Penn Veterinary Medicine | University of Pennsylvania

Description of Research Expertise

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)-?B transcription factor activation pathway that is critical for inflammation, innate and adaptive immunity and lymphocyte development. NF-?B activation is typically a rapid and transient response, however constitutive NF-?B activity has been described as a critical oncogenic survival signal in various tumors, leukemias and lymphomas. We therefore combine cellular, molecular and genetic approaches to determine the mechanisms that redirect normal NF-?B activation pathways into this functionally abnormal, constitutively active state.
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-?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-?B activity in cancer.

Currently our active areas of research are:

1. Determining the molecular mechanisms that underlie positive and negative regulation of NF-?B activity.
2. Identifying the precise defects in the NF-?B signaling pathway in specific cancer cells.
3. Developing novel targets for cell-permeable peptide inhibitors of NF-?B and other disease-relevant signaling pathways.
4. Investigating the signals that regulate vascular endothelial cell function in immune and inflammatory responses.

Selected Publications

Madge, Lisa A. Kluger, Martin S. Orange, Jordan S. May, Michael J.: 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(5): 3467-77, Mar 1 2008.

Huang, Guo N. Huso, David L. Bouyain, Samuel. Tu, Jianchen. McCorkell, Kelly A. May, Michael J. Zhu, Yuwen. Lutz, Michael. Collins, Samuel. Dehoff, Marlin. Kang, Shin. Whartenby, Katharine. Powell, Jonathan. Leahy, Daniel. Worley, Paul F.: NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science 319(5862): 476-81, Jan 25 2008.

Hanson, Eric P. Monaco-Shawver, Linda. Solt, Laura A. Madge, Lisa A. Banerjee, Pinaki P. May, Michael J. Orange, Jordan S.: Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. Journal of Allergy & Clinical Immunology 122(6): 1169-1177.e16, Dec 2008.

Pandey, Rahul. DeStephan, Christine M. Madge, Lisa A. May, Michael J. Orange, Jordan S.: NKp30 ligation induces rapid activation of the canonical NF-kappaB pathway in NK cells. Journal of Immunology 179(11): 7385-96, Dec 1 2007.

May, Michael J. Madge, Lisa A.: 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(22): 16105-16, Jun 1 2007.

Solt, Laura A. Madge, Lisa A. Orange, Jordan S. May, Michael J.: Interleukin-1-induced NF-kappaB activation is NEMO-dependent but does not require IKKbeta. Journal of Biological Chemistry 282(12): 8724-33, Mar 23 2007.

May, Michael J.: A nuclear factor in B cells and beyond.[comment]. [Review] [23 refs] Journal of Immunology 177(11): 7483-4, Dec 1 2006.

May, Michael J. Larsen, Signe E. Shim, Jae Hyuck. Madge, Lisa A. Ghosh, Sankar.: A novel ubiquitin-like domain in IkappaB kinase beta is required for functional activity of the kinase. Journal of Biological Chemistry 279(44): 45528-39, Oct 29 2004.

May, Michael J. Marienfeld, Ralf B. Ghosh, Sankar.: Characterization of the Ikappa B-kinase NEMO binding domain. Journal of Biological Chemistry 277(48): 45992-6000, Nov 29 2002.

May, M J. D'Acquisto, F. Madge, L A. Glockner, J. Pober, J S. Ghosh, S.: Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science 289(5484): 1550-4, Sep 1 2000.