| Project/Area Number |
08458193
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | The University of Tokyo (Faculty of Pharmaceutical Sciences) |
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Principal Investigator |
KATADA Toshiaki The University of Tokyo, Faculty of Pharmaceutical Sciences, Dept. of Physiol. Chem., Professor, 薬学部, 教授 (10088859)
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| Co-Investigator(Kenkyū-buntansha) |
HOSHINO Shin-ichi The University of Tokyo, Faculty of Pharmaceutical Sciences, Dept. of Physiol. C, 薬学部, 助手 (40219168)
KAZEKI Osamu The University of Tokyo, Faculty of Pharmaceutical Sciences, Dept. of Physiol. C, 薬学部, 助教授 (80142751)
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| Project Period (FY) |
1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1996: ¥6,800,000 (Direct Cost: ¥6,800,000)
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| Keywords | NAD / Cyclic ADP-ribose / NADase / G proteins / CD38 / Tyrosine phosphorylation / Signal transduction / 環状ADPリボース |
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| Research Abstract |
The human cell surface antigen CD38, which has an amino acid sequence homologous to Aplysia ADP-ribosyl cyclase, is a 46-kDa type II glycoprotein with a single-transmembrane domain. We previously demonstrated that the extracellular domain of CD38 exhibits NAD^+ glycohydrolase (NADase) activity and that the ecto-form NADase activity induced by all-trans retinoic acid (RA) in HL-60 cells is due to CD38. CD38 catalyzes not only the hydrolysis of NAD^+ but also the formation and hydrolysis of cyclic ADP-ribose, which is a novel candidate that mediates Ca^<2+> release from intracellular Ca^<2+> stores. In the present study, we obtained the following findings. 1. Stimulation of RA-differentiated HL-60 cells with anti-CD38 monoclonal antibodies (mAbs) induced rapid tyrosine phosphorylation of cellular proteins with the molecular weights of 120,000,87,000 and 77,000. One of the prominent phosphorylated proteins was identified as the c-cbl proto-oncogene product, p120^<c-cbl>.2. Superoxide formation in response to formyl-Met-Leu-Phe was markedly enhanced by the anti-CD38 mAbs in the differentiated HL-60 cells. 3. The epitopes recognized by these agonistic mAbs stimulating protein tyrosine phosphorylation were all mapped on the same carboxyl-terminal sequence of CD38, and the same sequence was also required for its ecto-NADase activity. 4. Fcgamma-II receptors appeared to be involved in the signal transduction pathway mediated through the agonistic anti-CD38 mAb-induced tyrosine phosphorylation of cellular proteins. 5. The expression of CD38 mRNA was mediated through nuclear RA receptors ; a RA receptor-responsive element was present in the first intron of CD38 gene.
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