Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors (Homo sapiens)
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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).<p>During embryonic development, AP-2 transcription factors stimulate proliferation and suppress terminal differentiation in a cell-type specific manner (Eckert et al. 2005).<p>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).<p>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).<p>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).<p>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).<p>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).<p>For review of the AP-2 family of transcription factors, please refer to Eckert et al. 2005. View original pathway at Reactome.</div>
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DataNodes
homodimer:HSPD1
genehomodimer:MYBL2
genehomo- and
heterodimers:CITED2,CITED4,(CITED1):EP300:CREBBPhomodimer:CDKN1A
genehomodimer:VEGFA
Genehomodimers:ESR1
GeneAnnotated Interactions
homodimer:HSPD1
genehomodimer:HSPD1
genehomodimer:MYBL2
genehomodimer:MYBL2
geneBinding of TFAP2A (AP-2 alpha) transcription factor to the CDKN1A promoter results in the activation of CDKN1A expression in a TP53 (p53) independent manner, which may be important during development and differentiation (Zeng et al. 1997, Williams et al. 2009, Scibetta et al. 2010).
Binding of TFAP2C (AP-2 gamma) transcription factor to the proximal AP-2 response element in the CDKN1A promoter (Scibetta et al. 2010) results in repression of CDKN1A transcription. TFAP2C may recruit histone deacetylases, such as HDAC2 to the CDKN1A promoter (Williams et al. 2009). TFAP2C cooperates with its interaction partners MYC and KDM5B in repression of the CDKN1A gene transcription. The mechanism may involve KDM5B-mediated removal of activating histone methylation mark at H3K4 from nucleosomes at the CDKN1A promoter. In the absence of TFAP2C, MYC can recruit KDM5B to the CDKN1A promoter via an AP-2 independent MYC-binding site, but this results in a lower level of CDKN1A gene repression. TFAP2C-mediated repression of CDKN1A transcription promotes G1/S transition (Wong et al. 2012). In contradiction, it has been reported that TFAP2C may induce, instead of repress CDKN1A transcription (Li et al. 2006).
homo- and
heterodimers:CITED2,CITED4,(CITED1):EP300:CREBBPhomodimer:CDKN1A
genehomodimer:CDKN1A
genehomodimer:VEGFA
Genehomodimer:VEGFA
Genehomodimers:ESR1
Genehomodimers:ESR1
Gene