The long-term goal of our laboratory is to understand, in molecular detail, how protein kinase signaling pathways together with phosphoserine/threonine-binding domains regulate multiple aspects of cell proliferation, including cell cycle progression and the cellular response to DMAdamage. In the present proposal, we explore the function of MAPKAP Kinase-2, a stress-responsive protein kinase activated by p38 MARK, as a critical regulator of S-phase and mitotic progression in response to environmental and endogenous types of DMA damage. We use a combination of extensive biochemistry and molecular cell biology to explore the signal transduction mechanisms involved in MAPKAP Kinase-2 activation after DMA damage induced by chemicals and UV-C irradiation, and examine how MAPKAP Kinase-2 functions together with other checkpoint kinases such as Chk1, to control cell cycle progression after genotoxic stress in cells in culture. We go on to develop a conditional MAPKAP Kinase-2 knock-out mouse to explore whether MAPKAP Kinase-2 functions as a tumor suppressor in genetically defined models of sarcoma and lung cancer, and in environmental carcinogen-induced models of colorectal and skin cancer. Finally, we explore whether down-regulation of MAPKAP Kinase-2 facilitates cell death after intentional chemically-induced DNA damage such as chemotherapy. These studies should clarify how signals from the p38 MAPK-MAPKAP Kinase-2 pathway, a global stress- responsive network that is activated by a wide variety of toxic insults, integrate with those from dedicated DNA damage response pathways,to regulate the cellular response to genotoxic stress. The results of the proposed experiments should reveal whether MAPKAP Kinase-2 functions as a tumor suppressor gene that modulates the risk of cancer after exposure to environmental agents, and whether specific targeting of MAPKAP Kinase-2 would be of therapeutic value for sensitizing tumors to the cytotoxic effects of conventional chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015339-05
Application #
7992456
Study Section
Cellular Signaling and Dynamics Study Section (CSD)
Program Officer
Balshaw, David M
Project Start
2006-12-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$344,968
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
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