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

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.

[1]  John McAnally,et al.  MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. , 2009, Genes & development.

[2]  P. Tam.  Faculty Opinions recommendation of miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. , 2009 .

[3]  Reuven Agami,et al.  The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. , 2009, Genes & development.

[4]  A. Russell,et al.  Regulation of STARS and its downstream targets suggest a novel pathway involved in human skeletal muscle hypertrophy and atrophy , 2009, The Journal of physiology.

[5]  G. Nuovo,et al.  MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. , 2009, Cardiovascular research.

[6]  J. Rossi,et al.  TGF-β activates Akt kinase via a microRNA-dependent amplifying circuit targeting PTEN , 2009, Nature Cell Biology.

[7]  D. Srivastava,et al.  MicroRNA regulation of cardiovascular development. , 2009, Circulation research.

[8]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[9]  Jin-Wu Nam,et al.  miR-29 miRNAs activate p53 by targeting p85α and CDC42 , 2009, Nature Structural &Molecular Biology.

[10]  E. Olson,et al.  microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. , 2008, Genes & development.

[11]  D. Srivastava,et al.  Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart , 2008, Proceedings of the National Academy of Sciences.

[12]  G. Condorelli,et al.  MicroRNAs: components of an integrated system controlling cardiac development, physiology, and disease pathogenesis. , 2008, Cardiovascular research.

[13]  Ru-Fang Yeh,et al.  miR-126 regulates angiogenic signaling and vascular integrity. , 2008, Developmental cell.

[14]  H. Akima,et al.  Age-related reductions in expression of serum response factor and myocardin-related transcription factor A in mouse skeletal muscles. , 2008, Biochimica et biophysica acta.

[15]  Isaac S. Kohane,et al.  Distinctive patterns of microRNA expression in primary muscular disorders , 2007, Proceedings of the National Academy of Sciences.

[16]  E. Olson,et al.  MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets. , 2007, The Journal of clinical investigation.

[17]  Chunxiang Zhang,et al.  MicroRNA Expression Signature and Antisense-Mediated Depletion Reveal an Essential Role of MicroRNA in Vascular Neointimal Lesion Formation , 2007, Circulation research.

[18]  E. Olson,et al.  Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity. , 2007, The Journal of clinical investigation.

[19]  Michael T. McManus,et al.  Dysregulation of Cardiogenesis, Cardiac Conduction, and Cell Cycle in Mice Lacking miRNA-1-2 , 2007, Cell.

[20]  E. Creemers,et al.  The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. , 2006, Genes & development.

[21]  E. Olson,et al.  Signaling pathways in skeletal muscle remodeling. , 2006, Annual review of biochemistry.

[22]  Jian-Fu Chen,et al.  The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation , 2006, Nature Genetics.

[23]  Yong Zhao,et al.  Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis , 2005, Nature.

[24]  E. Olson,et al.  Muscle-Specific Signaling Mechanism That Links Actin Dynamics to Serum Response Factor , 2005, Molecular and Cellular Biology.

[25]  A. Nordheim,et al.  Requirement for serum response factor for skeletal muscle growth and maturation revealed by tissue-specific gene deletion in mice. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. V. van Rossum,et al.  Association of small ankyrin 1 with the sarcoplasmic reticulum , 2005, Molecular membrane biology.

[27]  G. Yancopoulos,et al.  Conditional Activation of Akt in Adult Skeletal Muscle Induces Rapid Hypertrophy , 2004, Molecular and Cellular Biology.

[28]  G. Yancopoulos,et al.  The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. , 2004, Molecular cell.

[29]  Marco Sandri,et al.  Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy , 2004, Cell.

[30]  Michael D. Schneider,et al.  Sizing up the heart: development redux in disease. , 2003, Genes & development.

[31]  R. Treisman,et al.  Actin Dynamics Control SRF Activity by Regulation of Its Coactivator MAL , 2003, Cell.

[32]  C. Kahn,et al.  Regulation of Myocardial Contractility and Cell Size by Distinct PI3K-PTEN Signaling Pathways , 2002, Cell.

[33]  E. Olson,et al.  Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  E. Olson,et al.  Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Antonio Musarò,et al.  Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle , 2001, Nature Genetics.

[36]  D. Srivastava,et al.  A GATA-dependent right ventricular enhancer controls dHAND transcription in the developing heart. , 2000, Development.

[37]  B. Forget,et al.  The human ankyrin-1 gene is selectively transcribed in erythroid cell lines despite the presence of a housekeeping-like promoter. , 2000, Blood.

[38]  D. Srivastava,et al.  HRT1, HRT2, and HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic, and pharyngeal arch segments. , 1999, Developmental biology.

[39]  E. Olson,et al.  Transcriptional activity of MEF 2 during mouse embryogenesis monitored with a MEF 2-dependent transgene , 1999 .

[40]  J. J. Sharp,et al.  An alternative first exon in the distal end of the erythroid ankyrin gene leads to production of a small isoform containing an NH2-terminal membrane anchor. , 1998, Genomics.

[41]  Jeffrey Robbins,et al.  A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy , 1998, Cell.

[42]  B. Forget,et al.  An Alternate Promoter Directs Expression of a Truncated, Muscle-specific Isoform of the Human Ankyrin 1 Gene* , 1998, The Journal of Biological Chemistry.