Cell Cycle Arrest and Apoptosis Induction by Activator Protein 2α (AP-2α) and the Role of p53 and p21WAF1/CIP1 in AP-2α-mediated Growth Inhibition

Abstract

Activator protein 2alpha (AP-2alpha) is a sequence-specific DNA-binding transcription factor implicated in differentiation and transformation. In this study, we have made a replication-deficient recombinant adenovirus that expresses functional AP-2alpha (Ad-AP2). Cells infected with Ad-AP2 expressed induced levels of AP-2alpha protein, which bound to DNA in a sequence-specific manner and activated the AP-2-specific reporter 3X-AP2. Expression of AP-2alpha from Ad-AP2 inhibited cellular DNA synthesis and induced apoptosis. Ad-AP2 infection resulted in efficient inhibition of growth of cancer cells of six different types. In addition, prior expression of AP-2alpha increased the chemosensitivity of H460, a lung carcinoma cell line, to adriamycin (2.5-fold) and cisplatin (5-fold). Furthermore, the growth inhibition by AP-2alpha was found to be less efficient in the absence of p53 or p21, which correlated with reduced apoptosis in p53 null cells and lack of DNA synthesis inhibition in p21WAF1/CIP1 null cells by AP-2alpha, respectively. These results suggest that AP-2alpha inhibits the growth of cells by inducing cell cycle arrest and apoptosis and that the use of AP-2alpha should be explored as a therapeutic strategy either alone or in combination with chemotherapy.