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Dominant-Negative Mutations of the Tumor Suppressor p53 Relating to Early Onset of Glioblastoma Multiforme¹

Division of Cell Biology, Cancer Institute [M. M., H. T., M. Tad., M. Tak., H. K., Y. H., J-i. H., T. M.], Department of Internal Medicine III [M. M., M. A.], and Department of Neurosurgery [M. Tad.] Hokkaido University School of Medicine, Sapporo 060-8638, Japan

Previous experiments have suggested that some mutant forms of p53 are able to inactivate the endogenous wild-type p53 protein in a dominant-negative fashion. However, it remains unknown whether tumors with such dominant-negative (transdominant) p53 mutants have a biological significance that is different from that of recessive p53 mutants. In this study, we examined the dominant-negative potential of various p53 mutants using a yeast-based assay in which both wild-type and mutant p53 were efficiently expressed. We tested a total of 106 p53 mutants, which were identified in brain tumors, glioblastoma multiforme-derived cell lines, breast cancers, or premalignant lesions and squamous cell carcinomas of oral epithelium or were otherwise created by mutagenesis. In agreement with the previous studies, our results demonstrated that transdominant mutations affected amino acid residues that are essential for the stabilization of the DNA-binding surface in the p53 core domain and for the direct interaction of p53 with its DNA-binding sequence. Among 40 patients with sporadic glioblastomas, the average age at diagnosis was significantly younger in the patients with tumors harboring dominant-negative mutations (30.4 ± 14.7 years, n = 7) than it was in those with recessive mutations (55.2 ± 18.6 years, n = 9, P < 0.012) and in those without mutations (54.7 ± 17.1 years, n = 24, P < 0.003). Our data suggest that dominant-negative p53 mutants accelerate development and/or growth of glioblastoma anlagen.

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