Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486

Eric M. Small, Jason R. O'Rourke, Viviana Moresi, Lillian B. Sutherland, John McAnally, Robert D. Gerard, James A. Richardson, Eric N. Olson

Research output: Contribution to journalArticle

230 Citations (Scopus)

Abstract

microRNAs (miRNAs) play key roles in modulating a variety of cellular processes through repression of mRNA targets. In a screen for miRNAs regulated by myocardin-related transcription factor-A (MRTF-A), a coactivator of serum response factor (SRF), we discovered a muscle-enriched miRNA, miR-486, controlled by an alternative promoter within intron 40 of the Ankyrin-1 gene. Transcription of miR-486 is directly controlled by SRF and MRTF-A, as well as by MyoD. Among the most strongly predicted targets of miR-486 are phosphatase and tensin homolog (PTEN) and Foxo1a, which negatively affect phosphoinositide-3- kinase (PI3K)/Akt signaling. Accordingly, PTEN and Foxo1a protein levels are reduced by miR-486 overexpression,which, in turn, enhances PI3K/Akt signaling. Similarly, we show that MRTF-A promotes PI3K/Akt signaling by up-regulating miR-486 expression. Conversely, inhibition of miR-486 expression enhances the expression of PTEN and Foxo1a and dampens signaling through the PI3K/Akt-signaling pathway. Our findings implicate miR-486 as a downstream mediator of the actions of SRF/MRTF-A and MyoD in muscle cells and as a potential modulator of PI3K/Akt signaling.

Original languageEnglish (US)
Pages (from-to)4218-4223
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number9
DOIs
StatePublished - Mar 2 2010

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1-Phosphatidylinositol 4-Kinase
MicroRNAs
Phosphatidylinositol 3-Kinases
Serum Response Factor
Transcription Factors
Muscles
Phosphoric Monoester Hydrolases
Ankyrins
Introns
Muscle Cells
Messenger RNA
myocardin
Genes
Tensins
Proteins

Keywords

  • Akt signaling
  • Cardiomyocyte
  • MicroRNA
  • Muscle growth
  • Myocardin related transcription factor-A

ASJC Scopus subject areas

  • General

Cite this

Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. / Small, Eric M.; O'Rourke, Jason R.; Moresi, Viviana; Sutherland, Lillian B.; McAnally, John; Gerard, Robert D.; Richardson, James A.; Olson, Eric N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 9, 02.03.2010, p. 4218-4223.

Research output: Contribution to journalArticle

Small, Eric M. ; O'Rourke, Jason R. ; Moresi, Viviana ; Sutherland, Lillian B. ; McAnally, John ; Gerard, Robert D. ; Richardson, James A. ; Olson, Eric N. / Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 9. pp. 4218-4223.
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