Analysis of a Mutant p53 Protein Arising in a Medulloblastoma from a Mouse Transgenic for the JC Virus Early Region

Abstract

Background: JC virus (JCV) is a polyomavirus that causes progressive multifocal leukoencephalopathy (PML) in humans and is highly oncogenic in experimental animals. Transgenic mice with JCV T-antigen develop cerebellar tumors, which resemble human medulloblastomas, containing two distinct cell subpopulations, T-antigen positive and negative. In T-negative clones, a novel mutant p53 was detected (p53^mt). Materials and Methods: We have compared p53^mt to wild-type p53 (p53^wt) in p53-null cells. Results: p53^mt had lost the transcriptional transactivation activity of p53^wt, and unlike p53^wt, partially localized to the cytoplasm. Unlike mutant p53 from many human cancers, p53^mt did not show a gain of function or a dominant negative phenotype. Adenovirus expressing p53^wt but not p53^mt inhibited cell growth and induced apoptosis of p53-null cells. Conclusion: During the course of tumor evolution of the JCV T-antigen mouse medulloblastoma, a mutation occurred that inactivated p53 allowing tumor progression even in the absence of continued T-antigen expression.