Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of reversibly switchable transgenic model of Myc-mediated cell tumorigenesis treated with tamoxifen sacrificed after 2, 4, 8, 24 h of treatment (activation cohort) or 2, 4, 6, days after a 21 day tamoxifen treatment regime ended (regression cohort)

ABSTRACT: Transgenic mice expressing both the MycER and BclXL transgenes under the regulation of an insulin promoter were systemically injected with 4-hydroxytamoxifen to acutely activate MycER. Mice were sacrificed at 2, 4, 8 or 24hrs after injection or at time 0 (untreated control mice). For analysis of the effects of sustained Myc activation mice received daily doses of tamoxifen for 21days. Tumor regression was analysed by isolation of islets 2, 4 or 6 days after cessation of a 21 day course of treatment. All conditions were repeated in triplicate and gene expression levels compared between treated and untreated and activation and regression samples.

ORGANISM(S): Mus musculus

SUBMITTER: Elizabeth Lawlor

PROVIDER: E-GEOD-4356 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis.

Lawlor Elizabeth R ER Soucek Laura L Brown-Swigart Lamorna L Shchors Ksenya K Bialucha C Uli CU Evan Gerard I GI

Cancer research 20060501 9

Deregulated expression of the Myc transcription factor is a frequent causal mutation in human cancer. Thousands of putative Myc target genes have been identified in in vitro studies, indicating that Myc exerts highly pleiotropic effects within cells and tissues. However, the complexity and diversity of Myc gene targets has confounded attempts at identifying which of these genes are the critical targets mediating Myc-driven tumorigenesis in vivo. Acute activation of Myc in a reversibly switchable ...[more]

PMID: 16651409

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Project description:GLP-1 analogues, such as exendin-4, preserve functional Î²-cell mass in various model systems and are revolutionising management of type 2 diabetes. Yet, comparatively little is known about effectiveness in the face of severe Î²-cell depletion. Moreover, direct and sequential effects of exendin-4 on islet-specific gene expression over time in vivo are not well characterised. To address these issues and others, we have examined the time-dependent effects of exendin-4 treatment on Î²-cell mass regulation alongside accompanying changes in islet gene expression in vivo. Context-dependent actions were assessed by comparing effects on normal islets and also following massive toxigenetic Î²-cell ablation in pIns-MYCERTAM transgenic mice in vivo. Despite over 90% loss of Î²-cell mass, exendin-4 treatment normalised blood glucose and insulin levels in hyperglycaemic mice, though benefits rapidly waned on withdrawal of treatment. As exendin-4 did not arrest the decline in Î²-cell mass or turnover in this study, we could directly isolate effects on function of surviving Î²-cells. Improved glucose homeostasis was associated with dynamic changes in multiple islet genes and pathways in vivo favouring glucose-stimulated insulin secretion, such as Irs2, Pdx1, Sox4, glucokinase, and glycolysis pathway. Several key growth pathways and epigenetic regulators were also differentially expressed. Thus, even in the face of extensive Î²-cell loss exendin-4 can markedly improve hyperglycaemia by differential gene expression in surviving islet cells. Activation of MYCERTAM was achieved through administration of 1mg of 4 hydroxytamoxifen (4OHT; Sigma-Aldrich, St. Louis, MO) by daily intraperitoneal injection. To assess the effect of exendin-4 on MYCER-induced hyperglycaemia, mice were given either twice-daily subcutaneous (sc) injections of exendin-4 (50ug/kg dissolved in 5mls water), or equivalent volumes of water vehicle, starting 2 days prior to 4OHT injections. For microarray analyses parallel mouse experiments were set up using 8-12 week old pIns-MYCERTAM male mice either treated with 4OHT or vehicle (peanut oil) and exendin-4 or vehicle, as described, for 4, 8, 16, 32 and 72 hours (n=3 for each time point and for each of four conditions; 4OHT and exendin-4 treated, peanut oil and exendin-4 treated, 4OHT and water treated, peanut oil and water treated). !Sample_data_processing = After the quality control step, the following 8 samples out of 60 showing poor reproducibility were excluded from our further study: GSM930242, GSM930247, GSM930251, GSM930263, GSM930264, GSM930289, GSM930291, GSM930298.

Dataset Information

Transcription profiling of reversibly switchable transgenic model of Myc-mediated cell tumorigenesis treated with tamoxifen sacrificed after 2, 4, 8, 24 h of treatment (activation cohort) or 2, 4, 6, days after a 21 day tamoxifen treatment regime ended (regression cohort)

Publications

Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis.

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