1998 Fiscal Year Final Research Report Summary
Physiological functions of a novel family of nucleotide-metabolizing enzymes
| Project/Area Number |
09480160
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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 |
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Principal Investigator |
KATADA Toshiaki The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept.of Physiol.Chem., Professor, 大学院・薬学系研究科, 教授 (10088859)
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| Co-Investigator(Kenkyū-buntansha) |
HOSHINO Shin-ichi The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept.of Phy, 大学院・薬学系研究科, 助手 (40219168)
NISHINA Hiroshi The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept.of Phy, 大学院・薬学系研究科, 助教授 (60212122)
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| Project Period (FY) |
1997 – 1998
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| Keywords | CD38 / ecto-enzyme / NADase / cyclic ADP-ribose / retinoic acid / signal transduction |
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| Research Abstract |
Ecto-form NADase activity induced by retinoic acid(RA)in HL-60 cells is due to CD38, which has an amino acid sequence homologous to Aplysia ADP-ribosyl cyclase. CD38 catalyzes not only the hydrolysis of NAD^+, but also the formation and hydrolysis of cyclic ADP-ribose (cADPR), that is a novel mediator or modulator of Ca^<2+> release from intracellular Ca^<2+> stores. In the present study, we investigated the functions and properties of CD38 and its related ecto-enzyme, PC-1.1. Stimulation of RA-differentiated HL-60 cells with anti-CD38 monoclonal antibodies induced rapid tyrosine phosphorylation of cellular proteins including the c-cbl proto-oncogene product, pl20^<C-Cbl>. Superoxide formation in response to formyl-Met-Leu-Phe was markedly enhanced by the anti-CD38 mAbs. Fcgamma-II receptors appeared to be involved in the signal transduction pathway mediated through the anti-CD38 mAb-induced tyrosine phosphorylation. 2. CD38 was abundantly present in rat brain in addition to lymphocytes. In primary culture of rat glial and neuronal cells, CD38 was most abundantly observed in astrocyte cell surface. Confocal laser microscopic analysis revealed that immunoreactive CD38 and the enzyme activity were localized on the cell surface of astrocytes. The cell-surface CD38 was rapidly inactivated upon the addition of the enzyme substrates to the cultured astrocytes.
3. An RA response element (RARE) consisting of two direct-repeated TGACCT-like hexamer motifs with a 5-nucleotide spacer was found to be located in the first intron of CD38 gene. This RARE interacted with heterodimer composed of RA receptor and retinoid X receptor. Thus, the RA-induced expression of human CD38 gene was demonstrated to be mediated through the RARE located in the first intron.
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