Project: Research project

Project Details


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 date2/23/941/31/98


  • Cell Biology


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