JAMES N. IHLE
PROFESSOR

EDUCATION:
B.S. 1967, Iowa State University, Ames, Iowa (Zoology)
M.S. 1969, University of Georgia, Athens, Georgia (Biochemistry)
Ph.D. 1971, University of Georgia, Athens, Georgia (Biochemistry)

RESEARCH INTERESTS: The mechanisms regulating the growth, differentiation and transformation of hematopoietic cells represent the general areas of research interest. Our research efforts have focused on the lymphokine, interleukin 3 (IL-3), which we have shown supports the proliferation and differentiation of early hematopoietic progenitors and committed progenitors of the myeloid lineage. We are interested in the structure of the IL-3 receptor and its functional activity. This has been approached through biochemical purification and attempts to clone the gene. The signal transduction systems which IL-3 activates has been studied through biochemical studies and by employing retroviral vectors expressing various functions. Lastly, comparable approaches are being used to study the mechanisms by which IL-3 regulates specific gene expression in myeloid cells. Our efforts to study transformation involve identifying the genes which block the differentiation of IL-3-dependent myeloid cells. These studies employ a novel gene cloning strategy to identify new genes causing myeloid transformation. Once identified retroviral vector systems to study their effects on normal, IL-3 supported differentiation.

CURRENT RESEARCH SUPPORT:
NCI, 5 PO1 CA 20180 - 18, Project 5: "Cell Biology of Acute Myeloid Leukemia" July 23, 1993 - February 28, 1998; $137,850
NIDDK, 2 RO1 DK 429737-05 - 01 "Interleukin-3 Regulated Growth of Hematopoietic Cells" August 1, 1995 - July 31, 2000; $240,830
AMGEN - 02 "Erythropoietin Receptor Structure" May 28, 1994 - May 27, 1997 $192,593
NHLBI, 1 PO1 HL 53749 - 02, Project 1: "Signalling by the EPO Receptor in Erythropoiesis" September 30, 1994 - August 31, 1999; $151,015

GRADUATE STUDENTS:
Jian Feng, current student.

