DNA rearrangements that alter the myc family of proto-oncogenes have been more frequently linked to human and mouse cancers than any oncogene except ras. Chromosomal translocation, retrovirus insertion and gene amplification lead to deregulated or elevated expression of the myc protein and complex changes in cellular growth properties. Yet the mechanism by which deregulated myc expression disrupts cell growth remains unknown. The goal of this proposal is to determine how DNA rearrangements disrupt myc gene expression, and how deregulated expression contributes to the transformation of mouse lymphoid cells and causes plasmacytomas. The first goal of this project will be to determine the mechanism of c-myc mRNA turnover. An important feature of c-myc gene regulation is the very short half-life of the mRNA (less than 30 min). Chromosomal translocations usually displace the first exon of c-myc and induce mRNA stabilization. The cis-acting determinants of RNA turnover and the basic mechanism by which c-myc mRNA is degraded will be investigated. A related goal will be to determine the cis-acting determinants that mediate the differential regulation of c-myc and granulocyte-macrophages-CSF mRNA stability. The second goal of this project is to identify the secondary mutations that cause B cell lymphomas in a unique mouse transgenic model in which an immunoglobulin enhancer-linked N-myc transgene induces tumors with long latency (greater than one year). Retrovirus infection of these mice potentiates rapid (four mo) B cell lymphomas, suggesting that the retrovirus integration site will identify the secondary genetic lesions that collaborate with myc. The pathology of tumor progression will also be investigated to better understand the role that individual mutations play in the disease. The third goal of the project will be to understand the molecular basis of the c-myc promoter suppression in tumor cells. Specifically, the c-myc gene will be studied for suppression after microinjection into mouse embryos, or transfer of the extended chromosomal domain into cells by YAC cloning. Proper gene regulation may be dependent on either distant flanking sequences or developmental factors that are not reproduced in cultured cells. DNA rearrangements may primarily act by overriding the normal suppression of the c-myc gene so an understanding of the basic mechanism of gene suppression is critical to understanding malignant transformation.
| Sheppard, R D; Samant, S A; Rosenberg, M et al. (1998) Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors. Oncogene 17:2073-85 |
