Myc Antagonism and Tumor Suppression by Mnt
Principal Investigator: Peter Hurlin
Affiliation: Shriners Hospital for Children
Abstract: The Myc family of transcripton factors play a fundamental role in regulating cell proliferation and can promote tumorigenesis when deregulated and/or overexpressed. The ability of Myc proteins to bind DNA and activate transcription is mediated by heterodimerization with the protein Max through shared bHLHZip domains. Max also heterodimerizes with a several other bHLHZip proteins that appear to function as dedicated transcriptional repressors. One of these proteins, Mnt, is unique among this group of repressors in that it is coexpressed with Myc proteins in most, if not all proliferating cells. In cell culture assays, Mnt can suppress Myc-dependent oncogenic transformation and we have recently demonstrated that cells lacking Mnt behave remarkably similar to cells that overexpress Myc. Furthermore, deletion of Mnt in mouse mammary epithelium, like Myc overexpression in this tissue, leads to breast cancer. These and related results support the hypothesis that Mnt functions as a key cellular antagonist of Myc proteins. In this proposal we will elucidate mechanisms that define the antagonistic relationship between Myc and Mnt in cells. We will use coimmunoprecipitation, electrophoretic mobility shift and chromatin immunoprecipiation experiments to define how changes in cellular concentrations of Mnt:Max and Myc:Max that occur during entry into the cell cycle and in tumor cells controls target gene transcription. We will utilize conditional (Cre-Lox) Mnt and c-Myc knockout mice to conduct a series of gene deletion experiments specifically in B-cells in order to define the physiological relationship between c-Myc and Mnt in vivo. B-cells are a highly relevant model system, because B-lineage tumors frequently involve deregulation of c-Myc and because mouse B-cell models have proven highly effective in delineating Myc function in cell proliferation, differentiation and tumorigenesis. We will define the function of Mnt in B-cell biology, determine whether it functions as a B-cell tumor suppressor and elucidate the physiological relationship between Mnt and c-Myc by simultaneous ablation of both genes in B-cells. Results from these studies will provide insight into critical mechanisms that underlie Myc function in cells and will ultimately contribute to the development of strategies for disrupting the oncogenic activities of Myc proteins.
Funding Period: 2004-09-30 - 2009-06-30
more information: NIH RePORT