Studies on roles of poly (ADP-ribosyl) ation reaction in cell differentiation and programd cell death

聚(ADP-核糖基)化反应在细胞分化和程序性细胞死亡中的作用研究

• 批准号: 05454169
• 负责人: UEDA Kunihiro
• 金额: $ 4.29万
• 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: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454169/
• 关键词: Poly (ADP-ribose); Poly (ADP-ribose) synthetase; Teratocarcinoma EC cells; Induction of cell differentiation; Benzylvesnarinone; Heterocyclic amines; PhIP; Retinoic acid; 阻害剤; 賦活剤; ベスナリノン; テラトカルシノーマ細胞; 分化誘導; アポトーシス

(1) Discovery of poly (ADP-ribose) synthetase inhibitors : From an extensive survey of the synthetase inhibitors among various natural compounds and therapeutic drugs, we found many compounds to exhibit the inhibitory effect to a moderate degree (IC_<50>=1muM-1mM). They include heterocyclic amines produced from amino acids by pyrolysis, and derivatives of coumarine, chromone, phospholipids and vesnarinone (Arkin-Z^<TM>).(2) Induction of cancer cell differentiation by poly (ADP-ribose) inhibitors : Benzylvesnarinone and PhIP,that is an abundant heterocyclic amine in food, were found to induce most efficiently the neuronal differentiation of teratocarcinoma EC cells in culture.(3) Changes in poly (ADP-ribose) metabolism in differentiation-induced cells : Poly (ADP-ribose) synthesis was found to increase transiently at the very early stage (within 1 day) of teratocarcinoma EC cell differentiation induced by all-trans-retrinoic acid.This finding, unlike the current view of monotonous inactivation of poly (ADP-ribose) synthesis, suggested a possible involvement of DNA fragmentation and its regulation by poly (ADP-ribose) in the initiation of cell differentiation.

(1)聚ADP-核糖合成酶抑制剂的发现：通过对各种天然化合物和治疗药物中合成酶抑制剂的广泛调查，我们发现许多化合物表现出中等程度的抑制作用（IC_<50>= 1 μ M-1 mM）。它们包括通过热解由氨基酸产生的杂环胺，以及香豆素、色酮、磷脂和维司力酮（Arkin-Z）的衍生物<TM>。(2)通过聚（ADP-核糖）抑制剂诱导癌细胞分化：发现苄基维司力农和PhIP（其是食物中丰富的杂环胺）最有效地诱导培养的畸胎癌EC细胞的神经元分化。(3)Poly的变化分化诱导的细胞中的（ADP-核糖）代谢：聚（ADP-核糖）合成被发现在非常早期的阶段瞬时增加这一发现与目前认为的多聚维甲酸的单调失活不同，（ADP-核糖）的合成，提出了一个可能参与的DNA片段化和它的调节聚（ADP-核糖）在细胞分化的起始。

项目成果

Banasik,M.: "Activators and inhibitors of ADP-ribosylation reactions" Mol.Cell.Biochem.(in press).

Banasik,M.：“ADP-核糖基化反应的激活剂和抑制剂”Mol.Cell.Biochem.（出版中）。

Kawamata,J.: "Leu^<106>→Val(CTC→GTC)mutation of superoxide dismutase-1 gene in patient with familial amyotrophic lateral sclerosi in Japan" Lancet. 343. 1501- (1994)

Kawamata, J.：“日本家族性肌萎缩侧索硬化症患者超氧化物歧化酶 1 基因的 Leu^<106>→Val(CTC→GTC) 突变”Lancet 343. 1501- (1994)。

Kido, T.: "Ligand Western blotting for specific detection of active form of protease." Clin.Chim.Acta.(in press).

Kido, T.：“用于特异性检测活性蛋白酶形式的配体蛋白质印迹。”

Banasik,M.: "Dual inhibitory effects of dimethyl sulfoxide on poly(ADP-ribose)synthetase" J.Enz.Inhib.(in press). (1995)

Banasik,M.：“二甲基亚砜对聚（ADP-核糖）合成酶的双重抑制作用”J.Enz.Inhib.（出版中）。

上田國寛: "最新内科学大系 第4巻" 中山書店, 401 (1994)

上田国宏：《最新内科系统第4卷》中山书店，401（1994）