Female sex steroid hormonal regulation of cell proliferation and differentiation through the targeting of multiple pathways
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Female sex steroid hormones Estradiol-17beta(E2) and Progesterone (P4) cooperate to regulate cell proliferation and differentiation during the estrous cycle and early pregnancy. Thus the uterus serves as an excellent in vivo model to evaluate female hormone action and cell proliferation. The current study has shown that P4 blocks E2-induced uterine epithelial cell proliferation through PI3K→AKT→GSKbeta→cyclin D1→RB pathway. E2 causes an inhibitory phosphorylation of GSK-3beta at Ser9 through PI3 kinase activation of AKT. The inhibition of PI3 kinase activity by P4 results in the failure to block GSK-3beta activity and the resultant phosphorylation of cyclin D1 at Thr286 that leads to its egress from the nucleus.;To further attempt to identify the molecular mechanism we used analysis of gene expression patterns of the uterine luminal epithelial cells following E2 and P4E2 treatment. Over twenty genes associated with DNA replication were rapidly down regulated by P4. Amongst this group were all six MCM proteins suggesting that replication licensing is another key regulatory point. In depth study shows that P4 completely inhibits replication licensing during the early G1 phase at several levels. First, P4 in combination with E2 significantly reduced MCM transcripts and protein abundance. Secondly, P4 pre-treatment significantly delayed and lowered the E2-induced chromatin binding of MCM proteins. This reduction in chromatin binding paralleled the reduction of Cdt1 but not Cdc6 protein. A third level of P4 regulation was achieved by alterations in cellular localization of MCM proteins.;Gene expression profiling of luminal epithelial cells after E2 and P4E2 treatment also reveals approximately 200 up-regulated genes, which can be classified into 11 functional categories. We also verified several candidate genes whose expression during the peri-implantation period is coincident with the implantation window in epithelial-specific manner but with distinct patterns. The examples include myd88, CD14, ISG20, LRP2 and N-sulfotransferase.;The identification of the novel mechanism of inhibition of cell proliferation in sex steroid hormone responsive tissues may contribute to further the understanding the role of these hormones in cancers of the reproductive system.