title: GTPase Activating Protein (Sh3 Domain) Binding Protein 1 Regulates the Processing of MicroRNA-1 during Cardiac Hypertrophy.
abstract: BACKGROUND
  MicroRNAs (miR) are small, posttranscriptional regulators, expressed as part of a longer primary transcript, following which they undergo nuclear and cytoplasmic processing by Drosha and Dicer, respectively, to form the functional mature ~20mer that gets incorporated into the silencing complex. Others and we have shown that mature miR-1 levels decrease with pressure-induced cardiac hypertrophy, however, there is little or no change in the primary transcript encompassing miR-1 stem-loop, suggesting critical regulatory step in microRNA processing. The objective of this study was to investigate the underlying mechanisms regulating miR-1 expression in cardiomyocytes.
  
  
  RESULTS
  Here we report that GTPase-activating protein (SH3 domain) binding protein 1 (G3bp1), an endoribonuclease regulates miR-1 processing in cardiomyocytes. G3bp1 is upregulated during cardiac hypertrophy and restricts miR-1 processing by binding to its consensus sequence in the pre-miR-1-2 stem-loop. In accordance, exogenous G3bp1 is sufficient to reduce miR-1 levels, along with derepression of miR-1 targets; General transcription factor IIB (Gtf2b), cyclin dependent factor 9 (Cdk9) and eukaryotic initiation factor 4E (Eif4e). While Cdk9 and Gtf2b are essential for transcription, Eif4e is required for translation. Thus, downregulation of miR-1 is necessary for increase in these molecules. Similar to miR-1 knockdown, G3bp1 overexpression is not sufficient for development of cardiac hypertrophy. Conversely, knockdown of G3bp1 in hypertrophying cardiomyocytes inhibited downregulation of miR-1 and upregulation of its targets along with restricted hypertrophy, suggesting that G3bp1 is necessary for development of cardiac hypertrophy. These results indicate that G3bp1-mediated inhibition of miR-1 processing with growth stimulation results in decrease in mature miR-1 and, thereby, an increase of its targets, which play fundamental roles in the development of hypertrophy.
  
  
  CONCLUSIONS
  G3bp1 posttranscriptionally regulates miRNA-1 processing in the heart, and G3bp1 mediated downregulation of mature miRNA-1 levels is required for the derepression of its targets and increase in gene expression during cardiac hypertrophy.
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Minzhen
authors.initials: M
authors.lastname: He
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Maha
authors.initials: M
authors.lastname: Abdellatif
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Danish
authors.initials: D
authors.lastname: Sayed
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D004265:DNA Helicases; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D039561:Eukaryotic Initiation Factor-4E; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D014157:Transcription Factors; C467972:Cdk9 protein, mouse; D042863:Cyclin-Dependent Kinase 9; D004265:DNA Helicases; C492055:G3bp1 protein, mouse; D020365:RNA Helicases