The proposed research deals with changes in nuclear protein composition and metabolism during early stages of carcinogenesis in the colonic epithelium. In addition to the identification of specific changes in chromosomal protein composition, such as the appearance of characteristic DNA-binding proteins in rodent adenocarcinomas, we are focusing on post-synthetic modifications of nuclear proteins which are enzymatically catalyzed, or which occur as a result of direct action by the alkylating carcinogen, 1,2-dimethylhydrazine. Aberrant methylations of chromosomal proteins have been detected and are now being further characterized in histones and in proteins of the HMG class. New methods for the analysis of nuclear protein phosphorylation which allow recovery of protein molecules which have just been phosphorylated are being used to isolate protein molecules which are selectively phosphorylated at very early stages of colon carcinogenesis. Human colonic tumor proteins corresponding to those previously identified in mouse and rat adenocarcinomas, and in cell lines derived from a human adenocarcinoma, will be isolated and employed for the preparation of monoclonal antibodies directed against them. The antibodies will be used as a diagnostic probe for malignant transformation in lavage or biopsy specimens of individuals at high risk for colon cancer. New approaches to the chemotherapy of cancer, based on the selective inhibition of protein synthesis in tumor cells by cyanate metabolites, will continue to be explored.
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| Boffa, L C; Morris, P L; Carpaneto, E M et al. (1996) Invasion of the CAG triplet repeats by a complementary peptide nucleic acid inhibits transcription of the androgen receptor and TATA-binding protein genes and correlates with refolding of an active nucleosome containing a unique AR gene sequence. J Biol Chem 271:13228-33 |
