The anti-growth, antiviral and immuno-modulatory activities of interferons (IFNs) have made these cytokines a valuable tool in the treatment of cancer. The biological effects of IFNs are controlled in part by stimulation of early response genes regulated by the Jak/Stat pathway. The investigator has found that incubation of peripheral blood lymphocytes or the Jurkat T cell line with IFNalpha induces a rapid association with the alpha chain of the IFNalpha receptor (IFNalphaR1) of the protein tyrosine kinases Lck and ZAP-70 and the protein tyrosine phosphatase, CD-45. To explore the role of these signaling enzymes in the biological activities of IFNalpha, wild-type, CD45-, Lck- or ZAP-70-deficient Jurkat cells were examined, and the antiproliferative effects of IFNalpha were completely abrogated in cell lines which did not express each of these enzymes, unless they were reconstituted with CD45, Lck or ZAP-70 activity. These data provide evidence for a novel IFNalpha activated signaling cascade in T cells that requires components known to participate in the T cell receptor signaling network. The project proposed is based on the hypotheses that 1) IFNalpha activates another signaling cascade in addition to the Jak/Stat pathway in T cells which utilizes ZAP-70 Lck and CD45. 2) The downstream substrates phosphorylated by Lck and ZAP-70 are required for the antiproliferative effect of IFNalpha.
The specific Aims are: 1a) to define the domains in ZAP-70, CD45 and Lck which allow these proteins to associate with IFNaR1: 1b) to determine whether these domains or proteins missing these domains affect antiproliferative actions of IFNalpha; 1c) to determine whether domains which inhibit the antiproliferative actions of IFNa in thymocytes; 2) to determine if certain Jak and Stat proteins are required for IFN alpha activation of Lck and ZAP-70; and 3) to characterize and purify novel proteins which may be required for CD45, Lck, and ZAP-70 to exert their antiproliferative actions.
| Dong, F; Qiu, Y; Yi, T et al. (2001) The carboxyl terminus of the granulocyte colony-stimulating factor receptor, truncated in patients with severe congenital neutropenia/acute myeloid leukemia, is required for SH2-containing phosphatase-1 suppression of Stat activation. J Immunol 167:6447-52 |
| Dong, F; Gutkind, J S; Larner, A C (2001) Granulocyte colony-stimulating factor induces ERK5 activation, which is differentially regulated by protein-tyrosine kinases and protein kinase C. Regulation of cell proliferation and survival. J Biol Chem 276:10811-6 |
| Gamero, A M; Larner, A C (2001) Vanadate facilitates interferon alpha-mediated apoptosis that is dependent on the Jak/Stat pathway. J Biol Chem 276:13547-53 |
| Gamero, A M; Larner, A C (2000) Signaling via the T cell antigen receptor induces phosphorylation of Stat1 on serine 727. J Biol Chem 275:16574-8 |
