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

1.聚乙烯的发现（ADP-核糖）合成酶（PARS）抑制剂：我们发现在常用溶剂二甲基亚砜、强心药维司力酮和蛋白质热解产物Trp-P-1和PhIP中抑制PARS活性的弱至中等效力。2. PARS在癌细胞分化中的功能分析：我们成功地用维司力农或PhIP诱导畸胎癌EC细胞分化。我们还发现，在用全反式维甲酸诱导分化的EC细胞中，聚（ADP-核糖）合成短暂增加，然后显著减少，这些变化受PARS的自修饰和随后的有限蛋白水解的影响。3. PARS在细胞生死程序中的作用的阐明：我们发现，在通过暴露于高剂量的放射性同位素如2S或2 P诱导白血病T细胞凋亡时<35><32>，PARS被磷酸化，然后被蛋白酶caspase-3快速切割，这种切割发生在二分核定位信号之间，导致PARS的二分核丢失。我们确定DNA依赖性蛋白激酶是负责PARS磷酸化的酶。（ADP-核糖）在神经变性过程中的变化;我们发现了一个戏剧性的变化，刺激或减少，在阿尔茨海默氏淀粉样蛋白A β肽诱导的PC-12细胞变性过程中，PARS活性呈剂量和时间依赖性。局灶性脑缺血后的聚腺苷二磷酸核糖反应：我们发现在受人工脑缺血影响的脑区和随后的周围区域（半暗带），聚腺苷二磷酸核糖的合成显著增加。这些发现表明PARS在细胞的基本功能中起着重要作用，特别是在DNA损伤后决定细胞的命运，即存活还是死亡。

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.