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Identification of Molecular Pathways in Cancer Biology


Controlling the onset and progression of mitotic cell division is critical to prevent human cancer. Much of this regulation involves the timely activation and inactivation of cyclin-dependent protein kinases that regulate progression through the cell cycle. In addition, cells must ensure that their genetic information is accurately transmitted to each daughter cell by activating a series of DNA damage-response kinases to halt the cell cycle in response to genotoxic stress. Many details of the molecular events that occur downstream of mitotic and DNA damage-response kinases, however, are unknown. In this regard, phosphoSerine/Threonine (pSer/pThr)-binding domains such as 14-3-3 proteins, FHA domains, WW domains, and WD40 repeats are increasingly emerging as critical doma ns that link upstream kinase signaling cascades to downstream effector functions by directly mediating the phosphorylation-dependent formation of multi-protein signaling complexes. The long-term goals of the applicant are to identify and characterize (pSer/pThr)-binding domains involved in regulating cell proliferation. In this proposal we seek funds to develop and improve a new phosphopeptide library-based proteomic screening technology that simultaneously: (1) reveals specific pSer/pThr-binding domains downstream of cyclin-dependent kinases and DNA damage-responsive kinases; (2) allows determination of the optimal sequence motifs recognized by the newly-identified domain; (3) provides reagents for biophysical, cell biological, and structural studies of the function of the newly identified domain in regulating mitotic progression, as well as reagents for high-throughput screening for discovery of small molecule inhibitors; and (4) facilitates bioinformatics and systems biology efforts to identify specific kinase targets within signaling pathways that mediate cell cycle control. This technology will have a major impact on proteomicsand bioinformatics/systems-biology based approaches to define kinase-dependent molecular pathways in cancer biology and will identify new therapeutic targets for drug design.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.