APC +/- alters colonic fibroblast proteome in FAP
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1 Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
2 Cancer Prevention and Control, Fox Chase Cancer Center, Philadelphia, Pennsylvania
3 Cancer Biology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
4 Cell Culture facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania
5 Division of Genetic and Preventive Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
6 University of California at San Francisco, San Francisco, California
7 Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
* These authors contributed equally to this manuscript
Keywords: Adenomatous polyposis, APC, tumor suppressor, colon fibroblasts, heterozygosity, proteomics
Received: December 22, 2010; Accepted: March 15, 2011; Published: March 15, 2011;
Anthony T. Yeung, e-mail:
Levy Kopelovich, e-mail:
Here we compared the proteomes of primary fibroblast cultures derived from morphologically normal colonic mucosa of familial adenomatous polyposis (FAP) patients with those obtained from unaffected controls. The expression signature of about 19% of total fibroblast proteins separates FAP mutation carriers from unaffected controls (P < 0.01). More than 4,000 protein spots were quantified by 2D PAGE analysis, identifying 368 non-redundant proteins and 400 of their isoforms. Specifically, all three classes of cytoskeletal filaments and their regulatory proteins were altered as were oxidative stress response proteins. Given that FAP fibroblasts showed heightened sensitivity to transformation by KiMSV and SV40 including elevated levels of the p53 protein, events controlled in large measure by the Ras suppressor protein-1 (RSU-1) and oncogenic DJ-1, here we show decreased RSU1 and augmented DJ-1 expression in both fibroblasts and crypt-derived epithelial cells from morphologically normal colonic mucosa of FAP gene-carriers. The results indicate that heterozygosity for a mutant APC tumor suppressor gene alters the proteomes of both colon-derived normal fibroblasts in a gene-specific manner, consistent with a “one-hit” effect.
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