Fig. P1.

The molecular basis for inhibition of uterine epithelial cell proliferation by progesterone. In the uterine epithelium, estradiol-17β (E₂) stimulates DNA synthesis (S-phase of the cell cycle). In contrast, DNA synthesis is inhibited by progesterone (P₄). In the cell type depicted, P₄E₂ increases the synthesis of the transcription factor KLF15, which binds to the Mcm2 promoter at its binding motif. This binding recruits histone deacetylases (HDAC) that deacetylate core histone 3. Similarly the binding results in an increase in Histone 3 bi-methylation. These histone modifications prevent RNA polymerase II from binding to the transcription start site (TSS), indicated by the large arrow. Therefore, MCM2 expression that is under the regulation of E₂ is inhibited. MCM2 in a complex with its other five MCM partners must bind to the origin of DNA replication for DNA synthesis to begin. Thus, the inhibition of Mcm2 expression by P₄ blocks entry into S-phase, the time when DNA is synthesized, in the G1 phase of the cell cycle.