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MiRNA-27a controls FBW7/hCDC4-dependent cyclin E degradation and cell cycle progression

Mikael Lerner1, Josefin Lundgren, Shahab Akhoondi

  • 1Department of Oncology-Pathology; Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.

Cell Cycle (Georgetown, Tex.)
|May 21, 2011
PubMed

Insights

MicroRNA-27a suppresses the tumor suppressor FBW7, impacting cell cycle progression and cyclin E degradation. This microRNA regulation is implicated in pediatric B-ALL cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Cycle Regulation

Background:

  • FBW7 (F-box protein 7) is a crucial tumor suppressor.
  • It functions in an SCF ubiquitin ligase complex, degrading oncoproteins.
  • Regulation of FBW7 by microRNAs is largely unexplored.

Purpose of the Study:

  • To investigate microRNA regulation of FBW7.
  • To identify specific microRNAs targeting FBW7.
  • To understand the functional consequences of FBW7 microRNA regulation in cell cycle and cancer.

Main Methods:

  • Bioinformatic analysis and microRNA screening.
  • Luciferase reporter assays to validate microRNA targets.
  • Western blotting for protein levels and ubiquitylation assays.
  • Cell cycle analysis and DNA replication stress assays.
  • Analysis of microRNA and FBW7 expression in pediatric B-ALL patient samples.

Main Results:

  • MicroRNA-27a (miR-27a) was identified as a key suppressor of FBW7.
  • miR-27a inhibits FBW7-mediated ubiquitylation and degradation of cyclin E.
  • miR-27a's suppression of FBW7 is cell-cycle-dependent, with relief at the G1/S transition.
  • Overexpression of miR-27a leads to cell cycle defects and DNA replication stress.
  • miR-27a is overexpressed in pediatric B-ALL, inversely correlating with FBW7 in hyperdiploid cases.

Conclusions:

  • MicroRNA-27a plays a significant role in regulating FBW7 activity.
  • This regulation fine-tunes cell cycle progression, particularly cyclin E turnover.
  • Dysregulation of the miR-27a/FBW7 axis contributes to pediatric B-ALL pathogenesis.

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