Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis

Tumor suppressor p53 is frequently mutated in tumors. Mutant p53 (Mutp53) proteins often gain new activities in promoting tumorigenesis, defined as gain-of-function (GOF). Mutp53 often accumulates at high levels in tumors, which promotes mutp53 GOF in tumorigenesis. The mechanism of mutp53 accumulation is poorly understood. Here we find that MDM2 isoforms promote mutp53 accumulation in tumors. MDM2 isoform B (MDM2-B), the MDM2 isoform most frequently over-expressed in human tumors, interacts with full-length MDM2 to inhibit MDM2-mediated mutp53 degradation, promoting mutp53 accumulation and GOF in tumorigenesis. Furthermore, MDM2-B over-expression correlates with mutp53 accumulation in human tumors. In mutp53 knock-in mice, a MDM2 isoform similar to human MDM2-B is over-expressed in the majority of tumors, which promotes mutp53 accumulation and tumorigenesis. Thus, over-expression of MDM2 isoforms promotes mutp53 accumulation in tumors, contributing to mutp53 GOF in tumorigenesis. Furthermore, promoting mutp53 accumulation and GOF is an important mechanism by which MDM2 isoforms promote tumorigenesis.