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,
,,§
*
Virginia Mason Research Center, Seattle, WA 98101;
Fred Hutchinson Cancer Research Center, Seattle, WA 98104; and Departments of
Immunology and
§
Medicine, University of Washington, Seattle, WA 98195
Studies assessing the role of Stat5 in the IL-2 proliferative signal have produced contradictory, and thus inconclusive, results. One factor confounding many of these studies is the ability of IL-2R to deliver redundant mitogenic signals from different cytoplasmic tyrosines on the IL-2R ß-chain (IL-2Rß). Therefore, to assess the role of Stat5 in mitogenic signaling independent of any redundant signals, all cytoplasmic tyrosines were deleted from IL-2Rß except for Tyr510, the most potent Stat5-activating site. This deletion mutant retained the ability to induce Stat5 activation and proliferation in the T cell line CTLL-2 and the pro-B cell line BA/F3. A set of point mutations at or near Tyr510 that variably compromised Stat5 activation also compromised the proliferative signal and revealed a quantitative correlation between the magnitude of Stat5 activation and proliferation. Proliferative signaling by a receptor mutant with a weak Stat5 activating site could be rescued by overexpression of wt Stat5a or b. Additionally, the ability of this receptor mutant to induce c-myc, bcl-x, and bcl-2 was enhanced by overexpression of wt Stat5. By contrast, overexpression of a version of Stat5a lacking the C-terminal trans-activation domain inhibited the induction of these genes and cell proliferation. Thus, Stat5 is a critical component of the proliferative signal from Tyr510 of the IL-2R and regulates expression of both mitogenic and survival genes through its trans-activation domain.
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M. Minagawa, H. Watanabe, C. Miyaji, K. Tomiyama, H. Shimura, A. Ito, M. Ito, J. Domen, I. L. Weissman, and K. Kawai Enforced Expression of Bcl-2 Restores the Number of NK Cells, But Does Not Rescue the Impaired Development of NKT Cells or Intraepithelial Lymphocytes, in IL-2/IL-15 Receptor {beta}-Chain-Deficient Mice J. Immunol., October 15, 2002; 169(8): 4153 - 4160. [Abstract] [Full Text] [PDF]
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Z. S. Nagy, Y. Wang, R. A. Erwin-Cohen, J. Aradi, B. Monia, L. H. Wang, S. M. Stepkowski, H. Rui, and R. A. Kirken Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells: resistance to suppression of multiple serine kinase pathways J. Leukoc. Biol., October 1, 2002; 72(4): 819 - 828. [Abstract] [Full Text] [PDF]
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 R. Buettner, L. B. Mora, and R. Jove Activated STAT Signaling in Human Tumors Provides Novel Molecular Targets for Therapeutic Intervention Clin. Cancer Res., April 1, 2002; 8(4): 945 - 954. [Abstract] [Full Text] [PDF]
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J. Sonoyama, I. Matsumura, S. Ezoe, Y. Satoh, X. Zhang, Y. Kataoka, E. Takai, M. Mizuki, T. Machii, H. Wakao, et al. Functional Cooperation among Ras, STAT5, and Phosphatidylinositol 3-Kinase Is Required for Full Oncogenic Activities of BCR/ABL in K562 Cells J. Biol. Chem., March 1, 2002; 277(10): 8076 - 8082. [Abstract] [Full Text] [PDF]
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J. J. Moon and B. H. Nelson Phosphatidylinositol 3-Kinase Potentiates, but Does Not Trigger, T Cell Proliferation Mediated by the IL-2 Receptor J. Immunol., September 1, 2001; 167(5): 2714 - 2723. [Abstract] [Full Text] [PDF]
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 J. L. Arrington, D. N. McMurray, K. C. Switzer, Y.-Y. Fan, and R. S. Chapkin Docosahexaenoic Acid Suppresses Function of the CD28 Costimulatory Membrane Receptor in Primary Murine and Jurkat T Cells J. Nutr., April 1, 2001; 131(4): 1147 - 1153. [Abstract] [Full Text]
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A. L. Mora, J. Youn, A. D. Keegan, and M. Boothby NF-{{kappa}}B/Rel Participation in the Lymphokine-Dependent Proliferation of T Lymphoid Cells J. Immunol., February 15, 2001; 166(4): 2218 - 2227. [Abstract] [Full Text] [PDF]
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A. Martino, J. H. Holmes IV, J. D. Lord, J. J. Moon, and B. H. Nelson Stat5 and Sp1 Regulate Transcription of the Cyclin D2 Gene in Response to IL-2 J. Immunol., February 1, 2001; 166(3): 1723 - 1729. [Abstract] [Full Text] [PDF]
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G. B. Ehret, P. Reichenbach, U. Schindler, C. M. Horvath, S. Fritz, M. Nabholz, and P. Bucher DNA Binding Specificity of Different STAT Proteins. COMPARISON OF IN VITRO SPECIFICITY WITH NATURAL TARGET SITES J. Biol. Chem., February 23, 2001; 276(9): 6675 - 6688. [Abstract] [Full Text] [PDF]
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L. E. Cheng, C. Ohlen, B. H. Nelson, and P. D. Greenberg Enhanced signaling through the IL-2 receptor in CD8+ T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8+ T cells rather than promotion of cell death PNAS, March 5, 2002; 99(5): 3001 - 3006. [Abstract] [Full Text] [PDF]
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V. G. Tusher, R. Tibshirani, and G. Chu Significance analysis of microarrays applied to the ionizing radiation response PNAS, April 24, 2001; 98(9): 5116 - 5121. [Abstract] [Full Text] [PDF]
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