The c-myc protooncogene is deregulated and frequently amplified at a low level in colon carcinoma, perhaps as an early event. c-myc contributes to two pathways: stimulation of growth and cell proliferation, and stimulation of apoptosis, or programmed cell death. We hypothesize that a block in the normal pathways leading to differentiation and subsequent apoptosis is what favors deregulated c-myc effects on cell proliferation and tumor growth, and the consequent positive selection for c-myc overexpression and amplification in tumors. The idea that transformed cells are partially blocked in differentiation is not new. However, work in our laboratory has begun to dissect pathways which must be integrated for full cellular differentiation in colonic epithelial cells. We have shown that stimulation of at least one of the pathways by short-chain fatty acids (SCFAs) is sufficient to stimulate a more differentiated phenotype and stimulate cells into apoptosis. This application is to define how c-myc expression and activity interact with three pathways of differentiation (stimulated by SCFAs, TPA or forskolin) in determining the relative balance of differentiation, apoptosis and cellular proliferation in colonic epithelial cells, and the role of bcl-2, which appears to inhibit apoptosis in colonic epithelial cells as it does in other cell types, in determining cell fate. c-myc will be up-regulated in HT29 colonic carcinoma cells with an appropriate expression vector, or down-regulated by overexpression of the c-max gene, or by antisense methodology. We will take advantage of our recent observation that apoptosis can be demonstrated, quantitated and modulated in three different colonic epithelial cell lines in culture. We will also use a unique clonal derivative of HT29 colonic carcinoma cells in which differentiation along the goblet cell lineage is uncoupled from the apparently normal progression from differentiation to apoptosis in the colonic epithelium.
|Effective start/end date||2/23/94 → 1/31/98|
- National Cancer Institute: $165,734.00
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