The CGB (chorionic gonadotropin beta) gene promoter, similar to CGA (chorionic gonadotropin alpha) gene promoter, contains several putative AP-2 transcription factor binding sites. TFAP2A (AP-2 alpha) and TFAP2C (AP-2 gamma), which are both expressed in the placenta, can both bind to the CGB promoter (Johnson et al. 1997, LiCalsi et al. 2000). It has not been examined whether TFAP2A and TFAP2C bind the CGB promoter as homodimers or heterodimers and if CITED family members are involved in TFAP2A/C-mediated transactivation of CGB transcription.

Homodimers of AP-2 family transcription factors TFAP2A (AP-2 alpha) and TFAP2C (AP-2 gamma) directly stimulate CGB (chorionic gonadotropin beta) transcription by binding to the CGB3 gene promoter (Johnson et al. 1997, LiCalsi et al. 2000).

Human chorionic gonadotropin is a glycoprotein hormone produced in pregnancy. Its role is to maintain progesterone production by preventing the disintegration of the corpus luteum of the ovary and thus sustain the growing foetus (Rull & Laan 2005). Gonadotropin comprises an alpha subunit (CGA), common to the pituitary gonadotropin hormones (LH, FSH and TSH) and a distinct beta subunit (CGB3), unique for each hormone which confers receptor and biological specificity. The subunits are bound by six intrachain disulfide bonds, required for dimer formation (Beebe et al. 1990)

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 expression in luminal breast cancer (De Andrade et al. 2016). 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).

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.

Choriogonadotropin subunit beta 3