ALTERNATIVELY SPLICED MDM2 TRANSCRIPTS WITH LOSS OF P53 BINDING DOMAIN SEQUENCES - TRANSFORMING ABILITY AND FREQUENT DETECTION IN HUMAN CANCER

The mdm2 oncogene encodes a 90-kilodalton nuclear phosphoprotein that binds and inactivates the p53 tumor suppressor protein. Here we report the observation of five alternatively spliced mdm2 gene transcripts i n a range of human cancers and their absence in normal tissues. Transf ection of NIH 3T3 cells with each of these forms gave foci of morpholo gically transformed cells. A higher frequency of splice variants lacki ng p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding, consistent with partial deletion of sequences encodin g the p53 binding domain, but retain carboxyterminal zinc-finger domai ns. These observations suggest a reassessment of the transforming mech anisms of mdm2 and its relation to p53.