Dual Role of p300 in the Regulation of p53 Stability

Abstract

While the function of p300 as a transcriptional coactivator of p53 is well documented, its role in the regulation of p53 stability remains ill-defined since opposite effects of p300 on p53 levels have been reported. We show here that p300 stabilizes both p53 and its negative regulator MDM2, thereby enhancing the p53/MDM2 negative regulatory loop. Binding of p300 is associated with the retention of p53 in the nucleus, which results in the accumulation of p53 in an acetylase-independent manner. Stabilization of MDM2, on the other hand, requires the acetylase activity of p300. Importantly, MDM2, once expressed, is able to reverse the stabilizing effect of p300 on p53. A temperature-permissive p53-expressing cell line enabled us to demonstrate the completely opposite roles of p300 in the regulation of p53 stability, depending on the expression of MDM2. Prior to p53 activation, when MDM2 levels are low, p300 acts as a positive regulator to increase p53 levels. Upon shifting to permissive temperature, however, when MDM2 expression is induced, p300 becomes a negative regulator of p53 by stabilizing MDM2 and thereby augmenting MDM2's ability to target p53 for degradation.