权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ROLES OF POLY (ADP-RIBOSE) IN CARCINOGENESIS,CELL DIFFERENTIATION AND PROGRAMMED CELLDEATH

聚（ADP-核糖）在致癌、细胞分化和程序性细胞死亡中的作用

基本信息

批准号：
08458195
负责人：
UEDA Kunihiro
金额：
$ 4.86万
依托单位：
KYOTO 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

1.Discovery of poly (ADP-ribose) synthetase (PARS) inhibitors : We found a weak to intermediary potency to inhibit the PARS activity in a popular solvent, dimethylsulfoxide, a cardiotonic drug, vesnarinone, and pyrolysis products of protein, Trp-P-1 and PhIP.2.Analysis of PARS functions in cancer cell differentiation : We succeeded in inducing teratocarcinoma EC cell differentiation with vesnarinone or PhIP.We found also that, in the EC cells induced to differentiate by all-trans-retinoic acid, poly (ADP-ribose) synthesis increases transiently and then decreases markedly, and that these changes are effected by automodification and subsequent limited proteolysis of PARS.3.Elucidation of PARS roles in the cell life-deathprogram : We found that, upon induction of apoptosis of leukemic T-cells by exposure to a high-dose of radioisotopes such as ^<35>S or ^<32>P,PARS is phosphorylated and then rapidly cleaved by a protease, caspase-3, and that this cleavageoccurring in-between the bipartite nuclear localization signal leads to an extranuclearloss of PARS.We identified DNA-dependentprotein kinase as the enzyme responsible for the PARS phosphorylation.4.Analysis of poly (ADP-ribose) change during neurodegeneration ; We found a dramatic change, stimuation or reduction, in the PARS activity in PC-12 cells induced to degenerateby Alzheimer's amyloid Abeta peptide dose-and time-dependently.5.Discovery of poly (ADP-ribose) response after focal ischemia in brain : We found a marked increase of poly (ADP-ribose) synthesis in rat brain regions affectedby artificialischemia and later in the surrounding area (penumbra)., which conincided with the occurrence of delayd neuronal death.These findings, taken together, indicate a central role of PARS in the basic cell fubctions, in particular, determination of the fate, survival versus death, of the cell after DNA damage.

1.聚（ADP-核糖）合成酶（PARS）抑制剂的发现：我们在常用溶剂二甲亚砜、强心药维纳里酮以及蛋白质热解产物Trp-P-1和PhIP中发现了弱到中等的抑制PARS活性的能力。2.PARS在癌细胞分化中的功能分析：我们成功诱导用维纳里酮或 PhIP 诱导畸胎癌 EC 细胞分化。我们还发现，在全反式视黄酸诱导分化的 EC 细胞中，聚（ADP-核糖）合成短暂增加，然后显着减少，并且这些变化受到 PARS 的自动修饰和随后的有限蛋白水解的影响。3.阐明 PARS 在细胞生死程序中的作用：我们发现暴露于高剂量放射性同位素如^ 35 S或^ 32 P诱导白血病T细胞凋亡后，PARS被磷酸化，然后被蛋白酶caspase-3快速裂解，并且这种发生在二分核定位信号之间的裂解导致PARS的核外丢失。 DNA依赖性蛋白激酶作为负责PARS磷酸化的酶。4.神经变性过程中聚(ADP-核糖)变化的分析；我们发现，在阿尔茨海默病淀粉样蛋白 Abeta 肽诱导退化的 PC-12 细胞中，PARS 活性发生了显着的变化、刺激或降低，且呈剂量和时间依赖性。 5. 脑局灶性缺血后多聚 (ADP-核糖) 反应的发现：我们发现，在受人工缺血影响的大鼠脑区以及后来的大鼠脑区中，多聚 (ADP-核糖) 合成显着增加。这些发现综合起来表明 PARS 在基本细胞功能中的核心作用，特别是在 DNA 损伤后细胞的命运、生存与死亡的决定中。