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 #
5R01ES015339-04
Application #
7743725
Study Section
Cellular Signaling and Dynamics Study Section (CSD)
Program Officer
Balshaw, David M
Project Start
2006-12-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
4
Fiscal Year
2010
Total Cost
$348,794
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
Dreaden, Erik C; Kong, Yi Wen; Quadir, Mohiuddin A et al. (2018) RNA-Peptide nanoplexes drug DNA damage pathways in high-grade serous ovarian tumors. Bioeng Transl Med 3:26-36
Creixell, Pau; Pandey, Jai P; Palmeri, Antonio et al. (2018) Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity. Cell Syst 7:371-383.e4
Lam, Fred C; Morton, Stephen W; Wyckoff, Jeffrey et al. (2018) Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles. Nat Commun 9:1991
Hymel, David; Grant, Robert A; Tsuji, Kohei et al. (2018) Histidine N(?)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors. Bioorg Med Chem Lett 28:3202-3205
Suarez-Lopez, Lucia; Sriram, Ganapathy; Kong, Yi Wen et al. (2018) MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis. Proc Natl Acad Sci U S A 115:E4236-E4244
Cannell, Ian G; Merrick, Karl A; Morandell, Sandra et al. (2015) A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy. Cancer Cell 28:623-637
Hsu, Albert T; Barrett, Christopher D; DeBusk, George M et al. (2015) Kinetics and Role of Plasma Matrix Metalloproteinase-9 Expression in Acute Lung Injury and the Acute Respiratory Distress Syndrome. Shock 44:128-36
Bryson, Bryan D; Del Rosario, Amanda M; Gootenberg, Jonathan S et al. (2015) Engineered bromodomains to explore the acetylproteome. Proteomics 15:1470-5
Rameseder, Jonathan; Krismer, Konstantin; Dayma, Yogesh et al. (2015) A Multivariate Computational Method to Analyze High-Content RNAi Screening Data. J Biomol Screen 20:985-97
Qian, Wen-Jian; Park, Jung-Eun; Grant, Robert et al. (2015) Neighbor-directed histidine N (?)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles. Biopolymers 104:663-73

Showing the most recent 10 out of 47 publications