The overall purpose of this research program is to analyze the functional significance of oncogenes and tumor suppressor (TS) genes in human cancer. These two classes of gene are frequently altered during neoplastic progression, but the functional significance of these changes for human cancer is poorly understood. In particular, the claims for dominantly-acting oncogenes and their critical role in neoplastic conversion was derived from data obtained from rodent experimental systems. These claims have not been substantiated when human experimental model systems have been utilized. Four major aims are presented: 1) The molecular characterization of the QM gene - a highly conserved member of a multiple gene family which is a strong candidate for a tumor suppressor gene. Studies include characterization of the protein product, characterization of its properties as a transcription factor that interacts with c-jun, and analysis of its potential tumor suppressor function. 2) Transgenic mouse studies of the QM gene. These include the consequences of overexpression of human QM, both constitutively and tissue-specific, and targeted knockout of the mouse QM gene, thereby generating QM-deficient mice. These studies should shed insight into the role of QM in development, differentiation and cancer. 3) Continuation of our Wilms' tumor studies. We have expanded our in vitro models to include other bona fide Wilms' tumor cell lines. The functional roles of several candidate Wilms' tumor TS genes, namely WT1, QM and H19, will be examined. in addition, we continue to collaborate with Dr. Bernard Weissman in cloning the WT2 gene that maps to chromosome 11p15. 4) Continuation of our colorectal cancer studies. We will extend our studies on the functional role of APC, DCC and p53 cDNAs in controlling the tumorigenic phenotype of colorectal carcinoma cell lines as well as determining the possible functional consequences of restoring wild type expression of multiple TS genes. We continue to explore the interesting possibility that APC may regulate c-myc expression and the consequences of that on control of cell proliferation. Finally, we have initiated functional analyses of mismatch repair genes, with specific reference to the recessive or dominant-negative nature of these mutations and the result of restoring wild type activity on the transformed and tumorigenic phenotypes.
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