDP CCAAT displacement protein DBD, DD Repression of the hamster histone H3.2 promoter [71]
DEK Oncoprotein, chromatin remodeling n.d. Transcriptional activation [72]
E1A Transforming protein of adenovirus DBD, DD Repression of AP-2 target genes [73]
c-Myc Oncoprotein Carboxyl terminus Impairment of Myc/Max DNA-binding and transactivation [14]
PARP PolyADP-ribose polymerase Carboxyl terminus Transcriptional activation [74]
PAX-6 Transcription factor n.d. Stimulation of gelatinase B activation [75]
PC4 Coactivator Transcriptional activation [24]
P300/CBP Coactivator Amino terminus Transcriptional activation [69]
p53 Tumor suppressor n.d. Augmentation of p53-dependent transcription [76]
RAP74 Subunit of transcription factor TFIIF Central region containing DBD Unknown [74]
Rb Retinoblastoma tumor suppressor Amino terminus Repression of the hamster histone H3.2 promoter; transcriptional activation of the E-cadherin gene [77,78]
SP1 Transcription factor Basic region Transcriptional activation of the ovine CYP11A1 gene [79]
SV40T Transforming protein of SV40 virus n.d. Blocks DNA binding of AP-2 protein [12]
UBC9 E2-conjugating enzyme DBD, DD Sumoylation [80]
WWOX Tumor suppressor Amino terminus PY motif Cytoplasmic localization PPPY motif [17]
YB-1 Transcription factor n.d. Stimulation of gelatinase A transcription [81]
YY1 Transcription factor DBD, DD Stimulation of the hamster histone H3.2 promoter [82]

*Abbreviations: DBD, DNA-binding domain; DD, dimerization domain; n.d., not determined. It is currently not entirely clear whether Rb binds AP-2 only via the amino terminus [78], or whether the DNA-binding domain is also necessary [77].



Article Categories:
  • Protein Family Review


Previous Document:  New approaches to combating antimicrobial drug resistance.
Next Document:  The undertranslated transcriptome reveals widespread translational silencing by alternative 5' trans...