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

AP-2 dimers bind palindromic GC-rich DNA response elements that match the consensus sequence 5'-GCCNNNGGC-3'. 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. Transcriptional activity of AP-2 dimers in inhibited by binding of KCTD1 or KCTD15 to the AP-2 transactivation domain. Transcriptional activity of TFAP2A, TFAP2B and TFAP2C is negatively regulated by SUMOylation mediated by UBE2I (UBC9).

During embryonic development, AP-2 transcription factors stimulate proliferation and suppress terminal differentiation in a cell-type specific manner.

TFAP2A and TFAP2C directly stimulate transcription of the estrogen receptor ESR1 gene. 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. Association of TFAP2A with the YY1 transcription factor significantly increases the ERBB2 transcription rate. In addition to ERBB2, the expression of another receptor tyrosine kinase, KIT, is also stimulated by TFAP2A and TFAP2B, while the expression of the VEGF receptor tyrosine kinase ligand VEGFA is repressed by TFAP2A. TFAP2A stimulates transcription of the transforming growth factor alpha (TGFA) gene. 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.

In placenta, TFAP2A and TFAP2C directly stimulate transcription of both subunits of the human chorionic gonadotropin, CGA and CGB.

TFAP2A and/or TFAP2C, in complex with CITED2, stimulate transcription of the PITX2 gene, involved in left-right patterning and heart development.

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, TFAP2C represses CDKN1A transcription. Transcription of the TFAP2A gene may be inhibited by CREB and E2F1.

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