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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Cellular Signaling and Dynamics Study Section (CSD)
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Balshaw, David M
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Massachusetts Institute of Technology
Internal Medicine/Medicine
Schools of Arts and Sciences
United States
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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
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
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
Peterson, Laura B; Yaffe, Michael B; Imperiali, Barbara (2014) Selective mitogen activated protein kinase activity sensors through the application of directionally programmable D domain motifs. Biochemistry 53:5771-8
Morton, Stephen W; Lee, Michael J; Deng, Zhou J et al. (2014) A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways. Sci Signal 7:ra44
Shaul, Yoav D; Freinkman, Elizaveta; Comb, William C et al. (2014) Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell 158:1094-1109
Qian, Wen-Jian; Park, Jung-Eun; Lim, Dan et al. (2014) Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high Plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in HeLa cells. Biopolymers 102:444-55
Morandell, Sandra; Reinhardt, H Christian; Cannell, Ian G et al. (2013) A reversible gene-targeting strategy identifies synthetic lethal interactions between MK2 and p53 in the DNA damage response in vivo. Cell Rep 5:868-77

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