title: Dual association by TFAP2A during activation of the p21cip/CDKN1A promoter.
abstract: The cyclin-dependent kinase inhibitor p21cip/CDKN1A is induced to promote growth arrest in response to a variety of stimuli in normal cells and loss of correct regulation of this gene is frequently observed in cancer. In particular, the upregulation of CDKN1A by p53 is considered to be a central mechanism of tumour suppression. Other transcription factors with tumour suppressor activity can also regulate CDKN1A, including the developmentally regulated factor, TFAP2A. Here we identify a novel AP-2 binding site within the proximal promoter of the CDKN1A gene and show this is required for optimal, p53-independent expression of p21cip/CDKN1A. We further describe a non-tumourgenic breast epithelial cell line model to study the role of endogenous TFAP2A and p53 in the control of drug-induced p21cip expression using ChIP. Maximal expression of CDKN1A requires TFAP2A which binds to two regions of the promoter: the proximal region where the AP-2 site lies and upstream near the major p53 binding site. The pattern of binding alters with time post-induction, with the proximal, p53-independent site becoming more important at later stages of p21cip induction. This pattern of promoter interaction by TFAP2A is distinct from that seen for the TFAP2C family member which represses CDKN1A expression.
authors.affiliation: Centre for Tumour iology, Institute of Cancer, London, UK.
authors.forename: Angelo G
authors.initials: AG
authors.lastname: Scibetta
authors.forename: Ping-Pui
authors.initials: PP
authors.lastname: Wong
authors.forename: KaYi V
authors.initials: KV
authors.lastname: Chan
authors.forename: Monica
authors.initials: M
authors.lastname: Canosa
authors.forename: Helen C
authors.initials: HC
authors.lastname: Hurst
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D016159:Tumor Suppressor Protein p53