A role for the polyproline domain of p53 in its regulation by Mdm2

The p53 protein plays a key role in the cellular response to stress by indu cing cell growth arrest or apoptosis. The polyproline region of p53 has bee n shown to be important for its growth suppression activity, p53 protein la cking the polyproline region has impaired apoptotic activity and altered sp ecificity for certain apoptotic target genes. Here we describe the role of this region in the regulation of p53 by its inhibitor Mdm2. p53 lacking the polyproline region was identified to be more susceptible to inhibition by Mdm2. Furthermore, the absence of this region renders p53 more accessible t o ubiquitination, nuclear export, and Mdm2-mediated degradation. This incre ased sensitivity to Mdm2 results from an enhanced affinity of Mdm2 toward p 53 lacking the polyproline region. Our results provide a new explanation fo r the impaired growth suppression activity of p53 lacking this region. The polyproline region is proposed to be important in the modulation of the inh ibitory effects of Mdm2 on p53 activities and stability.