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Analysis of the p53 Gene and Its Expression in Human Glioblastoma Cells¹

Laboratory of Tumor Biology and Genetics, Neurosurgery Service, University Hospital (CHUV), rue de Bugnon 5, 1011 Lausanne[E. G. V. M., T. K., M. T., H. L., A-C. D., N. d. T.] Switzerland; Ludwig Institute for Cancer Research [E. G. V. M., H-J. S. H., W. K. C.] Departments of Pediatrics [B. E. W., T. F.] and Medicine [H-J. S. H., W. K. C.] and the Center for Molecular Genetics [T. F., W. K. C.], University of California, San Diego, California 92093

Chromosome 17p has been shown to be an early and frequent target for loss of heterozygosity through mitotic recombination in astrocytomas. These losses are frequently accompanied by point mutations in the p53 gene of the remaining allele, resulting in loss of wild type p53 function. However, a fraction of astrocytomas retain constitutional heterozygosity and do not have p53 mutations; some of these lose wild type p53 activity through binding to the protein product of amplified mdm2 genes. To test whether loss of wild type p53 biological function is a necessary step in astrocytoma progression we analyzed p53 expression and biological function in 13 glioma cell lines. All the cell lines expressed a 2.8-kilobase p53 transcript and showed various amounts of p53 protein by immunoprecipitation, except for cell line LN-Z308 which had only a small truncated p53 mRNA and no protein expression. To test whether the p53 expressed in these cell lines was functionally wild type or mutant we transfected them with a plasmid construct harboring a chloramphenicol acetyltransferase (CAT) reporter gene under the control of transcriptional elements that are induced by wild type but not mutant p53. Four lines were shown to retain wild type p53 function. Sequencing of the p53 gene in two of these cell lines confirmed the wild type genotype. These results show that inactivation of the p53 gene is not an obligatory step in glioblastoma genesis. This suggests either that two pathways (p53 inactivation dependent or independent) may lead to a tumor group classified histologically as glioblastoma or that in some cases p53 mutations are bypassed due to the presence of mutations in downstream effector genes.

¹ This work was supported in part by Advanced Fellowship 823A-030692 (E. G. V. M.) and Grant 3.595.087 (N. d. T.) of the Swiss National Science Foundation and by a "Paolo Baffi" Fellowship (E. G. V. M.) from the "Formazione per la Formazione Oncologica" and the European Institute of Oncology.

² To whom requests for reprints should be addressed at, Laboratory of Tumor Biology and Genetics, Service of Neurosurgery, University Hospital, (CHUV) rue du Bugnon 5, CH-1011 Tausanne, Switzerland.

Received 11/29/93. Accepted 12/17/93.

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