A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration

J Clin Invest. 2012 Mar;122(3):1097-108. doi: 10.1172/JCI46039. Epub 2012 Feb 13.

Abstract

MicroRNA-21 (miR-21) is thought to be an oncomir because it promotes cancer cell proliferation, migration, and survival. miR-21 is also expressed in normal cells, but its physiological role is poorly understood. Recently, it has been found that miR-21 expression is rapidly induced in rodent hepatocytes during liver regeneration after two-thirds partial hepatectomy (2/3 PH). Here, we investigated the function of miR-21 in regenerating mouse hepatocytes by inhibiting it with an antisense oligonucleotide. To maintain normal hepatocyte viability and function, we antagonized the miR-21 surge induced by 2/3 PH while preserving baseline expression. We found that knockdown of miR-21 impaired progression of hepatocytes into S phase of the cell cycle, mainly through a decrease in levels of cyclin D1 protein, but not Ccnd1 mRNA. Mechanistically, we discovered that increased miR-21 expression facilitated cyclin D1 translation in the early phase of liver regeneration by relieving Akt1/mTOR complex 1 signaling (and thus eIF-4F-mediated translation initiation) from suppression by Rhob. Our findings reveal that miR-21 enables rapid hepatocyte proliferation during liver regeneration by accelerating cyclin D1 translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Division
  • Cyclin D1 / biosynthesis*
  • Cytoplasm / metabolism
  • Gene Expression Regulation*
  • Hepatocytes / cytology
  • Liver / metabolism*
  • Liver Regeneration
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / biosynthesis*
  • RNA, Messenger / metabolism
  • rhoB GTP-Binding Protein / metabolism

Substances

  • MIRN21 microRNA, mouse
  • MicroRNAs
  • RNA, Messenger
  • Cyclin D1
  • rhoB GTP-Binding Protein