In the epithelial compartment of the uterus, estradiol-17β (E2) induces cell proliferation while progesterone (P4) inhibits this response and causes differentiation of the cells. In this study, we identified the mechanism whereby E2 and P4 reciprocally regulate the expression of minichromosome maintenance (MCM)-2, a protein that is an essential component of the hexameric MCM-2 to 7 complex required for DNA synthesis initiation. We show in the uterine epithelium that Kruppel-like transcription (KLF) factors, KLF 4 and 15, are inversely expressed; most importantly, they bind to the Mcm2 promoter under the regulation of E2 and P4E2, respectively. After P4E2 exposure and in contrast to E2 treated mice, the Mcm2 promoter displays increased histone 3 (H3) methylation and the recruitment of histone deacetylase 1 and 3 with the concomitant deacetylation of H3. This increased methylation and decreased acetylation is associated with an inhibition of RNA polymerase II binding, indicating an inactive Mcm2 promoter following P4E2 treatment. Using transient transfection assays in the Ishikawa endometrial cell line, we demonstrate that Mcm2 promoter activity is hormonally stimulated by E2 and that KLF15 inhibits this E2 enhanced transcription. KLF15 expression also blocks Ishikawa cell proliferation through inhibition of MCM2 protein level. Importantly, in vivo expression of KLF15 in an estrogenized uterus mimics P4’s action by inhibiting E2-induced uterine epithelial MCM-2 expression and DNA synthesis. KLF15 is therefore a downstream physiological mediator of progesterone’s cell cycle inhibitory action in the uterine epithelium.
The time required to recover from cold-induced paralysis (chill-coma) is a common measure of insect cold tolerance used to test central questions in thermal biology and predict the effects of climate change on insect populations. The onset of chill-coma in the fall field cricket (Gryllus pe ... mehr
Influenza recurs seasonally in temperate regions of the world; however, our ability to predict the timing, duration, and magnitude of local seasonal outbreaks of influenza remains limited. Here we develop a framework for initializing real-time forecasts of seasonal influenza outbreaks, usin ... mehr
Undifferentiated nasopharyngeal carcinomas (NPCs) are commonly present with latent EBV infection. However, events regulating EBV infection at early stages of the disease and the role of EBV in disease pathogenesis are largely undefined. Genetic alterations leading to activation of cyclin D1 ... mehr