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 growth 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 for rapid degradation by the ubiquitin pathway. We now describe a novel, highly 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 binding domain of mdm2. We propose that exon alpha induces translation re-initiation at an internal AUG codon within the mdm2 alpha mRNA isoform. The putative mdm2 alpha protein lacks the N-terminus of mdm2 and shows little, if any, binding capacity for p53. Mdm2 alpha mRNA is expressed in a tissue-specific 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 specific conditions of cell growth.