Proto-oncogenes are genes that when mutated can be involved in causing cancer. The research described in this 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 in chickens, mice, and humans. This knowledge might 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: little is known about either gene products that act upstream of myb, in concert with myb, or downstream genes that are targets of myb proteins. We identified and have been studying a myb-related gene 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 two temperature-sensitive mutant alleles of myb and shown that it is important for both embryonic and adult development. Furthermore, our studies demonstrate that a myb gene is essential for two cell cycle checkpoints: progression from G2 into M and suppression of premature re-entry into S phase. This research proposal is designed to further our understanding of the biochemical and cellular processes in which myb participates. We will perform experiments to: 1) generate null alleles of myb to determine the physiological effects of a complete lack of myb function; 2) identify genes that participate in the same signal transduction pathway(s) as myb, by searching for mutations in other genes that modify the mutant myb phenotype; 3) determine whether inappropriate or overexpression ob myb disrupts normal regulation of the cell cycle during development; 4) generate antisera to analyze the biochemical properties of the Drosophila Myb protein and determine its distribution during development in wild type and mutant animals; and 5) address the functional relationship between Drosophila myb and its vertebrate counterparts by determining whether they share biochemical activities. 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 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.
|Fitzpatrick, Carrie A; Sharkov, Nikolai V; Ramsay, Gary et al. (2002) Drosophila myb exerts opposing effects on S phase, promoting proliferation and suppressing endoreduplication. Development 129:4497-507|
|Fung, Siau-Min; Ramsay, Gary; Katzen, Alisa L (2002) Mutations in Drosophila myb lead to centrosome amplification and genomic instability. Development 129:347-59|
|Sharkov, Nikolai V; Ramsay, Gary; Katzen, Alisa L (2002) The DNA replication-related element-binding factor (DREF) is a transcriptional regulator of the Drosophila myb gene. Gene 297:209-19|
|Jackson, J; Ramsay, G; Sharkov, N V et al. (2001) The role of transcriptional activation in the function of the Drosophila myb gene. Blood Cells Mol Dis 27:446-55|