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KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

Sanhita Ray1, Jeffrey W Pollard

  • 1Department of Developmental and Molecular Biology, Specialized Cooperative Center for the Study of Reproduction and Infertility Research, Albert Einstein College of Medicine, NY 10461, USA.

Proceedings of the National Academy of Sciences of the United States of America
|April 28, 2012
PubMed

Insights

Progesterone (P4) inhibits uterine cell proliferation by regulating MCM2 expression via KLF15. This transcription factor mediates progesterone

Area of Science:

  • Reproductive Biology
  • Molecular Endocrinology
  • Cell Cycle Regulation

Background:

  • Estradiol (E2) stimulates uterine epithelial cell proliferation, while progesterone (P4) inhibits it and promotes differentiation.
  • Minichromosome maintenance complex (MCM-2) is crucial for DNA synthesis initiation and cell cycle progression.

Purpose of the Study:

  • To elucidate the molecular mechanism by which estradiol (E2) and progesterone (P4) reciprocally regulate MCM-2 expression in the uterine epithelium.
  • To identify the role of Kruppel-like transcription factors (KLFs) in mediating these hormonal effects on uterine cell proliferation and MCM-2 regulation.

Main Methods:

  • Analysis of KLF4 and KLF15 expression in the uterine epithelium.
  • Chromatin immunoprecipitation assays to assess histone modifications (methylation, acetylation) and RNA polymerase II binding at the Mcm2 promoter.
  • Transient transfection assays in Ishikawa endometrial cells to evaluate Mcm2 promoter activity and KLF15's effect.
  • In vivo studies using KLF15 expression in estrogenized mouse uteri.

Main Results:

  • KLF4 and KLF15 are inversely expressed in the uterine epithelium, regulated by E2 and P4 respectively.
  • P4 treatment leads to increased H3 methylation and decreased H3 acetylation at the Mcm2 promoter, inhibiting RNA polymerase II binding and MCM-2 expression.
  • KLF15 directly inhibits E2-stimulated Mcm2 promoter activity and MCM-2 protein levels in endometrial cells, thereby blocking cell proliferation.
  • In vivo KLF15 expression mimics P4's inhibitory action on E2-induced uterine epithelial MCM-2 expression and DNA synthesis.

Conclusions:

  • KLF15 is a key downstream mediator of progesterone's antiproliferative effects in the uterine epithelium.
  • Hormonal regulation of MCM-2 expression by E2 and P4 involves reciprocal control of KLF factors and epigenetic modifications at the Mcm2 promoter.
  • Understanding this mechanism provides insights into the hormonal control of uterine cell cycle and potential therapeutic targets for uterine disorders.

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