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Regulation of Caspase Expression and Apoptosis by Adenomatous Polyposis Coli^{1 ,2}

Departments of Interdisciplinary Oncology and Surgery [T. C., R. I., K. H. S., T. J. Y.], Drug Discovery [H. G. W.], Pathology [D. C., J. Q. C.], and H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612, and The Institute for Genomic Research, Rockville, Maryland [I. Y., J. Q.]

The adenomatous polyposis coli (APC) gene, a member of the WNT pathway, has been shown to assign intestinal epithelial cells to a program of proliferation or differentiation through regulation of the ß-catenin/TCF-4 complex. Wild-type APC, in certain cellular contexts, appears to induce differentiation and apoptosis, although mutant forms of APC, known to produce polyps and ultimately cancers, may suppress these events. Here, we show that mutant forms of APC can induce repression of select terminal caspases as a potential means of attenuating responses to apoptotic stimuli. Using gene expression profiling to interrogate the intact intestines of Apc^+/min mice harboring numerous polyps, we identified a reduction in the mRNA expression of both caspases 3 and 7. We additionally identified a reduction in protein levels of caspase-3, caspase-7, and caspase-9 in human colon cancer specimens known to harbor APC mutations. A reduction in caspase protein levels resulted in resistance to apoptotic-inducing agents and restoration of caspase levels reinstated apoptotic capacities. Consistent with Wnt pathway involvement, dominant negative TCF/LEF induced caspase protein expression. These data provide support for the hypothesis that one of the functions of APC is the regulation of caspase activity and other apoptotic proteins by controlling their expression levels in the cell.

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