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

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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.