| Project/Area Number |
12670799
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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 |
Pediatrics
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| Research Institution | Kurume University |
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Principal Investigator |
KATO Reiko (2001) Kurume University, Institute of Life Science, Assistant Professor, 分子生命科学研究所, 助手 (00333469)
神薗 慎太郎 (2000) 久留米大学, 医学部, 助手 (30261077)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIMURA Akihiko Kurume University, Institute of Life Science, Professor, 生体防御医学研究所, 教授 (90182815)
箕口 滋 久留米大学, 分子生命科学研究所, 助手 (60322757)
加藤 裕久 久留米大学, 医学部, 教授 (30080724)
加藤 玲子 久留米大学, 分子生命科学研究所, 助手
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2000: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | tyrosine kinase / JAK / oncogene / JAB / SOCS1 / cytokine / leukemia / tyrosine phosphorylation / ubiquitin ligase |
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| Research Abstract |
Fusion of the TEL gene on 12p13 to the JAK2 tyrosine kinase gene on 9p24 has been found in human leukemia. TEL-mediated oligomerization of JAK2 results in constitutive activation of the tyrosine kinase (JH1) domain and confers cytokine-independent proliferation to interleukin-3-dependent Ba/F3 cells. Forced expression of the JAK inhibitor gene SOCS1/JAB/SSI-1 induced apoptosis of TEL-JAK2-transformed Ba/F3 cells. This suppression of TEL-JAK2 activity was dependent on SOCS box-mediated proteasomal degradation of TEL-JAK2 rather than on kinase inhibition. Degradation of JAK2 depended on its phosphorylation and its high affinity binding with SOCS1 through the kinase inhibitory region and the SH2 domain. It has been demonstrated that von Hippel-Lindau disease (VHL) tumor-suppressor gene product possesses the SOCS box that forms a complex with Elongin B, C and Cullin-2, and functions as an ubiquitin ligase.
The SOCS box of SOCS1 has also been shown to interact with Elongins, however, ubiquitin ligase activity has not been demonstrated. We found that the SOCS box interacted with Cullin
2 and promoted ubiquitination of TEL-JAK2.Furthermore, overexpression of dominant negative Cullin 2 suppressed SOCS1-dependent TEL-JAK2 degradation. Our study demonstrates substrate-specific E3 ubiquitin-ligase like activity of SOCS1 for activated JAK2, and may provide a novel strategy for the suppression of oncogenic tyrosine kinases.
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