EXCEED THE SPACE PROVIDED. Cyclin-dependent kinases (Cdks) drive the events of the eukaryotic cell cycle. Cdks are thought to act by phosphorylating a large number of protein substrates in the cell, but few of these substrates have been identified. In the proposed studies, a novel biochemical strategy will be used to perform large scale searches for Cdk substrates in budding yeast and vertebrates. Our preliminary studies have led to the identification of about 200 Cdkl substrates in budding yeast, and in the first aim of the proposed work a subset of these substrates will be analyzed in detail. Other preliminary work has revealed that the identity of the associated cyclin subunit has a profound effect on the rate at which Cdkl phosphorylates many yeast substrates, and the second aim of the proposed studies will be to explore the molecular basis of this cyclin specificity and its physiological function in the cell. Methods will also be developed for the systematic identification and characterization of large numbers of Cdk substrates in vertebrate cells. Finally, a 'chemical genetic' approach will be employed to construct mice and mouse cell lines in which Cdkl or Cdk2 can be inhibited with high specificity, allowing rigorous analysis of their function in normal cell biology and in tumors. These studies promise to provide a wide range of new insights into the basic mechanisms by which Cdks drive cell-cycle events. Such insights are an important step toward a better understanding of the chromosome segregation defects and other cell-cycle defects that characterize the cancer cell. PERFORMANCE SITE ========================================Section End===========================================
Naylor, Stephen G; Morgan, David O (2014) Cdk1-dependent phosphorylation of Iqg1 governs actomyosin ring assembly prior to cytokinesis. J Cell Sci 127:1128-37 |
Lopez, Michael S; Choy, Jonathan W; Peters, Ulf et al. (2013) Staurosporine-derived inhibitors broaden the scope of analog-sensitive kinase technology. J Am Chem Soc 135:18153-9 |
Lyons, Nicholas A; Fonslow, Bryan R; Diedrich, Jolene K et al. (2013) Sequential primed kinases create a damage-responsive phosphodegron on Eco1. Nat Struct Mol Biol 20:194-201 |
Kõivomägi, Mardo; Valk, Ervin; Venta, Rainis et al. (2011) Cascades of multisite phosphorylation control Sic1 destruction at the onset of S phase. Nature 480:128-31 |
Lyons, Nicholas A; Morgan, David O (2011) Cdk1-dependent destruction of Eco1 prevents cohesion establishment after S phase. Mol Cell 42:378-89 |
Kõivomägi, Mardo; Valk, Ervin; Venta, Rainis et al. (2011) Dynamics of Cdk1 substrate specificity during the cell cycle. Mol Cell 42:610-23 |
Holt, Liam J; Tuch, Brian B; Villén, Judit et al. (2009) Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science 325:1682-6 |
Holt, Liam J; Krutchinsky, Andrew N; Morgan, David O (2008) Positive feedback sharpens the anaphase switch. Nature 454:353-7 |
Blethrow, Justin D; Glavy, Joseph S; Morgan, David O et al. (2008) Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates. Proc Natl Acad Sci U S A 105:1442-7 |
Goga, Andrei; Yang, Dun; Tward, Aaron D et al. (2007) Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat Med 13:820-7 |
Showing the most recent 10 out of 12 publications