Paul B. Rothman, M.D.

Dean, UI Carver College of Medicine
Professor of Medicine and Molecular Physiology & Biophysics

Yale University, 1984

Research Interests

Dr. Rothman's work centers on several projects directed at understanding the role cytokines and cytokine signaling plays in both normal lymphocyte development and leukemic transformation. One major project in the lab centers on trying to understand how cytokines signal cells to activate transcription. We have centered this work on the cytokine IL-4, a cytokine essential for allergic immune responses. 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 and performed structure-function work on STAT6 defining its transcriptional activation domain. In addition, we performed some initial structure function work on the IL-4 receptor complex. We are currently studying a series of novel genes that are activated by IL-4 and defining their role in activating gene expression downstream of IL-4. In addition, we have initiated 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 studying the PIM kinases. We have demonstrated that the PIM kinases can phosphorylateSOCS-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. 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. We have found that pre-B cells that are transformed by the Abelson Murine Leukemia Virus have activation of the IL-4 and IL-7 signaling pathways in the absence of these cytokines. We are extending this work to understand in more detail how this kinase is activating these pathways.

Selected Publications

1. Limnander A., Danial, N., and P. Rothman. v-Abl signaling disrupts SOCS-1 function in transformed pre-B cells. (2004) Molecular Cell. 15:329-341.

2. Canfield, S., Lee, Y., Schröder, A., and P. Rothman. IL-4 Induces Suppressor of Cytokine Signaling-3 Expression in B Cells by a Mechanism Dependent on Activation of p38 MAPK. (2005) J. Immunol. Cutting Edge, J. Immunol. 174:2494-2498.

3. Banks, A.S., Li, J., McKeag, L., Hribal, M.L., Kashiwada, M., Accili, D., and P. Rothman. Deletion of SOCS7 Leads to Enhanced Insulin Action. (2005) J.C.I., in press

4. Kashiwada, M., Cattoretti, G., McKeag, L., Rouse, T., Showalter, B.M, Al-Alem, U., Niki, M., Pandolfi, P.P., Field, E.H., and P. Rothman. Downstream of tyrosine kinases-1 and SH2-containing inositol 5'-phosphatase are required for regulation of CD4+CD25+T cell development. (2006) J. Immonol. 176(7):3958-65.