The goal of my lab is to understand and learn to exploit cell death pathways in cancer and immunity.  We have found that changes in cell metabolism that occur in cancer cells and activated lymphocytes can have profound effects on key cell death regulatory proteins.  In particular, elevated glucose uptake characteristic of these cells initiates a nutrient-dependent cell signaling pathway that we recently defined that both prevents cell death and promotes cell growth.  Regulation of glucose uptake and this novel signaling pathway may play important roles in development of cancer as well as autoimmunity.  We are now working to understand the interplay between glucose metabolism and cell death using three approaches.  (1) Using an in vitro cell biological approach, we are studying the mechanisms and pathways that regulate expression and trafficking of the glucose transporter, Glut1.  (2) We are addressing the signaling pathways and role of glucose uptake in lymphocyte development, survival, and lymphomagenesis using transgenic and knockout mice.  (3) We are also defining the role of glucose uptake on cell death via regulation of the Bcl-2 family of proteins.  Our approach of studying the mechanism and role of metabolic regulation in lymphocytes bridges immunology and metabolism research.  Through this approach we hope to address novel cell biological issues that affect lymphocyte survival, autoimmunity, and cancer.

Wofford, J.A., H.L. Wieman, S.R. Jacobs, Y. Zhao, J.C. Rathmell. 2007. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt1 to support T cell survival. Blood. Nov 27 Epub.

Juntilla, M.M*, J.A. Wofford*, M.J. Birnbaum, J.C. Rathmell, G Koretzky. 2007. Akt1 and Akt2 are required for immature ab thymocyte survival and differentiation. Proc. Natl. Acad Sci USA. 104:12105-10. *These authors contributed equally. Note that J.A. Wofford is a student in the Rathmell lab and J.C. Rathmell and G. Koretzky are listed as co-corresponding authors on this manuscript.

Zhao, Y., B.J. Altman, J.L. Coloff, C.E. Herman, S.R. Jacobs, H.L. Wieman, J.A. Wofford, L.N. Dimascio, O. Ilkayeva, A. Kelekar, T. Reya, and J.C. Rathmell. 2007. GSK-3α/β Mediate a Glucose-Sensitive Anti-Apoptotic Signaling Pathway to Stabilize Mcl-1. Mol Cell Biol. 27:4328-39.

Wieman, H.L., J.A. Wofford, J.C. Rathmell. 2007. Cytokine Stimulation Promotes Glucose Uptake via Phosphatidylinositol-3 kinase/Akt Regulation of Glut1 Activity and Trafficking. Mol. Biol. Cell. 18:1437-46.

Nutt, L.K., S.S. Margolis, M. Jensen, C.E. Herman, W.G. Dunphy, J.C. Rathmell, S. Kornbluth. 2005. Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of Caspase 2. Cell. 123:89-103. Article selected for cover art. See comment in Cell 123:3-5.

Cinalli, R.M., C.E. Herman, B. Lew, H.L. Wieman, K. Burridge, C.B. Thompson, J.C. Rathmell. 2005. T cell homeostasis requires GPCR-mediated access to trophic signals that promote growth and inhibit chemotaxis. Eur. J. Immunol. 35:786-795.

Rathmell, J.C., C. J. Fox, D.R. Plas, P. Hammerman, R.M. Cinalli, C.B. Thompson. 2003. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol. Cell. Biol. 23:7315-7328.

Rathmell, J.C., Elstrom, R.E., Cinalli, R.M., Thompson, C.B. 2003. Activated Akt promotes increased resting T cell size, CD28-indenpent T cell growth, and development of autoimmunity and lymphoma. Eur. J. Immunol. 33:2223-2232

Rathmell, J.C., C.B. Thompson. 2002. Pathways of apoptosis in lymphocyte development, homeostasis, and disease. Cell 109:S97-S107.

Plas, D.R., J.C. Rathmell, C.B. Thompson. 2002. Homeostatic control of lymphocyte survival: Potential origins and implications. Nature Immunol. 3:515-21.

Rathmell, J.C., T. Lindsten, W.-X. Zong, R.M. Cinalli, C.B. Thompson. 2002. Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nature Immunol. 3:932-939. See comment in Nature Immunol. 3:893-894.

Frauwirth, K.A., J.L. Riley, M.H. Harris, R.V. Parry, J.C. Rathmell, D.R. Plas, R.L. Elstrom, C.H. June, C.B. Thompson. 2002. The CD28 signaling pathway regulates glucose metabolism. Immunity 16:767-777.

Rathmell, J.C., E.A. Farkash, W. Gao, C.B. Thompson. 2001. IL-7 enhances the survival and maintains the size of naive T cells. J. Immunol. 167:6869-6876.

Rathmell, J.C., M.G. Vander Heiden, M.H. Harris, K.A. Frauwirth, C.B. Thompson. 2000. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol. Cell 6:683-692.