title: Regulation of caspase expression and apoptosis by adenomatous polyposis coli.
abstract: 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 beta-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.
authors.affiliation: Department of Interdisciplinary Oncology and Surgery, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Tingan
authors.initials: T
authors.lastname: Chen
authors.forename: Ivana
authors.initials: I
authors.lastname: Yang
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Irby
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Shain
authors.forename: Hong Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Yeatman
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D020169:Caspases / Q000096:biosynthesis* / Q000235:genetics; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics; D020869:Gene Expression Profiling; D017491:Genes, APC / Q000502:physiology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D007527:Isoenzymes; D014157:Transcription Factors; D020169:Caspases