Physiological functions of the cell surface antigen CD38

细胞表面抗原CD38的生理功能

基本信息

批准号：
09044268
负责人：
KATADA Toshiaki
金额：
$ 4.35万
依托单位：
The University of Tokyo (Graduate School of Pharmaceutical Sciences)
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044268/
关键词：
cyclin ADP-ribose CD38 ecto-enzyme NADase retinoic acid signal transduction リンパ球細胞内陥入

项目摘要

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 obtained the following findings. 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, p12O^<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 antiCD38 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 directrepeated 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.

HL-60 细胞中视黄酸 (RA) 诱导的外型 NADase 活性是由 CD38 引起的，CD38 具有与海兔 ADP-核糖基环化酶同源的氨基酸序列。 CD38不仅催化NAD^+的水解，还催化环ADP-核糖(cADPR)的形成和水解，cADPR是细胞内Ca^<2+>库释放Ca^<2+>的新型介质或调节剂。在本研究中，我们研究了 CD38 的功能和特性并获得了以下发现。 1.用抗CD38单克隆抗体刺激RA分化的HL-60细胞诱导细胞蛋白的快速酪氨酸磷酸化，包括c-cbl原癌基因产物p12O^<c-Cbl>。抗 CD38 mAb 显着增强了对甲酰基 Met-Leu-Phe 反应的超氧化物形成。 Fcgamma-II 受体似乎参与通过抗CD38 mAb 诱导的酪氨酸磷酸化介导的信号转导途径。 2.除了淋巴细胞外，大鼠脑中还大量存在CD38。在大鼠胶质细胞和神经元细胞的原代培养中，星形胶质细胞表面观察到最丰富的 CD38。共聚焦激光显微镜分析表明，免疫反应性 CD38 和酶活性位于星形胶质细胞的细胞表面。向培养的星形胶质细胞添加酶底物后，细胞表面 CD38 迅速失活。 3.发现由两个带有5个核苷酸间隔区的直接重复的TGACCT样六聚体基序组成的RA反应元件(RARE)位于CD38基因的第一个内含子中。该RARE与由RA受体和类维生素A X受体组成的异二聚体相互作用。因此，RA诱导的人CD38基因表达被证明是通过位于第一个内含子的RARE介导的。