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Using microarray technology, we previously demonstrated that IFN-gamma induces suppressor of cytokine signaling-3 (SOCS-3) in Stat1-/- mouse embryonic fibroblasts and bone marrow-derived macrophages. In this study, we have investigated the mechanism by which SOCS-3 is induced by Stat1-independent signal transduction pathway. Tyrosine kinases Jak1 and Jak2 are required for SOCS-3 induction by IFN-gamma in mouse embryonic fibroblasts. IFN-gamma stimulated strong and sustained activation of Stat1 whereas Stat3 activation was weak and transient in wild-type fibroblasts. In contrast, Stat3 is activated strongly and in a sustained manner in Stat1-/- fibroblasts. The Src kinase inhibitor SU6656 suppressed IFN-gamma activation of Stat3 in both wild-type and Stat1-/- fibroblasts. However, SU6656 inhibited IFN-gamma induction of SOCS-3 completely in Stat1-/- but not in wild-type fibroblasts. Knock down of Stat3 by short interfering RNA abrogated Stat3 activation and SOCS-3 induction by IFN-gamma in Stat1-/- fibroblasts. In human fibrosarcoma cell line 2fTGH, IFN-gamma activated Stat1 but not Stat3. SOCS-3 induction by IFN-gamma is strictly Stat1-dependent. The Stat1 docking site is required for SOCS-3 induction by IFN-gamma in human lung adenocarcinoma cells. We propose a model in which sustained activation of Stat1 or Stat3 mediates SOCS-3 induction by IFN-gamma in wild-type and Stat1-/- mouse embryonic fibroblasts, respectively. 相似文献
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Ingram JL Antao-Menezes A Mangum JB Lyght O Lee PJ Elias JA Bonner JC 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(6):4141-4148
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Qiao Y Prabhakar S Canova A Hoshino Y Weiden M Pine R 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(5):2935-2943
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M Matsumoto N Tanaka H Harada T Kimura T Yokochi M Kitagawa C Schindler T Taniguchi 《Biological chemistry》1999,380(6):699-703
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Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. 总被引:9,自引:0,他引:9
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James Turkson Tammy Bowman Jalila Adnane Yi Zhang Julie Y. Djeu Madhavi Sekharam David A. Frank Lawrence B. Holzman Jie Wu Said Sebti Richard Jove 《Molecular and cellular biology》1999,19(11):7519-7528