Dual role of p300 in the regulation of p53 stability

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 h ere that p300 stabilizes both p53 and its negative regulator MDM2, thereby enhancing the p53/MDM2 negative regulatory loop. Binding of p300 is associa ted with the retention of p53 in the nucleus, which results in the accumula tion of p53 in an acetylase-independent manner. Stabilization of MDM2, on t he 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, d epending on the expression of MDM2. Prior to p53 activation, when MDM2 leve ls are low, p300 acts as a positive regulator to increase p53 levels. Upon shifting to permissive temperature, however, when MDM2 expression is induce d, p300 becomes a negative regulator of p53 by stabilizing MDM2 and thereby augmenting MDM2's ability to target p53 for degradation.