miR-22 Forms a Regulatory Loop in PTEN/AKT Pathway and Modulates Signaling Kinetics

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 year

  2010

• Venue

  PLoS ONE

• Publication date

  2010-05-27

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0010859PMID 20523723PMCID 2877705
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Many roads to maturity: microRNA biogenesis pathways and their regulation

  2009cited by this paper
• Origins and Mechanisms of miRNAs and siRNAs.

  2009cited by this paper
• TGF-β activates Akt kinase via a microRNA-dependent amplifying circuit targeting PTEN

  2009cited by this paper
• The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo.

  2009cited by this paper
• miR-22 Inhibits Estrogen Signaling by Directly Targeting the Estrogen Receptor α mRNA

  2009cited by this paper
• Chromatin structure analyses identify miRNA promoters.

  2008cited by this paper
• The impact of microRNAs on protein output

  2008cited by this paper
• MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN.

  2008cited by this paper
• A Translation Initiation Element Specific to mRNAs with Very Short 5′UTR that Also Regulates Transcription

  2008cited by this paper
• Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes

  2008cited by this paper
• Chromatin structure analyses identify miRNA promoters

  2008influential reference
• MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer.

  2007cited by this paper
• Lentivirus-mediated antagomir expression for specific inhibition of miRNA function

  2007cited by this paper
• MicroRNA targeting specificity in mammals: determinants beyond seed pairing.

  2007cited by this paper
• Differential Regulation of NF-κB by Elongation Factors Is Determined by Core Promoter Type

  2007cited by this paper
• A mammalian microRNA expression atlas based on small RNA library sequencing.

  2007cited by this paper
• Control of translation and mRNA degradation by miRNAs and siRNAs.

  2006cited by this paper
• RNA polymerase III transcribes human microRNAs

  2006influential reference
• Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.

  2005cited by this paper
• Principles of MicroRNA–Target Recognition

  2005cited by this paper
• FOXO transcription factors at the interface between longevity and tumor suppression

  2005cited by this paper
• The Widespread Impact of Mammalian MicroRNAs on mRNA Repression and Evolution

  2005cited by this paper
• Combinatorial microRNA target predictions

  2005cited by this paper
• Principles of MicroRNATarget Recognition

  2005cited by this paper
• Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs

  2005cited by this paper
• Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation.

  2005cited by this paper
• Human MicroRNA Targets

  2004cited by this paper
• Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs.

  2004cited by this paper
• MicroRNA genes are transcribed by RNA polymerase II

  2004cited by this paper
• Elongation Inhibition by DRB Sensitivity-Inducing Factor Is Regulated by the A20 Promoter via a Novel Negative Element and NF-κB

  2004cited by this paper
• Promoter analysis of tumor suppressor gene PTEN: identification of minimum promoter region.

  2002cited by this paper
• The multiple roles of PTEN in tumor suppression.

  2000cited by this paper
• New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway.

  1999cited by this paper

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