| Project/Area Number |
06044068
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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 Institution | The University of Tokyo |
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Principal Investigator |
INOUE Junichiro Institute of Medical Science, University of Tokyo, Associate Professor, 医科学研究所, 助教授 (70176428)
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| Co-Investigator(Kenkyū-buntansha) |
VERMA Inder M. The Salk Institute, Professor, 教授
OTSUKA Masami Institute for Chemical Research, Kyoto University, Associate Professor, 化学研究所, 助教授 (40126008)
UMEMORI Hisashi Institute of Medical Science, University of Tokyo, Research Associate, 医科学研究所, 助手 (20242117)
MATSUDA Satoru Institute of Medical Science, University of Tokyo, Research Associate, 医科学研究所, 助手 (50242110)
YAMAMOTO Tadashi Institute of Medical Science, University of Tokyo, Professor, 医科学研究所, 教授 (40134621)
山梨 裕司 東京大学, 医科学研究所, 助手 (40202387)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1995: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1994: ¥3,800,000 (Direct Cost: ¥3,800,000)
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| Keywords | Signal transduction / Transcription factor / B cell differentiation / Apoptosis / Rel / NFkappaB / CD40 / Re1 / 活性酸素 / 分子生物学 |
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| Research Abstract |
1. CD40 signalings are linked to induction of the Bcl-xL,Cdk4 and Cdk6 proteins whose expression was significantly suppressed by the apoptotic signal through sIgM.Mutational analyzes of CD40 revealed taht the domain of human CD40 required for blocking apoptosis coincides with that required for Bcl-xL induction. sIgM signalings arrest cells in G_1 followed by apoptosis, while constitutive expression of Bcl-xL leads to the inhibition of apoptosis. Bcl-xL fails to induce S phase entry. By CD40 signalings, both Cdk4 and Cdk6 resume their normal expression levels which are sufficient for passing the restriction point in G_1 even in the presence of the apoptotic signals. These results suggest that co-operation of Bcl-xL,Cdk4 and Cdk6 induced by CD 40 signalings plays a key role in CD40-mediated selective growth of B cells. CD40 signalings activate Rel, but the role of Rel activation in blocking apoptosis remains to be elucidated.
2. Yeast two-hybrid system has been performed to identify proteins which interact with cytoplasmic tail of CD40. Two candidates have been analyzed.
3. IkappaBalpha is rapidly phosphorylated and degraded in response to the stimulation. We have delineated the domain in IkappaBalpha required for TNFalpha-induced phosphorylation and rapid degradation. In contrast to the previous reports, the PEST-like sequences are dispensable for TNFalpha-induced degradation. The ankyrin repeats, essential for forming a complex with RelA,are required for TNFalpha-induced degradation suggesting that the putative IkappaB protease could interact with IkappaBalpha in complex with RelA.Our data also indicate that neither the ankyrin repeats nor the PEST-like sequences, are essential for TNFalpha-induced phosphorylation.
4. Phosphorylation activity which associates with amino-terminus of IkappaB has been identified.
5. Novel heterocyclic compounds which inhibit the DNA binding activity of Rel have been synthesized. (298 words)
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