Dominant and recessive oncogenes play an important role in carcinogenesis. The mechanisms by which dominant nuclear oncogenes act remain to be elucidated. An interaction with genes regulating the cell surface Major Histocompatibility (MHC) class I antigens may be especially important. Colon carcinoma as well as a variety of other tumors are known to have reduced expression of MHC class I antigens. Tumor cells with reduced levels of these antigens may be resistant to cytotoxic T-cell mediated immune surveillance, even if they express strong tumor-associated antigens. The studies included in this proposal will explore these processes and their control at a molecular level. Initial efforts will exploit neuroblastoma as a powerful experimental system parallelling the processes in colon cancer. In neuroblastoma, N-myc, a dominant nuclear oncogene, is known to suppress MHC class I gene expression. This proposal describes studies to elaborate the molecular mechanism through which this occurs. Toward this goal, the gene that encodes the nuclear transcription factor, H2TFI, will be isolated and sequenced, and antibodies will be prepared against the H2TFI protein. Additionally, N-myc induced alterations in protein kinase C expression will be defined and its effects on N-myc modulation of MHC class I gene expression examined. These studies will be used as a foundation to explore the role of c-myc overexpression and amplification in colon cancer and the insights it offers into regulation of growth related genes in colonic epithelial cells. Studies will define the possible downregulation of MHC class I genes as well as other cellular genes, protein kinase C and DCC (deletion in colon cancer), by c-myc in colon cancer. An understanding of tumorigenesis in neuroblastoma and colon cancer will provide insights into the mechanisms of molecular regulation of genes which modulate growth and differentiation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Cancer Institutional Fellowship Review Committee (CT)
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Massachusetts General Hospital
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Rall, C J; Yan, Y X; Graeme-Cook, F et al. (1996) Ki-ras and p53 mutations in pancreatic ductal adenocarcinoma. Pancreas 12:10-7
Rall, C J; Rivera, J A; Centeno, B A et al. (1995) Peritoneal exfoliative cytology and Ki-ras mutational analysis in patients with pancreatic adenocarcinoma. Cancer Lett 97:203-11
Rall, C J; Rustgi, A K (1995) CD44 isoform expression in primary and metastatic pancreatic adenocarcinoma. Cancer Res 55:1831-5
Schroy, P C; Rustgi, A K; Ikonomu, E et al. (1994) Growth and intestinal differentiation are independently regulated in HT29 colon cancer cells. J Cell Physiol 161:111-23