A novel exon within the mdm2 gene modulates translation initiation in vitro and disrupts the p53-binding domain of mdm2 protein

The mdm2 protein interacts with a number of proteins involved in cell growt h control. Such interactions favour cell proliferation and may explain the oncogenic potential of mdm2 when over-expressed in cells. Interaction with the tumour suppressor p53 involves the N-terminus of mdm2 and targets p53 f or rapid degradation by the ubiquitin pathway, We now describe a novel, hig hly conserved exon of mdm2 (exon alpha) which includes an in-frame UGA stop codon. Expression of exon alpha disrupts in vitro translation of the p53 b inding domain of mdm2. We propose that exon alpha induces translation re-in itiation at an internal AUG codon within the mdm2 alpha mRNA isoform. The p utative mdm2 alpha protein lacks the N-terminus of mdm2 and shows little, i f any, binding capacity for p53. Mdm2 alpha mRNA is expressed in a tissue-s pecific manner and is observed predominantly in testis and peripheral blood lymphocytes. We propose that mdm2 alpha expression may provide a mechanism for uncoupling mdm2-p53 interaction in certain cell types and/or under spe cific conditions of cell growth.