The long-term goal of our laboratory is to understand how specific protein kinase signaling pathways and phosphoserine/threonine-binding domains regulate cell cycle progression and the response to DNA damage. In response to genotoxic stress, cells activate two canonical protein kinase pathways, the ATR-Chk1 pathway, and the ATM-Chk2 pathway. We recently identified a third DNA damage response pathway mediated by p38MAPK and MAPKAP Kinase-2 (MK2) that is absolutely essential for p53-defective tumor cells to survive after DNA damage. Importantly, this pathway is largely dispensable in cells with intact p53 function, making it an ideal target for specifically impairing the DNA damage response in cancer cells. Furthermore, unlike the ATR-Chk1 and ATM-Chk2 pathways that are dedicated to responding solely to signals from DNA damage per se, the p38 MAPK-MK2 pathway is a much more global stress-response pathway that can also be activated by other types of cellular stress, and plays a critical role in cytokine production during inflammation and tumorigenesis Thus, we believe that the p38MAPK-MK2 pathway plays a particularly novel role during oncogenic and genotoxic stress by integrating DNA damage response pathways within tumor cells with inflammation and cytokine signaling in the adjacent tumor microenvironment. In this proposal we define the role of MK2 in both tumor development and therapeutic response using novel conditional knock-out mouse models, identify the molecular mechanism by which MK2 regulates the G1/S checkpoint, and define its role in post-transcriptional regulation of gene expression through phosphorylation of RNA-binding proteins, which we then explore through a structural and mechanistic approach. Finally, we identify new MK2, Chk1 and Chk2 substrates involved in cell cycle control and DNA damage responses. Data emerging from the proposed experiments should (1) substantially enhance our understanding of the roles of tumor- and stromal derived MK2 in cancer development and progression, (2) expand our knowledge of signaling pathways that control environmental risk for cancer, and (3) identify and validate new molecular targets against which both cancer prevention strategies and anti-cancer therapies can be designed, including MK2 itself and RNA-binding proteins.

Public Health Relevance

Human tumors frequently develop in the setting of inflammation, and contain mutations that affect their response to DNA damage. Defects in how tumor cells respond to DNA damage not only underlie cancer development, but also explain why tumors are killed by chemotherapy and radiation treatment. We believe that the protein kinase MK2 functions as a lynchpin at the crossroads of inflammation and cancer, and that therapeutic targeting of this molecule will both reduce the incidence of tumor formation in response to environmental/inflammatory stimuli, and dramatically enhance the ability of tumor cells to be killed by conventional anti-cancer agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015339-07
Application #
8719102
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Balshaw, David M
Project Start
2006-12-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
$498,230
Indirect Cost
$178,852
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
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
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

Showing the most recent 10 out of 47 publications