Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors

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Homo sapiens
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The AP-2 (TFAP2) family of transcription factors includes five proteins in mammals: TFAP2A (AP-2 alpha), TFAP2B (AP-2 beta), TFAP2C (AP-2 gamma), TFAP2D (AP-2 delta) and TFAP2E (AP-2 epsilon). The AP-2 family transcription factors are evolutionarily conserved in metazoans and are characterized by a helix-span-helix motif at the C-terminus, a central basic region, and the transactivation domain at the N-terminus. The helix-span-helix motif and the basic region enable dimerization and DNA binding (Eckert et al. 2005).

AP-2 dimers bind palindromic GC-rich DNA response elements that match the consensus sequence 5'-GCCNNNGGC-3' (Williams and Tjian 1991a, Williams and Tjian 1991b). Transcriptional co-factors from the CITED family interact with the helix-span-helix (HSH) domain of TFAP2 (AP-2) family of transcription factors and recruit transcription co-activators EP300 (p300) and CREBBP (CBP) to TFAP2-bound DNA elements. CITED2 shows the highest affinity for TFAP2 proteins, followed by CITED4, while CITED1 interacts with TFAP2s with a very low affinity. Mouse embryos defective for CITED2 exhibit neural crest defects, cardiac malformations and adrenal agenesis, which can at least in part be attributed to a defective Tfap2 transactivation (Bamforth et al. 2001, Braganca et al. 2002, Braganca et al. 2003). Transcriptional activity of AP-2 dimers in inhibited by binding of KCTD1 or KCTD15 to the AP-2 transactivation domain (Ding et al. 2009, Zarelli and Dawid 2013). Transcriptional activity of TFAP2A, TFAP2B and TFAP2C is negatively regulated by SUMOylation mediated by UBE2I (UBC9) (Eloranta and Hurst 2002, Berlato et al. 2011, Impens et al. 2014, Bogachek et al. 2014).

During embryonic development, AP-2 transcription factors stimulate proliferation and suppress terminal differentiation in a cell-type specific manner (Eckert et al. 2005).

TFAP2A and TFAP2C directly stimulate transcription of the estrogen receptor ESR1 gene (McPherson and Weigel 1999). TFAP2A expression correlates with ESR1 expression in breast cancer, and TFAP2C is frequently overexpressed in estrogen-positive breast cancer and endometrial cancer (deConinck et al. 1995, Turner et al. 1998). TFAP2A, TFAP2C, as well as TFAP2B can directly stimulate the expression of ERBB2, another important breast cancer gene (Bosher et al. 1996). Association of TFAP2A with the YY1 transcription factor significantly increases the ERBB2 transcription rate (Begon et al. 2005). In addition to ERBB2, the expression of another receptor tyrosine kinase, KIT, is also stimulated by TFAP2A and TFAP2B (Huang et al. 1998), while the expression of the VEGF receptor tyrosine kinase ligand VEGFA is repressed by TFAP2A (Ruiz et al. 2004, Li et al. 2012). TFAP2A stimulates transcription of the transforming growth factor alpha (TGFA) gene (Wang et al. 1997). TFAP2C regulates EGFR in luminal breast cancer (De Andrade et al. 2016).

TFAP2C plays a critical role in maintaining the luminal phenotype in human breast cancer and in influencing the luminal cell phenotype during normal mammary development (Cyr et al. 2015).

In placenta, TFAP2A and TFAP2C directly stimulate transcription of both subunits of the human chorionic gonadotropin, CGA and CGB (Johnson et al. 1997, LiCalsi et al. 2000).

TFAP2A and/or TFAP2C, in complex with CITED2, stimulate transcription of the PITX2 gene, involved in left-right patterning and heart development (Bamforth et al. 2004, Li et al. 2012).

TFAP2A and TFAP2C play opposing roles in transcriptional regulation of the CDKN1A (p21) gene locus. While TFAP2A stimulates transcription of the CDKN1A cyclin-dependent kinase inhibitor (Zeng et al. 1997, Williams et al. 2009, Scibetta et al. 2010), TFAP2C represses CDKN1A transcription (Williams et al. 2009, Scibetta et al. 2010, Wong et al. 2012). Transcription of the TFAP2A gene may be inhibited by CREB and E2F1 (Melnikova et al. 2010).

For review of the AP-2 family of transcription factors, please refer to Eckert et al. 2005.

Literature References
PubMed ID Title Journal Year
16420676 The AP-2 family of transcription factors

Eckert, D, Buhl, S, Weber, S, Jäger, R, Schorle, H

Genome Biol. 2005
25114211 Mapping of SUMO sites and analysis of SUMOylation changes induced by external stimuli

Impens, F, Radoshevich, L, Cossart, P, Ribet, D

Proc. Natl. Acad. Sci. U.S.A. 2014
9850080 Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways

Turner, BC, Zhang, J, Gumbs, AA, Maher, MG, Kaplan, L, Carter, D, Glazer, PM, Hurst, HC, Haffty, BG, Williams, T

Cancer Res. 1998
11694877 Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator

Bamforth, SD, Bragança, J, Eloranta, JJ, Murdoch, JN, Marques, FI, Kranc, KR, Farza, H, Henderson, DJ, Hurst, HC, Bhattacharya, S

Nat. Genet. 2001
24835590 Sumoylation pathway is required to maintain the basal breast cancer subtype

Bogachek, MV, Chen, Y, Kulak, MV, Woodfield, GW, Cyr, AR, Park, JM, Spanheimer, PM, Li, Y, Li, T, Weigel, RJ

