This proposal takes a genetic approach to characterize the role of the Mdm2 proto- oncogene in the regulation of cell growth and in tumorigenesis. The MDM2 gene is amplified to high copy numbers in approximately one-third of all human sarcomas, and is overexpressed in a wide range of human cancers, including osteosarcomas, malignant fibrous histiocytomas, rhabdomyosarcomas, liposarcomas, leiomyosarcomas. glioblastomas, astrocytomas myeloid leukemias, B-cell lymphomas, and oral squamous cell carcinomas. The Mdm2 protein forms a complex with the p53 tumor suppressor protein, and Mdm2 has been shown to regulate normal cell growth primarily by binding to p53 and inhibiting p53 activity. However, the results of several studies indicate that Mdm2 may play an additional role in promoting cell growth and tumorigenesis, especially when Mdm2 is overexpressed. The research outlined in this proposal utilizes genetically defined cells and mice to examine the role of Mdm2 overexpression in cell growth and in neoplasia. Analysis of the effects of Mdm2 overexpression on the growth of mouse embryonic fibroblasts, and on tumorigenesis in transgenic mice bearing amplified copy numbers of the Mdm2 gene and/or which overexpress specific spliced forms of Mdm2 will permit characterization of Mdm2 functions to be performed in minimally-perturbed experimental systems. In addition, this proposal explores a possible mechanism for Mdm2-mediated inactivation of other cell growth regulatory proteins. The results of the proposed study should define clearly the tumorigenic effects induced by Mdm2- overexpression in cancer.
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