Date of Award
Doctor of Philosophy
Astrocytic gliomas are the most common brain cancers of adults. The goal of this research was to examine the molecular genetic determinants of gliomas, with particular emphasis on the tumor suppressor gene P53. First, I studied the frequency, nature and timing of P53 mutations in human gliomas. I observed that glioma-prone families do not have inherited mutations of P53, nor of the Nf1-GRD, Nf2, MTS1, MTS2, or CDK4 genes. However, a high frequency of loss of heterozygosity at chromosome 9p was noted in gliomas that cluster in families. In a second study of low-grade gliomas that progressed to higher grade malignancies, I observed that those with P53 mutations progressed slowly to anaplastic pathology whereas those without mutation progressed directly to glioblastoma omitting the anaplastic stage. Next, I studied the biological consequences of P53 disruption on tumorigenesis and brain development in mice. I introduced a disrupted P53 gene into astrocytoma-susceptible inbred mice to augment astrocytoma formation and generate an experimental model. These P53-null mice did not exhibit enhanced incidence of astrocytic glioma but did develop high grade lymphomas at a significantly younger age than control P53-null mice. Lastly, I examined gene expression in the brains of wild-type and P53-null mouse embryos. Expression of the WAF1/p21 and IGF-BP3 genes in the developing head responded to loss of p53 in a gender-specific manner, suggesting that female-restricted defects of neural tube closure in P53-null mice may be explained by insufficient compensatory gene expression. I also noted that P53-deficiency causes lethal developmental defects other than exencephaly in females. Loss of one copy of P53 caused a moderate decrease in the number of female embryos relative to males early in gestation, while loss of both copies resulted in additional perinatal attrition of females. Together, the experiments described in this thesis contribute to our knowledge of the role of P53 in glioma predisposition and progression in humans, and to tumorigenesis and nervous system development in mice.
van, Meyel Donald, "P53-dependent Tumorigenesis And Gene Expression In Mammalian Brain" (1996). Digitized Theses. 2663.