Regulation of caspase expression and apoptosis by adenomatous polyposis coli

Tingan Chen, Ivana Yang, Rosalyn Irby, Kenneth H. Shain, Hong-Gang Wang, John Quackenbush, Domenico Coppola, Jin Q. Cheng, Timothy J. Yeatman

Research output: Contribution to journalArticle

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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 β-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.

Original languageEnglish (US)
Pages (from-to)4368-4374
Number of pages7
JournalCancer Research
Volume63
Issue number15
StatePublished - Aug 1 2003

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Adenomatous Polyposis Coli
Caspases
Apoptosis
Caspase 7
Polyps
Caspase 3
Proteins
APC Genes
Catenins
Wnt Signaling Pathway
Caspase 9
Gene Expression Profiling
Colonic Neoplasms
Intestines
Epithelial Cells
Messenger RNA
Mutation
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chen, T., Yang, I., Irby, R., Shain, K. H., Wang, H-G., Quackenbush, J., ... Yeatman, T. J. (2003). Regulation of caspase expression and apoptosis by adenomatous polyposis coli. Cancer Research, 63(15), 4368-4374.
Chen, Tingan ; Yang, Ivana ; Irby, Rosalyn ; Shain, Kenneth H. ; Wang, Hong-Gang ; Quackenbush, John ; Coppola, Domenico ; Cheng, Jin Q. ; Yeatman, Timothy J. / Regulation of caspase expression and apoptosis by adenomatous polyposis coli. In: Cancer Research. 2003 ; Vol. 63, No. 15. pp. 4368-4374.
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Chen, T, Yang, I, Irby, R, Shain, KH, Wang, H-G, Quackenbush, J, Coppola, D, Cheng, JQ & Yeatman, TJ 2003, 'Regulation of caspase expression and apoptosis by adenomatous polyposis coli', Cancer Research, vol. 63, no. 15, pp. 4368-4374.

Regulation of caspase expression and apoptosis by adenomatous polyposis coli. / Chen, Tingan; Yang, Ivana; Irby, Rosalyn; Shain, Kenneth H.; Wang, Hong-Gang; Quackenbush, John; Coppola, Domenico; Cheng, Jin Q.; Yeatman, Timothy J.

In: Cancer Research, Vol. 63, No. 15, 01.08.2003, p. 4368-4374.

Research output: Contribution to journalArticle

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AU - Chen, Tingan

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AU - Irby, Rosalyn

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AU - Cheng, Jin Q.

AU - Yeatman, Timothy J.

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N2 - 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 β-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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Chen T, Yang I, Irby R, Shain KH, Wang H-G, Quackenbush J et al. Regulation of caspase expression and apoptosis by adenomatous polyposis coli. Cancer Research. 2003 Aug 1;63(15):4368-4374.