| Project/Area Number |
14570983
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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 | Yamaguchi University |
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Principal Investigator |
ISHIKAWA Hideki Yamaguchi University, Graduate School of Medicine, Bio-Signal Analysis, Associate Professor, 大学院・医学研究科, 助教授 (40294623)
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| Co-Investigator(Kenkyū-buntansha) |
TSUYAMA Naohiro Yamaguchi University, Graduate School of Medicine, Bio-Signal Analysis, Research Associate, 大学院・医学研究科, 助手 (10335747)
KAWANO Michio Yamaguchi University, Graduate School of Medicine, Bio-Signal Analysis, Professor, 大学院・医学研究科, 教授 (40161343)
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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: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | myeloma / IL-G / IGF-I receptor / IL-6Rα / Akt / cell proliferation / cell survival / raft / IGF-I / FGFR3 / IL-6Rα / CD45 / Lyn / PLC / CD19 / サブトラクション |
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| Research Abstract |
Interleukin-6 (IL-6) stimulation induced the phosphorylation of insulin-like growth factor-I (IGF-I) receptors in a human myeloma cell line, NOP2 highly expressing IL-6 receptor a chain (IL-6Rα) and in the IL-6Rα-transfected U266 but not in other myeloma cell lines, ILKM2 and ILKM3. IL6-dependent complex formation of IL-6Rα with TGF-I receptor β was found in NOP2 where IL-6Rα colocalized with IGF-1 receptors at lipid rafts. Moreover, IL-6-induced phosphorylation of IGF-1 receptor β was not blocked by a Janus kinase (Jak) 2 inhibitor, AG490, indicating that the IL-6-activated Jaks are unlikely to pnnicipute in this process. In addition to the activation of signal vansducer and activator of transcription 3 (Stat3) and extracellular signal-regulated kinase 1/2 (ERK1/2), IL-6 led to the activation of Akt downstream of phosphatidylinositol-3 kinase (PI3-K) presumably following the phosphorylation of IGF-I receptors and insulin receptor substrate-1. In serum-free conditions d,-6 was sufficient for the proliferation of NOP2 but not of ILKM2 and ILKM3 that instead remained viable with insulin or IGF-I capable of activating the PI3-K-Akt pathway. Inhibitors selective for PI3-K or MEK1/2 abolished the biological effect of IL-6 on NOP2 and effect of insulin or IGF-I on ILKM2 and ILKM3, indicating an important role of both pathways in preventing myeloma cells from apoptosis. Forkhead transcription factor, p27^<Kip1> and p53 seemed to be target molecules for the activated Akt that inhibited their functions. Thus, these results suggest that in NOP2 IL-6Rα and IGF-I receptors exist on plasma membrane in close proximity, facilitating efficient assembly of two receptors in response to IL-6. The synergistic effects of highly expressed IL-6Rα on IGF-I receptor-mediated signals provide a novel insight into a Jak-independent IL-6 signaling mechanism of receptor cross-talk in human myeloma cells
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