The broad objective of this study is to characterize the role of protein kinase C (PKC) in the proliferative potential of glioblastoma and medulloblastoma, the most common brain tumors occurring in adults and children, respectively. The specific research goals will be to identify the specific isoforms of PKC in each tumor phenotype, to characterize their specific intracellular substrates, to determine the therapeutic efficacy of PKC inhibitors on the proliferative and differentiative capacity of the tumor, and to determine if inhibition of expression or over-expression of PKC isoforms in human glioblastoma or medulloblastoma cells or in non-tumorigenic glial cell cultures abrogates or accelerates cell growth. Since glioblastomas (and some medulloblastomas) are refractory to all known therapeutic modalities including chemotherapy and radiation therapy, a search for novel and effective chemotherapeutic agents is warranted. Several studies suggest that PKC may be a useful molecular target for chemotherapy and that a therapeutic approach based on the ability of PKC inhibitors to produce differentiation or interfere with the growth factor-dependent autocrine loops in human malignant glioma cells warrants further investigation. Therefore, the specific aims of this proposal will be to: 1) characterize the tumor-specific isoforms of PKC in glioblastoma, medulloblastoma and immortalized glial cells, 2) determine the effects of PKC inhibitors in the growth and differentiation of glioblastoma and medulloblastoma cell lines, 3) determine if the phosphorylation of the cytoskeletal glial-specific intermediate filament, glial fibrillary acidic protein (GFAP) or other endogenous substrates for PKC is required for tumor cell proliferation and 4) determine if inhibition of transcription or overexpression of the tumor-associated isoform(s) of PKC results in an attenuation or acceleration of the malignant potential of the cell.
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