The MDM2-a splice variant of MDM2 alters transformation in vitro and the tumor spectrum in both Arf- and p53-null models of tumorigenesis.

MDM2-A is a common splice variant of murine double minute 2 (MDM2) that is frequently detected in many tumor types. Our previous work has characterized MDM2-A as an activator of p53, and therefore, in a wild-type p53 background, this splice variant would be predicted to confer p53-dependent tumor protection. To test this hypothesis, we used Mdm2-a transgenic mice to assess transformation and tumorigenesis in tumor susceptible murine models. A MDM2-A-dependent decrease in transformation was observed in Arf-null mouse embryonic fibroblasts (MEF) or when wild-type MEFs were exposed to the carcinogen ethylnitrosourea. However, this reduced transformation did not confer tumor protection in vivo; Mdm2-a/Arf-null mice and ethylnitrosourea-treated MDM2-expressing mice developed similar tumor types with equivalent latency compared with their respective controls. Interestingly, when p53 was deleted, MDM2-A expression enhanced transformation of p53-null MEFs and altered tumor spectrum in vivo. In addition, p53-heterozygous mice that expressed MDM2-A developed aggressive mammary tumors that were not observed in p53-heterozygous controls. In conclusion, we found that although MDM2-A expression enhances p53 activity and decreases transformation in vitro, it cannot confer tumor protection. In contrast, MDM2-A seems to exhibit a novel transforming potential in cells where p53 function is compromised. These data show that MDM2 splice variants, such as MDM2-A, may provide protection against transformation of normal tissues having intact p53. However, when such splice variants are expressed in tumors that have defects in the p53 pathway, these isoforms may contribute to tumor progression, which could explain why their expression is often associated with aggressive tumor types.