BioProject

Deregulated expression of the Myc transcription factor is a frequent causal mutation in human cancer. More...

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 transgenic model of Myc-mediated β cell tumorigenesis induces rapid tumor onset whereas subsequent Myc de-activation triggers equally rapid tumor regression. Thus, sustained Myc activity is required for tumor maintenance. We have used this reversibly switchable kinetic tumor model in combination with high-density oligonucleotide microarrays to develop an unbiased strategy for identifying candidate Myc-regulated genes responsible for maintenance of Myc-dependent tumors. Consistent with known Myc functions, some Myc-regulated genes are involved in cell growth, cycle and proliferation. In addition, however, many Myc-regulated genes are specific to β cells, indicating that a significant component of Myc action is cell-type specific. Finally, we identify a very restricted cadre of genes whose expression is inversely regulated upon Myc activation-induced tumor progression and de-activation-induced tumor regression. By definition, such genes are candidates for tumor maintenance functions. Combining reversibly switchable, transgenic models of tumor formation and regression with genomic profiling offers a novel strategy with which to deconvolute the complexities of oncogenic signaling pathways in vivo Keywords: in vivo kinetic analyis myc function Overall design: 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. Less...