PUBLICATIONS - (Selected publications since 1994):
Rothman, P., Kreider, B.L., Azam, M., Levy, D., Wegenka, U., Eilers, A., Decker, T., Horn, F., Kashleva, H., Ihle, J.N., and Schindler, C. (1994) Cytokines and growth factors signal through tyrosine phosphorylation of a family of related transcription factors. Immunity, 1, 457-468.
Yi, T., Zhang, J., Miura, O., and Ihle, J.N. (1995) Hematopoietic cell phosphatase (HCP) associates with the erythropoietin receptor following Epo induced receptor tyrosine phosphorylation: Identification of potential binding sties. Blood, 85, 87-95.
Morishita, K., Suzukawa, K., Taki, T., Ihle, J.N., and Yokota, J. (1995) EVI-I zinc finger protein works as a transcriptional activator via binding to a consensus sequence of GACAAGATAAGATAAN1-28CTCATCTTC. Oncogene, 10, 1961-1967.
Ihle, J.N. and Kerr, I.M. (1995) JAKs and STATs in signalling by the cytokine receptor superfamily. Trends in Genetics, 11, 69-74.
Azam, A., Erdjument-Bromage, H., Kreider, B., Min, X., Quelle, F.W., Basu, R., Saris, C., Tempst, P., Ihle, J.N., and Schindler, C. (1995) Purification of interleukein-3 stimulated DNA binding factors demonstrates the involvement of multiple isoforms of Stat5 in signaling. EMBO J., 14(7), 1402-1411.
Beading, C., Guschin, D., Witthuhn, B.A., Ziemiecki, A., Ihle, J.N., Kerr, I.M., and Cantrell, D.A. (1994) Activation of JAK kinases and STAT proteins by interleukin-2 and interferon a but not the T cell antigen receptor in human T lymphocytes. EMBO J., 15, 5605-5615.
Campbell, G.S., Argetsinger, L.S., Ihle, J.N., Kelly, P.A., Rillema, J.A., and Carter-Su, C. (1994) Activation of JAK2 tyrosine kinase by prolactin receptors in Mb2 cells and mouse mammary gland explants. Proc. Natl. Acad. Sci. USA, 91, 5232-5236.
Guschin, D., Rogers, N., Briscoe, J., Witthuhn, B.A., Watling, D., Horn, F., Pellegrini, S., Yasukawa, K., Heinrich, P., Stark G.R., Ihle, J.N., and Kerr, I.M. (1995) A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO. J., 14, 1421-1429.
Morella, K.K., Lai, C., Kumaki, S., Kumaki, N., Wang, Y., Bluman, E.M., Witthuhn, B.A., Ihle, J.N., Giri, J., Gearing, D.P., Cosman, D., Ziegler, S.F., Tweardy, D.J., Compos, S.P., and Baumann, H. (1995) The action of interleukin-2 receptor subunits defines a new type of signaling mechanism for hematopoietic receptors in hepatic cells and fibroblasts. J. Biol. Chem., 270, 8298-8310.
Ihle, J.N., Witthuhn, B.A., Quelle, F.W., Yamamoto, K., and Silvennoinen O. (1995) Signaling through the hematopoietic cytokine receptors. Annu. Rec. Immunol., 15, 369-398.
Bellefroid, E.J., Marine, J-C., Matera, A.G., Bourguignon, C., Desai, T., Healey, K., Bray-Ward, P., Martia, J.A., Ihle, J.N., and Ward, D.C. (1995) Emergency of the ZNF91 KRAB-zinc finger gene family after the divergency between the anthropoid and prosimian primate lineages. PNAS, in press.
Cleveland, J.L. and Ihle, J.N. (1995) Contenders in FasL/TNF death signalling. Cell, 81, 479-482.
Quelle, F.W., Shimoda, K., Thierfelder, W., Fischer, C., Kim., A., Ruben, S.M., Cleveland, J.L., Pierce, J.H., Keegan, A.D., Nelms, K., Paul, W.E., and Ihle, J.N. (1995) Cloning of murine stat6 and human stat6, stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol. Cell Biol., 15, 3336-3343.
Kotenko, S.V., Izotova, L.S., Pollack, B.P., Mariano, T.M., Donnelly, R.J., Muthukumaran, G., Cook, J.R., Garotta, G., Silvennoinen, O., Ihle, J.N., and Pestka, S. (1995) Interaction between the components of the interferon gamma receptor complex. J. Biol. Chem., submitted.
Quelle, F.W., Thierfelder, W., Witthuhn, B.A., Tang, B., Cohen, S., and Ihle, J.N. (1995) Phos-phorylation and activation of the DNA binding activity of purified Stat1 by the Janus protein tyrosine kinases and epidermal growth factor receptor. J. Biol. Chem., 270, 20775-20780.
Fujii, H., Nakagawa, Y., Schindler, U., Kawahara, A., Mori, H., Gouilleux, F., Groner, B., Ihle, J.N, Minami, Y., Miyazaki, T, and Taniguchi, T. (1995) Activation of Stat 5 by interleukein 2 requires a carboxyl-terminal region of the interleukin 2 receptor b chain but is not essential for the proliferative signal transmission. PNAS, 92, 5482-5486.
Nosaka, T., van Deursen, J.M.A., Trrip, R.A., Thierfelder, W.E., Witthuhn, B.A., McMickle, A.P., Doherty, P.C., Grosveld, G.C., and Ihle, J.N. (1995) Defective lymphoid development in mice lacking Jak3. Science, in press.
Matsugi, T., Kreider, B.L., Delwel, R., Cleveland, J.L., Askew, D.S., and Ihle, J.N. (1995) The Evi-1 zinc finger myeloid transforming protein binds to genomic fragments containing (GATA)n sequences. Oncogene, 11, 191-198.
Yin, T., Keller, S.R., Quelle, F.W., Witthuhn, B.A., Tsang, M.L., Lienhard, G.E., Ihle, J.N., and Yang, Y. (1995) Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases. J. Biol. Chem., 270, 20497-20502.