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Activation Of A Ca2+−Mg2+‐dependent Endonuclease As An Early Event In Castration‐induced Prostatic Cell Death
Published 1988 · Biology, Medicine
Previous studies have demonstrated that castration‐induced androgen withdrawal results in the fragmentation of prostatic DNA into nucleosomal oligomers, and this process comprises an early event in the activation of programed cell death in the rat ventral prostate. This DNA fragmentation could be due to changes in the chromatin conformation increasing its sensitivity to preexisting nucleases and/or to increases in the activity of the nucleases themselves. However, comparative kinetic analysis of in vitro DNA fragmentation induced by exogenous nucleases did not reveal any differences in the sensitivity of prostatic chromatin between intact and castrated rats. In contrast to these negative findings, using [3H] DNA as an exogenous substrate, it was shown that within the first day following castration there was a twofold increase in a Ca2+‐Mg2+‐dependent nuclease activity without a concomitant increase in other nuclear nucleases. This Ca2+‐M2+‐dependent nuclease activation occurred coincidental with the initial increase in nuclear DNA fragmentation following castration and preceded the enhanced appearance of morphological changes characteristic of dying cells (i.e., apoptosis), as well as the major increase in prostatic DNA loss. These results suggest that castration‐induced androgen deprivation leads to a sequential activation of a Ca2+‐Mg2+‐dependent nuclease leading to the fragmentation of the genome into discrete nucleosomal‐sized fragments of DNA, subsequently followed by the fragmentation of the nucleus itself (i.e., apoptosis) and eventually with the complete digestion of the nucleosomal oligomers into component nucleotides (i.e., DNA loss).