Negative regulation of IL-1 2/STAT4 induced signal transduction
| Project/Area Number |
14570967
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
YAMAMOTO Koh Tokyo Medical and Dental University, Department of Hematology and Oncology, 医学部附属病院, 助手 (00281717)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Interleukin-12 / STAT4 / SOCS / Proteasome / Ubiquitin / インターロイキンー12 / SOCS / プロテオゾーム / インターロイキン12 / 受容体 / JAKキナーゼ / STAT |
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| Research Abstract |
IL-12 promotes the proliferation of T cells as well as NK cells and plays a critical role in induction of the Th 1 differentiation. IL-12 mediates its biological activities through activation of the receptor-associated JAK family kinases and STAT4, which is recruited to phosphorylated Tyr-800 in the human IL-12 receptor β2 subunit (IL-12Rβ2). Here we demonstrate that suppressor of cytokine signaling-3 (SOCS-3) is also recruited to IL-12Rβ2 by the interaction involving the SOCS-3 SH2 domain and phosphorylated Tyr-800 in IL-12Rβ2. Furthermore, SOCS-3, but not its SH2 domain-defective mutant, inhibited the IL-12-induced activation of DNA binding and transcriptional activities of STAT4. These results suggest that SOCS-3, expressed at high levels in Th2 cells, plays an inhibitory role in STAT4-mediated IL-12 signaling by binding to the STAT4 docking site in IL-12Rβ2, thus raising a possibility that SOCS-3 may play a role in regulation of Th differentiation. Also, IL-12 induces proteasome-dependent proteolysis of STAT4 and ubiquitination of STAT4 and JAK2 in human lymphocytes. Ubiquitin-proteasome pathway may negatively regulates tyrosine JAK2 and STAT4 in IL-12 signaling.
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Report
(3 results)
Research Products
(18 results)
