The AP2 transcription factor family is a set of developmentally regulated, retinoic acid inducible genes composed of four related factors, AP2alpha, AP2beta, AP2gamma, and AP2delta. AP2 factors orchestrate a variety of cell processes including apoptosis, cell growth, and tissue differentiation during embryogenesis. In studies of primary malignancies, AP2alpha has been shown to function as a tumor suppressor in breast cancer, colon cancer, and malignant melanoma. In cell culture models, overexpression of AP2alpha inhibits cell division and stable colony formation, whereas, a dominant-negative AP2alpha mutant increases invasiveness and tumorigenicity. Here we show that AP2alpha targets the p53 tumor suppressor protein. Studies with chromatin immunoprecipitation demonstrate that AP2alpha is brought to p53 binding sites in p53-regulated promoters. The interaction between AP2alpha and p53 augments p53-mediated transcriptional activation, which results in up-regulation of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). AP2alpha is able to induce G(1) and G(2) cell cycle arrest only in the presence of wild-type p53. Thus, we conclude that the tumor suppressor activity of AP2alpha is mediated through a direct interaction with p53. These results also provide a mechanism to explain patterns of gene expression in cancers where AP2alpha is known to function as a tumor suppressor.