Research Abstract:
My laboratory is interested in how the human cell division cycle is regulated and how perturbations in cell cycle control contribute to human cancer. Cancer cells arise through a process of cellular evolution due to the accumulation of multiple genetic changes. As cancers arise and progress there is a selection for those genetic changes that give the cancer cell a proliferative advantage over normal cells. Thus, mutations in proteins involved in cell cycle progression and in checkpoint control are consistent features of cancer cells. Tremendous strides have been made over the past several years to advance our understanding of how progression through the cell division cycle is regulated. A general paradigm has emerged in which complexes composed of cyclins and cyclin-dependent protein kinases (Cdks) regulate this process. This laboratory applies molecular biological, biochemical, cell biological targeted gene knock-out and molecular imaging approaches to understand how the Cdk's are regulated throughout the cell cycle; to identify upstream regulators and downstream targets of the Cdks; to elucidate mechanistically how proteins involved in checkpoint control interact with cell cycle regulators to inhibit key cell cycle transitions; to determine how cell cycle- and checkpoint-controls are perturbed in human cancers; to elucidate how cells establish and maintain polarity; and, collaborations with the Molecular Imaging Center are being carried out to image signaling pathways in animals. Finally, high throughput technologies are being developed and implemented on a genome-wide scale to identify novel regulators and inhibitors of the cell division cycle.
Selected Publications:
King JB, Gross J, Lovly CM, et al. Accurate mass-driven analysis for the characterization of protein phosphorylation- a study of the human Chk2 protein kinase. Anal Chem 2006 78:2171-2181.
Ferguson AM, White LS, Donovan PJ, et al. Normal cell cycle and checkpoint responses in mice and cells lacking Cdc25B and Cdc25C protein phosphatases. Mol Cell Biol 2005 25:2853-2860.
Puc J, Keniry M, Li HS, et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 2005 7:193-204.
Luker K, Luker G, Smith MCP, et al. Optimized luciferase protein fragment complementation permits noninvasive imaging of regulated protein-protein interactions in cells and living animals. Proc Natl Acad Sci USA 2004 101:12288-12293.
Bulavin DV, Higashimoto Y, Demidenko ZN, et al. Dual phosphorylation controls Cdc25 phosphatases and mitotic entry. Nat Cell Biol 2003 5:545-551.
Last Updated: 08/17/2006 |