| |
Mutations
in the adenomatous polyposis coli (APC) gene, which initiate almost
all human colon cancers, directly target the proto-oncogene, c-myc,
by elevating beta-catenin/T-cell factor (TCF) signaling. We have shown
that agents ascribed chemopreventive activity for colon cancer in fact
also stimulate beta-catenin/TCF activity in vitro. Their effects on
c-myc transcription were assayed using a novel variant of fluorescence
in situ hybridization that detects c-myc transcription sites in intact
nuclei. Increased transcriptional initiation of c-myc induced by the
short-chain fatty acid, butyrate, consistent with elevated beta-catenin/TCF
activity, was efficiently abrogated by a block to transcriptional elongation,
resulting in decreased c-myc expression. 1alpha,25-Dihydroxyvitamin
D(3) also induced transcriptional blockage. In contrast, the nonsteroidal
anti-inflammatory drug, sulindac, increased c-myc expression, an effect
attributable at least in part to its failure to induce transcriptional
blockage. We have described a novel approach for evaluating the effects
of chemopreventive agents on the expression of a gene critical in colonic
tumorigenesis. |
|
