Immunology Graduate Group

Mike May, Ph.D.
Assistant Professor
Department of Animal Biology

3800 Spruce Street (OVH 200E)
Office: 215 573 0940
Lab: 215 573 0941
Fax: 215 573 5186
maym@vet.upenn.edu

Dr. May's Vet School page
Dr. May's Cell & Molecular Biology page

Education:
Post-doctoral fellow, Yale University
Ph.D., King's College London (UK)
M.Sc., University of Manchester (UK)
B.Sc., University of Glasgow (UK)

Research Interests:

• NF- k B signaling in inflammation and cancer
• Defining the signals that control vascular endothelial cell function in immunity and inflammation
• Cell-permeable peptide transduction approaches to manipulate signal transduction pathways in vitro and in vivo

Research Summary:

Our laboratory studies the 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)- k B transcription factor activation pathway that is critical for inflammation, innate and adaptive immunity and lymphocyte development. NF- k B activation is typically a rapid and transient response, however constitutive NF- k 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- k 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- kB activity (the NBD peptide: see fig) 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- kB activity in cancer.

Currently our active areas of research are:

1. Determining the molecular mechanisms that underlie positive and negative regulation of NF- k B activity.

2. Identifying the precise defects in the NF- k B signaling pathway in specific cancer cells.

3. Developing novel targets for cell-permeable peptide inhibitors of NF- k B and other disease-relevant signaling pathways.

4. Investigating the signals that regulate vascular endothelial cell function in immune and inflammatory responses.

Recent Publications:

Madge, L.A., Kluger, M.S. Orange, J.S. & May, M.J. (2008) Lymphotoxin-a1b2 and LIGHT induce classical and non-canonical NF-κB-dependent pro-inflammatory gene expression in vascular endothelial cells. J.Immunol. 180: 3467-3477.

Huang, G.N., Huso, D., Bouyain,, S., Tu, J., McCorkell, K.A., May,, M.J., Zhu, Y., Lutz, M., Collins, S., Dehoff, M., Kang, S., Whartenby, K., Powell, J., Leahy, D, & Worley, P.F. (2008) NFAT Binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science. 319: 476-481.

Pandey, R., DeStephan, C.M., Madge, L.A., May, M.J. & Orange, J.S. (2007) NKp30 ligation induces rapid activation of the canonical NF-κB pathway in NK cells. J.Immunol. 179: 7385-7396.

Hawkins, B.J., Solt, LA., Chowdhury, I., Kazi, A.S., Abid, RM., Aird, WC., May, MJ., Foskett, KJ., and Madesh, M. (2007) GPCR Ca2+-linked mROS is essential for endothelial cell activation and monocyte adherence. Mol.Cell.Biol. 27: 7582-7593.

Tas, S.W., Vervoordeldonk, M.J., Hajji, N., Schuitemaker, J.H.N., van der Sluijs, K.F., May, M.J., Ghosh, S., Kapsenberg, M.L., Tak, P.P. & de Jong, EC. (2007) Non-canonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood 110: 1540-1549.

May, M.J. & Madge, L.A. (2007) Caspase inhibition sensitizes IKKβ-deficient fibroblasts to necrotic cell death via the generation of free radicals. J.Biol.Chem. J.Biol.Chem. 282: 16105-16116

Zaph, C., Troy, A.E., Taylor, B.C., Berman-Booty, L.D., Guild, K.J., Du, Y., Yost, E.A., Gruber, A.D., May, M.J., Greten, F.R., Eckman, L., Karin, M. & Artis, D. (2007) Epithelial cell-intrinsic IKKβ expression regulates innate and adaptive immunity in the gut. Nature. 446: 552-556.

Solt, L.A., Madge, L.A., Orange, J.S & May, M.J. (2007) IL-1-induced NF-κB activation is NEMO-dependent but does not require IKKβ. J.Biol.Chem. 282: 8724-8733.

May, M.J. (2006). A Nuclear Factor in B Cells and Beyond. J. Immunol. 177: 7483-7484.

De Plaen, I.G., Han, X-B., Liu, X., Hsueh, W, Ghosh, S. & May, M.J. (2006) Lipopolysaccharide induces CXCL2 / Macrophage Inflammatory Protein-2 gene expression in enterocytes via Nuclear Factor-κB    activation: Independence from endogenous Tumor Necrosis Factor-a and Platelet-Activating Factor. Immunology. 118: 153-163.

Shapira, S., Harb, O., Magret, J., Matrajt, M., Han, J., Hoffman, A., Freedman, B., May, M.J., Roos, D. & Hunter, C.A. (2005) Initiation and termination of NF-κB signaling by the intracellular protozoan parasite Toxoplasma gondii. J.Cell Science. 118: 3501-3508.

Nadjar, A, Bluthe, R-M., May, M.J., Dantzer, R. & Parnet, P. (2005) Inactivation of the cerebral NF-κB pathway inhibits interleukin-1ß-induced sickness behavior and c-Fos expression in various brain nuclei. Neuropsychopharmacology. 30: 1492-1499.

Tas, S.W., de Jong, E.C., Hajji, N., Kapsenberg, M.L., May, M.J., Ghosh, S., Vervoordeldonk, M.J. & Tak, P.P. (2005) Selective inhibition of NF-κB in dendritic cells by the NEMO-binding domain peptide efficiently blocks maturation and prevents T cell proliferation and polarization. Eur.J.Immunol. 35: 1164-1174.

May, M.J., Larsen, S.E., Shim, J-H., Madge, L.A. & Ghosh, S. (2004) A novel ubiquitin-like domain in IκB Kinase b is critical for the functional activity of the kinase. J.Biol.Chem. 279: 45528-45539.

Jimi, E., Aoki, K., Saito, H., D’Acquisto, F., May, M.J., Nakamura, I., Sudo, T., Ohya, K, & Ghosh, S. (2004) Selective Inhibition of NF-κB Blocks Osteoclastogenesis and Prevents Inflammatory Bone Destruction In Vivo.  Nature Medicine.  10: 617-624.

May, MJ., Marienfeld, R.B. & Ghosh, S. (2002) Characterization of the IkB-kinase NEMO binding domain (NBD). J.Biol.Chem. 277: 45992-46000.

Zhong, H., May, M.J., Jimi, E., & Ghosh, S. (2002). Phosphorylation of NF-κB determines its association with CBP/p300 or HDAC-1. Mol. Cell.  9: 625-636.

May, M.J., D’Acquisto, F., Madge, L.A., Glockner, J., Pober, J.S. & Ghosh,S. (2000). Selective inhibition of NF-kB activation by a peptide that blocks the interaction of NEMO with the IkB kinase complex. Science. 289: 1550-1554.

 

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