Cyclin B1-Cyclin Dependent Kinase 1 (CDK1) is a fundamental regulator of mitotic entry and exit. This kinase complex has a large number of mitotic substrates, and localization of the kinase may play an important role in regulating substrate phosphorylation. We have recently identified specific sequence elements in cyclin B1 that tether the kinase complex to chromatin during mitosis, but the functional significance of this association remains unclear. The goal of this proposal is to explore the mechanism by which cyclin B1 associates with chromatin and to determine the functional consequences of this interaction. Specifically, the first aim of this proposal is to further characterize the sequence elements within the cyclin B1 protein that mediate the interaction with chromatin. Next, a novel conditional knockdown-and-rescue strategy will be employed to ascertain if there are mitotic defects in cells that express cyclin B1 that fails to associate with chromatin. Finally, a biochemical approach will be undertaken to identify the protein or proteins that mediate cyclin B1 interaction with chromatin. These experiments will yield novel insight into the significance of cyclin B1-CDK1 localization to chromatin. Public Health/Relevance: Overall, cancer is the second leading cause of mortality in the United States, and cancer research remains an active field for both basic researchers and clinical investigators. This proposal investigates the function of the cyclin B1-CDK1 complex, whose expression has been shown to be misregulated in some tumors, when it is associated with DMA during cell division. CDK inhibitors are being investigated as potential therapeutic agents, and this research may yield novel insight into potential inhibitory targets or mechanisms. ? ? ?
| Pfaff, Kathleen L; King, Randall W (2013) Determinants of human cyclin B1 association with mitotic chromosomes. PLoS One 8:e59169 |
| Zeng, Xing; Sigoillot, Frederic; Gaur, Shantanu et al. (2010) Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage. Cancer Cell 18:382-95 |
