Proliferating cell nuclear antigen (PCNA), a processivity factor of DNA synthesis, has often been used as a marker that reveals proliferating cells. However, it also plays a role other than in DNA replication. The aim of this study was to examine the relationship between the expression of PCNA and cell proliferation, and also its relation to cell death in the uterine epithelium under various hormonal conditions. Rats with regular estrous cycles were killed at various stages of the cycle, and their uteri were removed for the detection of PCNA and apoptosis by immunohistochemical and terminal deoxynucleotidyl transferase-mediated nick end-label staining respectively. There was an inverse relationship between the expression of PCNA and apoptosis in the uterine epithelium during the estrous cycle. From diestrus to proestrus, the expression of PCNA increased, and few apoptotic cells were detected in the luminal epithelium. However, at estrus, apoptosis occurred markedly, and the expression of PCNA disappeared. To study further the effects of estrogen on PCNA expression and cell growth in the uterus, rats were ovariectomized and then implanted s.c. with estrogen capsules 2 weeks later. In ovariectomized rats, only a few PCNA-positive cells were observed in the uterine epithelium. After estrogen treatment, PCNA was expressed strongly in the luminal and glandular epithelia. In these rats, the removal of estrogen capsules resulted in apoptotic death and surprisingly strong PCNA expression in the cells of luminal epithelium. Our results demonstrate that PCNA is expressed not only in the estrogen-stimulated uterine growth, but also in the processes of regression induced by the withdrawal of estrogen. Although the expression of PCNA has been reported to represent cell proliferation, our results implicate functions other than cell replication for PCNA in the uterus.

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