期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 38, 页码 14021-14026出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0601271103
关键词
DNA replication; minichromosome maintenance; uterus; cell cycle; microarray
资金
- NCI NIH HHS [R01 CA9617, P30 CA013330, R01 CA089617, P30 CA13330] Funding Source: Medline
In the uterus, progesterone (P-4) acts early in G, as a physiological inhibitor of estradiol-17 beta (E-2)-induced epithelial cell proliferation. Gene expression profiling of uterine epithelial cell RNA isolated 3 h after hormonal treatment of ovariectomized mice revealed the co-coordinate down-regulation by P-4 of > 20 genes whose functions are associated with DNA replication. This group included all of the minichromosome maintenance (MCM) proteins that are required for DNA replication licensing. E-2 regulated loading of these MCM proteins onto chromatin in parallel with its induction of DNA synthesis. E-2 caused this chromatin loading by retention of MCM proteins in the nucleus and through the induction of the loading factor Cdt1, which is necessary for the MCM heterohexamer to bind to the origin of DNA replication. P-4 dramatically reduced the binding of the MCMs to chromatin by a number of mechanisms. First, MCM mRNA and protein abundance was down-regulated. Second, P-4 inhibited the E-2 induction of Cdt1. Third, P-4 treatment sequestered the normally nuclear MCM proteins into the cytoplasm. This reduced MCM binding resulted in the complete inhibition of E-2-induced DNA synthesis by P-4. These data reveal mechanisms not only for female sex steroid hormone action but also in the regulation of DNA replication licensing.
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