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Glyco-Signals in Regulatory Mechanisms For Proliferation, Differentiation, Senescence And Apoptosis of Hematopoietic Cells.

造血细胞增殖、分化、衰老和凋亡调节机制中的糖信号。

基本信息

批准号：
08457270
负责人：
SAITO Masaki
金额：
$ 4.99万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

During the period from 1996 to 1997, the following new findings were obtained, and most of them were presented in some of the international conferences, and published in the specialized journals : (1) The interaction of the extracellular matrix glycoprotein, fibronectin, with the integrin VLA-5 was shown to be intimately related with the apoptotic phenomena of hematopoietic cells. (2) A significant enhancement of the expression of VLA-5 mRNA was observed only in the monocytic, but not granulocytic, differentiation of human myelogenous leukemia HL-60 cells. (3) The expression of integrin VLA-5 on the cell surface was enhanced exclusively in the process of monocytic differentiation, and the most prominent expression was observed on the surface of peripheral mature monocytes. (4) The sensitivity of fibronectin-induced apoptosis was remarkably increased during monocytic differentiation, and the anti-VLA-5 monoclonal antibody or the RGD peptide completely abolished it. (5) Apoptosis of the … More normal monocytes, but not granulocytes, from peripheral blood was significantly increased by the extracellular matrix fibronectin, and the anti-fibronectin monoclonal antibody suppressed the apoptosis and increased the survival time of normal monocytes. (6) Expression of the extracellular matrix glycoprotein, tenascin, was restricted spatially and temporally during the formation of tumor tissues, depending upon the stromal-epithelial interactions, and the de novo synthesis of tenascins was induced by the soluble growth factor EGF,being also dependent on the stromal-epithelial interactions. Human tenascin C is shown to have the EGF-like domain, but this domain and its derivative peptide could not induce the expression of tenascin. (7) With all the current data taken together, it is concluded that the ECM glycoprotein fibronectin might play an important role as the negative regulator for the survival of monocytes in collaboration with the integrin VLA-5, which characteristically increases during the process of monocytic differentiation.In the latter part of the present research projects, the following novel findings were demonstrated : (8) Using the elaborately-devised expression cloning method, we have succeeded for the first time in isolating and molecularly characterizing a new and relevant gene (cDNA and its genome) which encodes a key glycosyltransferase, ganglioside GM3 synthase (sialyltransferase-1) , responsible for the biosynthesis of a ubiquitous but intriguing membraneous molecule of the simplest structure, ganglioside GM3. GM3 was previously demonstrated to exhibit a variety of biological functions intimately related to the cell growth control, malignant transformations, the cell-to-cell recognitions, and the differentiation-induction of human myelogenousleukemia cells. Less

1996 ~ 1997年期间，在造血细胞凋亡研究中取得了以下新的发现，其中大部分在国际会议上发表，并在专业期刊上发表：（1）细胞外基质糖蛋白纤连蛋白（fibronectin）与整合素VLA-5的相互作用与造血细胞凋亡现象密切相关。(2)VLA-5 mRNA的表达仅在单核细胞分化的HL-60细胞中显著增强，而在粒细胞分化的HL-60细胞中不显著增强。(3)整合素VLA-5在细胞表面的表达仅在单核细胞分化过程中增强，并且在外周成熟单核细胞表面上观察到最突出的表达。(4)在单核细胞分化过程中，FN诱导凋亡的敏感性显著增加，抗VLA-5单克隆抗体或RGD肽可完全消除FN诱导凋亡的敏感性。 ...更多信息来自外周血的正常单核细胞而不是粒细胞被细胞外基质纤连蛋白显著增加，并且抗纤连蛋白单克隆抗体抑制正常单核细胞的凋亡并增加其存活时间。(6)细胞外基质糖蛋白腱生蛋白的表达在肿瘤组织形成期间在空间和时间上受到限制，这取决于基质-上皮的相互作用，并且腱生蛋白的从头合成由可溶性生长因子EGF诱导，也取决于基质-上皮的相互作用。人腱生蛋白C具有EGF样结构域，但该结构域及其衍生肽不能诱导腱生蛋白的表达。(7)综合目前的所有数据，可以得出结论，ECM糖蛋白纤连蛋白可能与整合素VLA-5协同作用，作为单核细胞存活的负调节因子发挥重要作用，整合素VLA-5在单核细胞分化过程中特征性地增加。（8）利用精心设计的表达克隆方法，我们首次成功地分离和分子表征了一个新的相关基因。（cDNA及其基因组），其编码关键糖基转移酶，神经节苷脂GM 3合酶（唾液酸转移酶-1），负责最简单结构的普遍存在但有趣的膜状分子神经节苷脂GM 3的生物合成。GM 3具有多种生物学功能，与细胞生长控制、恶性转化、细胞间分化、人髓性白血病细胞的分化诱导等密切相关。少