Proto-oncogenes are genes that when mutated can be involved in causing cancer. This research proposal addresses the function of the proto-oncogene Myb. An understanding of its normal activities should help to illuminate how the activated gene contributes to the genesis of neoplastic disease. This knowledge may also help to design strategies for the diagnosis or treatment of cancers in which myb has been implicated (e.g. leukemia, breast cancer, colon carcinoma). Myb genes encode DNA-binding proteins that regulate transcription, but the signal transduction pathway(s) in which Myb participates remain elusive. We identified and have been studying a Myb-related gene, Dm myb, in the fruit fly, Drosophila melanogaster, because it provides a powerful genetic and developmental system in which to dissect cellular and biochemical processes. We have generated both loss-of-function mutant alleles of Dm myb and transgenic lines that can be induced to ectopically express wild type and altered versions of the DMyb protein. Using these genetic tools, we have demonstrated that Dm myb functions to maintain the integrity of the genome. Specifically, it is required for progression into and through mitosis, suppression of endoreduplication, and maintenance of the appropriate number of centrosomes. In addition, ectopic expression of DMyb activity induces S-phase in diploid cells while suppressing S-phase in endocycling larval cells. This proposal is designed to further our understanding of the biochemical and cellular processes in which myb participates. We will perform experiments to: 1) identify genes that are physiologically relevant targets of transcriptional regulation by DMyb through a combination of molecular and genetic approaches; 2) gain further understanding of Dm myb function by characterizing its role in oogenesis/early embryogenesis, a setting in which we may be able to determine the primary defects caused by mutations in Dm myb; and 3) determine some of the mechanisms that govern the activity of the DMyb protein. Since all multicellular organisms face similar challenges during development of how to regulate cellular division and differentiation, the signal transduction pathways used for these purposes have been highly conserved during evolution. Therefore, insights gained from our studies in Drosophila should also enhance our understanding of Myb function in regulating cell proliferation and differentiation in vertebrates. ? ?