Cancer Cell 2014
9162057 Transcription factor AP-2 controls transcription of the human transforming growth factor-alpha gene

Wang, D, Shin, TH, Kudlow, JE

J. Biol. Chem. 1997
10648798 AP-2 family members regulate basal and cAMP-induced expression of human chorionic gonadotropin

LiCalsi, C, Christophe, S, Steger, DJ, Buescher, M, Fischer, W, Mellon, PL

Nucleic Acids Res. 2000
24469049 TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis

Cyr, AR, Kulak, MV, Park, JM, Bogachek, MV, Spanheimer, PM, Woodfield, GW, White-Baer, LS, O'Malley, YQ, Sugg, SL, Olivier, AK, Zhang, W, Domann, FE, Weigel, RJ

Oncogene 2015
22735262 CITED2 mutation links congenital heart defects to dysregulation of the cardiac gene VEGF and PITX2C expression

Li, Q, Pan, H, Guan, L, Su, D, Ma, X

Biochem. Biophys. Res. Commun. 2012
15475956 Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway

Bamforth, SD, Bragança, J, Farthing, CR, Schneider, JE, Broadbent, C, Michell, AC, Clarke, K, Neubauer, S, Norris, D, Brown, NA, Anderson, RH, Bhattacharya, S

Nat. Genet. 2004
21375726 Alternative TFAP2A isoforms have distinct activities in breast cancer

Berlato, C, Chan, KV, Price, AM, Canosa, M, Scibetta, AG, Hurst, HC

Breast Cancer Res. 2011
19798054 AP-2gamma promotes proliferation in breast tumour cells by direct repression of the CDKN1A gene

Williams, CM, Scibetta, AG, Friedrich, JK, Canosa, M, Berlato, C, Moss, CH, Hurst, HC

EMBO J. 2009
9182571 Regulation of the human chorionic gonadotropin alpha- and beta-subunit promoters by AP-2

Johnson, W, Albanese, C, Handwerger, S, Williams, T, Pestell, RG, Jameson, JL

J. Biol. Chem. 1997
2010091 Analysis of the DNA-binding and activation properties of the human transcription factor AP-2

Williams, T, Tjian, R

Genes Dev. 1991
19115315 The interaction of KCTD1 with transcription factor AP-2alpha inhibits its transactivation

Ding, X, Luo, C, Zhou, J, Zhong, Y, Hu, X, Zhou, F, Ren, K, Gan, L, He, A, Zhu, J, Gao, X, Zhang, J

J. Cell. Biochem. 2009
8988173 AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression

Zeng, YX, Somasundaram, K, el-Deiry, WS

Nat. Genet. 1997
1998122 Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins

Williams, T, Tjian, R

Science 1991
21084835 Dual association by TFAP2A during activation of the p21cip/CDKN1A promoter

Scibetta, AG, Wong, PP, Chan, KV, Canosa, M, Hurst, HC

Cell Cycle 2010
14744778 Activator protein 2alpha inhibits tumorigenicity and represses vascular endothelial growth factor transcription in prostate cancer cells

Ruiz, M, Pettaway, C, Song, R, Stoeltzing, O, Ellis, L, Bar-Eli, M

Cancer Res. 2004
26832794 EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

De Andrade, JP, Park, JM, Gu, VW, Woodfield, GW, Kulak, MV, Lorenzen, AW, Wu, VT, Van Dorin, SE, Spanheimer, PM, Weigel, RJ

Mol. Cancer Ther. 2016
9687504 Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis

Huang, S, Jean, D, Luca, M, Tainsky, MA, Bar-Eli, M

EMBO J. 1998
22371483 Histone demethylase KDM5B collaborates with TFAP2C and Myc to repress the cell cycle inhibitor p21(cip) (CDKN1A)

Wong, PP, Miranda, F, Chan, KV, Berlato, C, Hurst, HC, Scibetta, AG

Mol. Cell. Biol. 2012
23382213 Inhibition of neural crest formation by Kctd15 involves regulation of transcription factor AP-2

Zarelli, VE, Dawid, IB

Proc. Natl. Acad. Sci. U.S.A. 2013
12586840 Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2

Bragança, J, Eloranta, JJ, Bamforth, SD, Ibbitt, JC, Hurst, HC, Bhattacharya, S

J. Biol. Chem. 2003
7891714 Transcriptional regulation of estrogen receptor in breast carcinomas

deConinck, EC, McPherson, LA, Weigel, RJ

Mol. Cell. Biol. 1995
8895516 A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma

Bosher, JM, Totty, NF, Hsuan, JJ, Williams, T, Hurst, HC

Oncogene 1996
20805990 CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma

Melnikova, VO, Dobroff, AS, Zigler, M, Villares, GJ, Braeuer, RR, Wang, H, Huang, L, Bar-Eli, M

PLoS ONE 2010
10497269 AP2alpha and AP2gamma: a comparison of binding site specificity and trans-activation of the estrogen receptor promoter and single site promoter constructs

McPherson, LA, Weigel, RJ

Nucleic Acids Res. 1999
11744733 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

Bragança, J, Swingler, T, Marques, FI, Jones, T, Eloranta, JJ, Hurst, HC, Shioda, T, Bhattacharya, S

J. Biol. Chem. 2002
15870067 Yin Yang 1 cooperates with activator protein 2 to stimulate ERBB2 gene expression in mammary cancer cells

Begon, DY, Delacroix, L, Vernimmen, D, Jackers, P, Winkler, R

J. Biol. Chem. 2005
12072434 Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo

Eloranta, JJ, Hurst, HC

J. Biol. Chem. 2002
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