Comparative study of the p53-mdm2 and p53-MDMX interfaces

Mdm2 and MDMX are two structurally related p53-binding proteins which show the highest level of sequence similarity in the N-terminal p53-binding doma ins, Apart from its ability to inhibit p53 mediated transcription, a featur e it shares with mdm2, very little is known about the physiological functio ns of MDMX, It is clearly distinct from mdm2 since its expression appears n ot to be regulated by p53 and it cannot compensate for lack of mdm2 in earl y development. We present data on the structural similarity between the p53 binding pockets of mdm2 and MDMX using p53- and phage-selected peptides, F rom the results we conclude that our recently devised innovative approach t o reverse the mdm2-mediated inhibition of p53's transactivation function in vivo would probably target MDMX as well. Strategies for selectively target ing mdm2 and MDMX are suggested and a possible mechanism for regulating the p53-mdm2/MDMX interactions by protein phosphorylation is discussed.