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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA109661-02
Application #
6915512
Study Section
Special Emphasis Panel (ZRG1-CDF-2 (90))
Program Officer
Couch, Jennifer A
Project Start
2004-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$140,077
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Floyd, Scott R; Pacold, Michael E; Huang, Qiuying et al. (2013) The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature 498:246-50
Reinhardt, H Christian; Yaffe, Michael B (2009) Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Curr Opin Cell Biol 21:245-55