The microRNA 424/503 cluster reduces CDC25A expression during cell cycle arrest imposed by transforming growth factor β in mammary epithelial cells

Mol Cell Biol. 2014 Dec 1;34(23):4216-31. doi: 10.1128/MCB.00611-14. Epub 2014 Sep 29.

Abstract

Recently, we demonstrated that the microRNA 424(322)/503 [miR-424(322)/503] cluster is transcriptionally controlled by transforming growth factor β (TGF-β) in the mammary epithelium. Induction of this microRNA cluster impacts mammary epithelium fate by regulating apoptosis and insulin-like growth factor 1 (IGF1) signaling. Here, we expanded our finding to demonstrate that miR-424(322)/503 is an integral component of the cell cycle arrest mediated by TGF-β. Mechanistically, we showed that after TGF-β exposure, increased levels of miR-424(322)/503 reduce the expression of the cell cycle regulator CDC25A. miR-424(322)/503-dependent posttranscriptional downregulation of CDC25A cooperates with previously described transcriptional repression of the CDC25A promoter and proteasome-mediated degradation to reduce the levels of CDC25A expression and to induce cell cycle arrest. We also provide evidence that the TGF-β/miR-424(322)/503 axis is part of the mechanism that regulates the proliferation of hormone receptor-positive (HR(+)) mammary epithelial cells in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Line
  • Cell Proliferation / genetics
  • Down-Regulation
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Female
  • G1 Phase Cell Cycle Checkpoints / genetics
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / growth & development*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Promoter Regions, Genetic
  • Pyrazoles / pharmacology
  • Pyrroles / pharmacology
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism*
  • cdc25 Phosphatases / biosynthesis*
  • cdc25 Phosphatases / genetics

Substances

  • IGF1 protein, human
  • LY2109761
  • MIRN424 microrna, human
  • MIRN503 microRNA, human
  • MicroRNAs
  • Pyrazoles
  • Pyrroles
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Transforming Growth Factor beta
  • Insulin-Like Growth Factor I
  • CDC25A protein, human
  • cdc25 Phosphatases