miR-22 forms a regulatory loop in PTEN/AKT pathway and modulates signaling kinetics

PLoS One. 2010 May 27;5(5):e10859. doi: 10.1371/journal.pone.0010859.

Abstract

Background: The tumor suppressor PTEN (phosphatase and tensin homolog) is a lipid phosphatase that converts PIP3 into PIP2 and downregulates the kinase AKT and its proliferative and anti-apoptotic activities. The FoxO transcription factors are PTEN downstream effectors whose activity is negatively regulated by AKT-mediated phosphorylation. PTEN activity is frequently lost in many types of cancer, leading to increased cell survival and cell cycle progression.

Principal findings: Here we characterize the widely expressed miR-22 and report that miR-22 is a novel regulatory molecule in the PTEN/AKT pathway. miR-22 downregulates PTEN levels acting directly through a specific site on PTEN 3'UTR. Interestingly, miR-22 itself is upregulated by AKT, suggesting that miR-22 forms a feed-forward circuit in this pathway. Time-resolved live imaging of AKT-dependent FoxO1 phosphorylation revealed that miR-22 accelerated AKT activity upon growth factor stimulation, and attenuated its down regulation by serum withdrawal.

Conclusions: Our results suggest that miR-22 acts to fine-tune the dynamics of PTEN/AKT/FoxO1 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Base Sequence
  • Cell Line
  • Conserved Sequence / genetics
  • Down-Regulation / genetics
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Humans
  • Kinetics
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Biological
  • Molecular Sequence Data
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Polymerase II / metabolism
  • Signal Transduction*
  • TATA Box / genetics
  • Transcription, Genetic

Substances

  • 3' Untranslated Regions
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • MIRN22 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-akt
  • RNA Polymerase II
  • PTEN Phosphohydrolase
  • PTEN protein, human