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Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells.

ABSTRACT: In colorectal cancer cells, APC, a tumor suppressor protein, is commonly expressed in truncated form. Truncation of APC is believed to disrupt degradation of ?-catenin, which is regulated by a multiprotein complex called the destruction complex. The destruction complex comprises APC, Axin, ?-catenin, serine/threonine kinases, and other proteins. The kinases CK1? and GSK -3?, which are recruited by Axin, mediate phosphorylation of ?-catenin, which initiates its ubiquitination and proteosomal degradation. The mechanism of regulation of ?-catenin degradation by the destruction complex and the role of truncation of APC in colorectal cancer are not entirely understood. Through formulation and analysis of a rule-based computational model, we investigated the regulation of ?-catenin phosphorylation and degradation by APC and the effect of APC truncation on function of the destruction complex. The model integrates available mechanistic knowledge about site-specific interactions and phosphorylation of destruction complex components and is consistent with an array of published data. We find that the phosphorylated truncated form of APC can outcompete Axin for binding to ?-catenin, provided that Axin is limiting, and thereby sequester ?-catenin away from Axin and the Axin-recruited kinases CK1? and GSK -3?. Full-length APC also competes with Axin for binding to ?-catenin; however, full-length APC is able, through its SAMP repeats, which bind Axin and which are missing in truncated oncogenic forms of APC, to bring ?-catenin into indirect association with Axin and Axin-recruited kinases. Because our model indicates that the positive effects of truncated APC on ?-catenin levels depend on phosphorylation of APC, at the first 20-amino acid repeat, and because phosphorylation of this site is mediated by CK1?, we suggest that CK1? is a potential target for therapeutic intervention in colorectal cancer. Specific inhibition of CK1? is predicted to limit binding of ?-catenin to truncated APC and thereby to reverse the effect of APC truncation.

SUBMITTER: Barua D

PROVIDER: S-EPMC3784502 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells.

Barua Dipak D Hlavacek William S WS

PLoS computational biology 20130926 9

In colorectal cancer cells, APC, a tumor suppressor protein, is commonly expressed in truncated form. Truncation of APC is believed to disrupt degradation of β-catenin, which is regulated by a multiprotein complex called the destruction complex. The destruction complex comprises APC, Axin, β-catenin, serine/threonine kinases, and other proteins. The kinases CK1α and GSK -3β, which are recruited by Axin, mediate phosphorylation of β-catenin, which initiates its ubiquitination and proteosomal degr ...[more]

PMID: 24086117

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Project description:The adenomatous polyposis coli (APC) tumour suppressor gene is mutated in about 80% of colorectal cancers (CRC) Brannon et al. (2014) [1]. APC is a large multifunctional protein that regulates many biological functions including Wnt signalling (through the regulation of beta-catenin stability) Reya and Clevers (2005) [2], cell migration Kroboth et al. (2007), Sansom et al. (2004) [3], [4], mitosis Kaplan et al. (2001) [5], cell adhesion Faux et al. (2004), Carothers et al. (2001) [6], [7] and differentiation Sansom et al. (2004) [4]. Although the role of APC in CRC is often described as the deregulation of Wnt signalling, its other biological functions suggest that there are other factors at play that contribute to the onset of adenomas and the progression of CRC upon the truncation of APC. To identify genes and pathways that are dysregulated as a consequence of loss of function of APC, we compared the gene expression profiles of the APC mutated human CRC cell line SW480 following reintroduction of wild-type APC (SW480 + APC) or empty control vector (SW480 + vector control) Faux et al. (2004) . Here we describe the RNA-seq data derived for three biological replicates of parental SW480, SW480 + vector control and SW480 + APC cells, and present the bioinformatics pipeline used to test for differential gene expression and pathway enrichment analysis. A total of 1735 genes showed significant differential expression when APC was restored and were enriched for genes associated with cell polarity, Wnt signalling and the epithelial to mesenchymal transition. There was additional enrichment for genes involved in cell-cell adhesion, cell-matrix junctions, angiogenesis, axon morphogenesis and cell movement. The raw and analysed RNA-seq data have been deposited in the Gene Expression Omnibus (GEO) database under accession number GSE76307. This dataset is useful for further investigations of the impact of APC mutation on the properties of colorectal cancer cells.

Dataset Information

Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells.

Publications

Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells.

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