The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1)

Abstract

We have previously shown that the anti-apoptotic transcription factor, Brn-3a and the pro-apoptotic p53 factor have antagonistic effects on the promoter of the gene encoding the anti-apoptotic Bcl-2 protein, with p53 abolishing activation by Brn-3a. Here we demonstrate that this antagonism is also observed on the gene encoding the pro-apoptotic Bax protein with Brn-3a abolishing the ability of p53 to activate the Bax promoter and induce Bax protein expression. In contrast, Brn-3a and p53 co-operative to induce maximal activation of another p53 target gene encoding the cyclin dependent kinase inhibitor, p21(CIP1/Waf1). These differential effects of Brn-3a on p53-inducible genes involved in apoptosis or growth arrest are paralleled by its effects on these processes themselves. Thus, we show that Brn-3a antagonises the anti-apoptotic effect of p53 but co-operates with p53 to induce cell cycle arrest. The potential role of Brn-3a in determining the outcome of enhanced p53 levels is discussed.