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| Regulation of Cytokine Signal Transduction | ||||||
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The work in Dr. Rothman's laboratory focuses on understanding the signaling pathways that regulate lymphocyte growth, differentiation, and cellular transformation. One major focus of this work has centered on the cells involved in allergic diseases. These projects include studies of the molecular mechanisms underlying the regulation of IgE production by the cytokine IL-4 and IFN-γ, IL-4 and IFN-γ cytokine signal transduction, and studies investigating the T cell subsets that produce these cytokines.
One major project in the lab centers on trying to understand how IL-4 signal cells to activate transcription. We have defined several molecules involved in the IL-4 signaling cascade. We identified a novel IL-4 induced factor STAT6, a member of the STAT family of transcription factors. We performed studies to determine the mechanism by which IL-4 signaling is down modulated. These studies have led us to identify at least two natural inhibitors of IL-4 signaling. We have demonstrated that the SOCS-1 protein as an inducible inhibitor of IL-4 signaling. We are determining how SOCS-1 functions in cells, how SOCS-1 protein expression is regulated, and if SOCS-1 plays a role in regulating allergy. We are also studying the PIM kinases. We have demonstrated that the PIM kinases can phosphorylate SOCS-1 and stabilize SOCS-1 protein. We are determining the mechanism by which this occurs and if Pim kinases regulate the immune system. We are also studying other SOCS proteins and how they may regulate cytokine signaling. We have demonstrated that SOCS-7 regulates IRS proteins. We have generated and analyzed a mouse lacking SOCS-7. This mouse is hyper-responsive to insulin and IGF. The mouse also has increased IgE and IL-4 levels and has an unusual skin disease that we are studying. Another major group in the lab is trying to understand the mechanisms underlying the ability of the v-abl oncogene to transform pre-B cells and cause leukemia. We have found that pre-B cells that are transformed by the Abelson Murine Leukemia Virus have activation of the JAK/STAT signaling pathways. The ability of v-Abl to overcome the mechanisms that normally shut down these signaling pathways is being studied. |
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| Selected Publications | ||||||
| Click Here for a Complete List of Articles | ||||||
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Chen, J.-L., Limnander, A. and Rothman P.B. Pim-1 and Pim-2 Kinases Are Required for Efficient Pre-B Cell Transformation by v-Abl Oncogene. Blood 111:1677-85, 2008.
Cassel, S., Eisenbarth, S., Lyer, S., Sadler, J., Rothman P., Flavell, R. and Sutterwala, F. The Nalp3 Inflammasome is Critical for the Development of Silicosis. PNAS, USA. 105:26, 9035-904, 2008. Knisz, J., Banks, A., McKeag, L., Metcalfe, D.D., Rothman P. and Brown, J.M. The loss of SOCS7 in mice results in severe skin disease and increased mast cell activation. Clinical Immunology 2009 132(2):277-84, 2009. Kashiwada, M., Levy, D.M., McKeag, L., Murray, K., Schröder, A.J., Canfield, S.M. and Rothman P.B. Interleukin-4-induced transcription factor NFIL3/E4BP4 controls IgE class switching (submitted). |
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| Department/Program Affiliations |
| Internal Medicine |
| Biosciences |
| Immunology |
| Microbiology |
| Molecular Physiology and Biophysics |
| MSTP |