The May laboratory investigates signal transduction pathways that lead to altered patterns of gene expression in immune and inflammatory responses. We are particularly interested in understanding how the loss of control of normal signaling contributes to the progression of diseases such as chronic inflammation and cancer. Our goal is to determine the specific molecular events underlying aberrant signals and to define realistic targets for selectively blocking abnormal, while maintaining physiologically normal responses. The focus of our work is the Nuclear Factor (NF)-kappa B transcription factor activation pathway that is critical for inflammation, innate and adaptive immunity and lymphocyte development. NF-kappa B activation is typically a rapid and transient response, however constitutive NF- kappa B activity occurs at sites of chronic inflammation and in various tumors, leukemias and lymphomas. We combine cellular, molecular and genetic approaches to determine the mechanisms that redirect normal NF-kappa B activation pathways into this functionally abnormal, constitutively active state. In addition to determining the basic mechanisms of NF-kappa B activation we have a long-standing interest in understanding the role of NF-kappa B in regulating the phenotype and function of vascular endothelial cells.
A second related interest is to explore the experimental and therapeutic potential of peptide transduction technology as a strategy for modulating specific cell signaling responses. We previously described a small cell-permeable peptide inhibitor of NF-kappa B activity and demonstrated the feasibility of this approach both in vitro and in vivo. We will continue to exploit this exciting novel strategy to fully dissect deregulated NF-kappa B activity in chronic inflammatory diseases.
Currently our active areas of research are:
1. Determining the biochemical and molecular mechanisms that regulate the activity of the I Kappa B Kinase complex.
2. Investigating the signals that regulate vascular endothelial cell function in immune and inflammatory responses.
3. Developing novel targets for cell-permeable peptide inhibitors of NF-kappa B.
May MJ & Madge LA. Caspase inhibition sensitizes inhibitor of NF-kappaB kinase beta-deficient fibroblasts to caspase-independent cell death via the generation of reactive oxygen species. Journal of Biological Chemistry 282: 16105-16, 2007.Solt LA, Madge LA, Orange JS & May MJ. Interleukin-1-induced NF-kappaB activation is NEMO-dependent but does not require IKKbeta. Journal of Biological Chemistry 282: 8724-33, 2007.Madge LA, Kluger MS, Orange JS & May MJ. Lymphotoxin-alpha 1 beta 2 and LIGHT induce classical and noncanonical NF-kappa B-dependent proinflammatory gene expression in vascular endothelial cells. Journal of Immunology 180: 3467-77, 2008.Madge LA & May MJ Classical NF-kappaB activation negatively regulates non-canonical NF-kappaB-dependent CXCL12 expression. The Journal of biological chemistry 285 : 38069-077, 2010.Neely R J, Brose M S, Gray C M, McCorkell K A, Leibowitz J M, Ma C, Rothstein J L & May M J The RET/PTC3 oncogene activates classical NF-kappaB by stabilizing NIK. Oncogene 6: 87-96, 2011.Yatherajam G, Banerjee PP, McCorkell KA, Solt LA, Hanson EP, Madge LA, Kang S, Worley PF, Orange JS & May MJ. Cutting edge: association with I kappa B kinase beta regulates the subcellular localization of Homer3. Journal of immunology 185: 2665-9, 2010.Solt LA, Madge LA & May MJ NEMO-binding domains of both IKKalpha and IKKbeta regulate IkappaB kinase complex assembly and classical NF-kappaB activation. The Journal of biological chemistry 284: 27596-608, 2009.Wharry CE, Haines KM, Carroll RG & May MJ. Constitutive non-canonical NFkappaB signaling in pancreatic cancer cells. Cancer biology & therapy 8: 1567-76, 2009.Sehnert B, Burkhardt H, Wessels J T, Schröder Ag, May M J, Vestweber D, Zwerina J, Warnatz K, Nimmerjahn F, Schett G, Dübel S, Voll R E NF-?B inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-?B in immune-mediated diseases. Proceedings of the National Academy of Sciences of the United States of America 110: 16556-61, 2013.Gray Carolyn M, Remouchamps Caroline, McCorkell Kelly A, Solt Laura A, Dejardin Emmanuel, Orange Jordan S, May Michael J Noncanonical NF-?B Signaling Is Limited by Classical NF-?B Activity. Science Signaling 7: ra13, 2014.
Ph.D. (Vascular Biology Research Centre) King’s College London, UK. , 1996M.Sc. (Department of Immunology) University of Manchester, UK, 1992B. Sc. (Department of Immunology) University of Glasgow, UK, 1988