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Studies on the Role of Poly (ADP-ribosyl) Action in Cell Differentiation and Oncogenesis

聚（ADP-核糖基）作用在细胞分化和肿瘤发生中作用的研究

基本信息

批准号：
01480146
负责人：
UEDA Kunihiro
金额：
$ 4.22万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

项目摘要

1. Cloning of cDNA coding for poly (ADP-ribose) synthetase : A complete amino acid sequence of bovine poly (ADP-ribose) synthetase was determined by cDNA cloning. A comparison of the sequence with those of human and mouse enzymes revealed that various structural units (e. g., Zn-binding fingers) important to enzymatic functions such as DNA-binding, automodification, and NAD-binding have been almost completely conserved throughout evolution. For the use of homology analysis at levels of regions or domains, we invented a new plot termed "homology profile".2. Discovery of specific inhibitors of poly (ADP-ribosyl) action : From among 300 compounds tested, we found a number of potent inhibitors of poly (ADP-ribose) synthetase, including 1,8-naphthalimide, 6 (5H) -phenanthridinone, 1-hydroxyisoquinoline, their derivatives, and 4-hydroxyquinazoline ; theywee more potent and specific than known inhibitors such as nicotinamide and benzamide derivatives. We also found that vitamin K as well as novobiocin was much more specific for mono- than poly (ADP-ribosyl) action.3. Induction of tumor cell differentiation : We succeeded in inducing differentiation of teratocarcinoma cells in culture by administrating our new inhibitors of poly (ADP-ribosyl) ation, such as 4-hydroxyquinazoline and arachidonic acid.

1.聚（ADP-核糖）合成酶cDNA的克隆：通过cDNA克隆确定了牛聚（ADP-核糖）合成酶的完整氨基酸序列。将该序列与人类和小鼠酶的序列进行比较，发现各种结构单元（例如，例如，在一个实施例中，锌结合指）重要的酶功能，如DNA结合，自修饰，NAD结合几乎完全保守的整个进化。为了在区域或结构域水平上进行同源性分析，我们发明了一种新的称为“同源性谱”的图。聚（ADP-核糖）作用的特异性抑制剂的发现：从测试的300种化合物中，我们发现了许多聚（ADP-核糖）合成酶的有效抑制剂，包括1，8-萘二甲酰亚胺、6（5 H）-菲啶酮、1-羟基异喹啉、它们的衍生物和4-羟基喹唑啉;它们比已知的抑制剂如烟酰胺和苯甲酰胺衍生物更有效和特异。我们还发现，维生素K以及新生霉素对单聚（ADP-核糖基）作用的特异性要高得多。肿瘤细胞分化的诱导：我们成功地诱导分化的畸胎瘤细胞培养物中的聚（ADP-核糖基）化，如4-羟基喹唑啉和花生四烯酸我们的新抑制剂。