Despite rapid advances during the past few years in our understanding of cell division, some steps of the cell division program, including the exit from mitosis, remain poorly characterized. Although many of the players in this complex dance (including the protein kinases Cdc5, Cdc15, and Dbf2, and the protein phosphatase Cdc14) have been identified in budding yeast by genetic analysis, little is known about how they work together to choreograph the return to interphase. A deeper understanding of this process in budding yeast will undoubtedly illuminate the corresponding events in human cells, since Dbf2, Cdc14, Cdc15, and Cdc5 have homologs in human cells. Mutations in 7 genes (TAB1-7) can bypass the essential requirement for Cdc15. The product of one of these genes, Tab2, assembles into a complex with Cdc14, suggesting that the Tab2-Cdc14 complex is a key signaling module that functions downstream or parallel to Cdc15 to regulate the exit from mitosis. I propose to investigate the functional relationships between Tab2, Cdc14, Cdc15, and Dbf2. Biochemical and genetic studies proposed here will test the hypothesis that Tab2 negatively regulates the exit from mitosis, and that Tab2, Cdc14, Cdc15, and Dbf2 are organized into a signaling pathway that controls the timing of mitotic exit. The functions of the remaining tab genes will also be investigated, since they are likely to shed key insights into how budding yeast cells negotiate the exit from mitosis. Proteins that regulate the cell cycle are highly conserved - at both the structural and functional levels - between yeast and human cells. Thus, sophisticated insights into the mechanism and regulation of cell division obtained from genetic and biochemical analyses in yeast are helping to fuel impressive advances in our understanding of cell cycle control in normal and diseased human cells. All cells must successfully exit mitosis to divide. Since cell division is fundamental to the growth of tumors, a detailed understanding of each step of the cell division program is essential to understanding the biology of cancer. It is hoped that molecular insights into the mechanisms of mitotic exit that emerge from the studies proposed here will provide a rich new source of potential targets for anti-cancer chemotherapy.
| Mohl, Dane A; Huddleston, Michael J; Collingwood, Therese S et al. (2009) Dbf2-Mob1 drives relocalization of protein phosphatase Cdc14 to the cytoplasm during exit from mitosis. J Cell Biol 184:527-39 |
| Mah, Angie S; Elia, Andrew E H; Devgan, Geeta et al. (2005) Substrate specificity analysis of protein kinase complex Dbf2-Mob1 by peptide library and proteome array screening. BMC Biochem 6:22 |
| Azzam, Ramzi; Chen, Susan L; Shou, Wenying et al. (2004) Phosphorylation by cyclin B-Cdk underlies release of mitotic exit activator Cdc14 from the nucleolus. Science 305:516-9 |
| Shou, W; Sakamoto, K M; Keener, J et al. (2001) Net1 stimulates RNA polymerase I transcription and regulates nucleolar structure independently of controlling mitotic exit. Mol Cell 8:45-55 |
| Mah, A S; Jang, J; Deshaies, R J (2001) Protein kinase Cdc15 activates the Dbf2-Mob1 kinase complex. Proc Natl Acad Sci U S A 98:7325-30 |
