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年至1997年期间，获得了以下新发现，其中大部分在一些国际会议上发表，并发表在专业期刊上：（1）细胞外基质糖蛋白纤连蛋白与细胞外基质糖蛋白的相互作用整合素VLA-5被证明与造血细胞的凋亡现象密切相关(2)仅在造血细胞中观察到VLA-5 mRNA的表达显着增强。人粒细胞白血病HL-60细胞向单核细胞分化，但不向粒细胞分化。 (3)细胞表面整合素VLA-5的表达仅在单核细胞分化过程中增强，且在表面表达最为突出。 (4)单核细胞分化过程中纤连蛋白诱导的细胞凋亡的敏感性显着增加，并且抗VLA-5单克隆抗体或RGD肽完全。 (5) 细胞外基质纤连蛋白显着增加外周血中正常单核细胞的凋亡，但抗纤连蛋白单克隆抗体可抑制细胞凋亡并延长正常单核细胞的存活时间 6。 ) 细胞外基质糖蛋白、生腱蛋白的表达在肿瘤组织形成过程中在空间和时间上受到限制，具体取决于基质-上皮相互作用和 de生腱蛋白的新合成是由可溶性生长因子EGF诱导的，也依赖于基质-上皮相互作用，人生腱蛋白C具有EGF样结构域，但该结构域及其衍生肽不能诱导生腱蛋白的表达。 (7)综合当前所有数据，得出结论：ECM糖蛋白纤连蛋白可能与整合素协同作用，作为单核细胞存活的负调节因子发挥重要作用。 VLA-5，在单核细胞分化过程中特征性增加。在本研究项目的后半部分，展示了以下新发现：（8）使用精心设计的表达克隆方法，我们首次获得成功分离和分子表征一个新的相关基因（cDNA 及其基因组），该基因编码关键的糖基转移酶、神经节苷脂 GM3 合酶（唾液酸转移酶-1），负责神经节苷脂 GM3 是一种普遍存在但结构最简单的膜分子，此前已被证明具有与细胞生长控制、恶性转化、细胞间识别和分化密切相关的多种生物学功能。诱导人骨髓性白血病细胞较少。