1998 Fiscal Year Final Research Report Summary
Signal transduction of IL-6 in myeloma cells
| Project/Area Number |
09044301
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
Hematology
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| Research Institution | Osaka University |
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Principal Investigator |
YOSHIZAKI Kazuyuki School of Health & Sport Sciences, Osaka University, 健康体育部, 教授 (90144485)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIMOTO Norihiro School of Healt & Sport Sciences, Osaka University, Associate Professor, 健康体育部, 助教授 (80273663)
ANDERSON Ken ハーバード大学ダナ, ファーバー癌研究所, 助教授
KUBAGAWA Hiromi University of Alabama at Birmingham Medical School, Associate Professor, 医学部, 助教授
ANDERSON Kenneth C. Dana Farber Cancer Research, University of Harvard, Associate Professor
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| Project Period (FY) |
1997 – 1998
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| Keywords | multiple myeloma / IL-6 / SSI-1 / MAPK / STAT1 / STAT3 / negative feedback |
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| Research Abstract |
Interleukin-6(IL-6) is known to be a potent growth factor of multiple myeloma(MM) cells. It also prevents some myeloma cells fremapeptosis induced by corticosteroids, and crosslinking of Fas antigen (CD95). IL-6 has been shown to use two intracytoplasmic signal transducing pathways : (i) gpl3O * Ras * MARK * NF-IL6. (ii) gpl30 * JAK * STAT3 and/or STAT1 In the first year of this study, our collegue Dr.Anderson elucidated that the formrer pathway was used for growth stimulatory signal We also demonstrated that one of the STAT3-target gene products could inhibit the phosphorylatinn of STAT3 and was designated as STATs-induced STAT inhibitor-1 (SSI-1. The SSI-1 appears to act as a negative feedback factor of JAK-STAT signaling pathway. To elucidate a possible role in the pathogenesis of MM of SSI-1 and its family molecules which have a constructive homology with SSI-1, we have examined their expression and induction in six myeloma cell line in response to IL-6 stimulation. Close relation was found between disability in tyrosine-phosphorylation of STAT3 by IL-6 and constitutive expression of SSI-1 but not of SSI-2 SSI-3, SSI-4 or SSI-6, suggesting the abnormal expression of SSI-1 may cause the impaired JAK-STAT signaling of IL-6 in some myeloma cells. Artificial constitutive expression of SSI-1 markedly suppressed STAT3 phosphorylation in OCI-My5 cells which represent MM cells whose STAT3 could be phosphorylated by lL-6. On the contrary, tyrosime-phosphorylation of STAT3 was restored by introducing anti-sense SSI-1 gene in ARH77 which represent MM cells whose STAT3 could not be phosphorylated by IL-6.
These data confirmed deregulated constitutive expression of SSI-1 caused the lack of response to IL-6 in some MM cell lines.
Further study will be required to understand the mechanisms for such transcriptional deregulation of SSI-1.
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[Publications] Futatani T,T.Miyawaki, S.Tsukada, S.Hashimoto, T.Kunikata, S.Arai, M.Kurimoto, Y.Niida, H.Matsuoka, Y.Sakiyama, T.Iwata, S.Tsuchiya, O.Tatsuzawa, K.Yoshizaki, Kishimoto T: "Deficient expression of Bruton's tyrosine kinase in monocytes from X-Linked Agammaglobulinemia as evaluated by a flowcytometric analysis and its clinical application to carrier detection." Blood. 91. 1-9 (1998)
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「研究成果報告書概要(欧文)」より
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