Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

B-catenin deficiency, but not c-Myc deletion, suppresses the immediate phenotypes of Apc loss in the liver

ABSTRACT: Dysregulated Wnt signalling is seen in approximately 30% of hepatocellular cancers, thus finding pathways downstream of activation of Wnt signalling is key. Using cre lox technology we have deleted the the adenomatous polyposis coli tumour suppressor protein (Apc) within the adult mouse liver and observed a rapid increase in nuclear beta-catenin and C-Myc. This is associated with an induction of proliferation leading to hepatomegally within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes we analysed the impact of inactivating Apc in the context of deficiency of the potentially key effectors beta-catenin and c-Myc. beta-catenin loss rescues both the proliferation and hepatomegally phenotypes following Apc loss. However c-Myc deletion, which rescues the phenotypes of Apc loss in the intestine, had no effect on the phenotypes of Apc loss. The consequences of deregulation the Wnt pathway within the liver are therefore strikingly different to those observed within the intestine, with the vast majority of Wnt targets beta-catenin dependent but c-Myc independent in the liver. Samples were collected from Genetcially modified mice of the genotypes indicated in the characteristics field. Gene recombination was induced using IP administration of beta-napthoflavone. Cohorts of samples were used to compare the affects of APC loss, cMYC loss and combined APC and cMYC loss in the liver (and compared to matched control samples in which the genes were not recombined).

ORGANISM(S): Mus musculus

SUBMITTER: Karen Reed

PROVIDER: E-GEOD-65476 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver.

Reed Karen R KR Athineos Dimitris D Meniel Valerie S VS Wilkins Julie A JA Ridgway Rachel A RA Burke Zoé D ZD Muncan Vanesa V Clarke Alan R AR Sansom Owen J OJ

Proceedings of the National Academy of Sciences of the United States of America 20081124 48

Dysregulated Wnt signaling is seen in approximately 30% of hepatocellular carcinomas; thus, finding pathways downstream of the activation of Wnt signaling is key. Here, using cre-lox technology, we deleted the Apc gene in the adult mouse liver and observed a rapid increase in nuclear beta-catenin and c-Myc, which is associated with an induction of proliferation that led to hepatomegaly within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes, we ana ...[more]

PMID: 19033191

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Project description:Lee2003 - Roles of APC and Axin in Wnt Pathway (without regulatory loop) This model is described in the article: The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. Lee E, Salic A, Krüger R, Heinrich R, Kirschner MW. PLoS Biol. 2003 Oct; 1(1): E10 Abstract: Wnt signaling plays an important role in both oncogenesis and development. Activation of the Wnt pathway results in stabilization of the transcriptional coactivator beta-catenin. Recent studies have demonstrated that axin, which coordinates beta-catenin degradation, is itself degraded. Although the key molecules required for transducing a Wnt signal have been identified, a quantitative understanding of this pathway has been lacking. We have developed a mathematical model for the canonical Wnt pathway that describes the interactions among the core components: Wnt, Frizzled, Dishevelled, GSK3beta, APC, axin, beta-catenin, and TCF. Using a system of differential equations, the model incorporates the kinetics of protein-protein interactions, protein synthesis/degradation, and phosphorylation/dephosphorylation. We initially defined a reference state of kinetic, thermodynamic, and flux data from experiments using Xenopus extracts. Predictions based on the analysis of the reference state were used iteratively to develop a more refined model from which we analyzed the effects of prolonged and transient Wnt stimulation on beta-catenin and axin turnover. We predict several unusual features of the Wnt pathway, some of which we tested experimentally. An insight from our model, which we confirmed experimentally, is that the two scaffold proteins axin and APC promote the formation of degradation complexes in very different ways. We can also explain the importance of axin degradation in amplifying and sharpening the Wnt signal, and we show that the dependence of axin degradation on APC is an essential part of an unappreciated regulatory loop that prevents the accumulation of beta-catenin at decreased APC concentrations. By applying control analysis to our mathematical model, we demonstrate the modular design, sensitivity, and robustness of the Wnt pathway and derive an explicit expression for tumor suppression and oncogenicity. This model is hosted on BioModels Database and identified by: BIOMD0000000658. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

B-catenin deficiency, but not c-Myc deletion, suppresses the immediate phenotypes of Apc loss in the liver

Publications

B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver.

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