title: Serum response factor regulates expression of phosphatase and tensin homolog through a microRNA network in vascular smooth muscle cells.
abstract: OBJECTIVE
  Serum response factor (SRF) is a critical transcription factor in smooth muscle cells (SMCs) controlling differentiation and proliferation. Our previous work demonstrated that depleting SRF in cultured SMCs decreased expression of SMC markers but increased proliferation and inflammatory mediators. A similar phenotype has been observed in SMCs silenced for phosphatase and tensin homolog (PTEN), suggesting that SRF and PTEN may lie on a common pathway. Our goal was to determine the effect of SRF depletion on PTEN levels and define mechanisms mediating this effect.
  
  
  RESULTS
  In SRF-silenced SMCs, PTEN protein levels but not mRNA levels were decreased, suggesting posttranscriptional regulation. Reintroduction of PTEN into SRF-depleted SMCs reversed increases in proliferation and cytokine/chemokine production but had no effect on SMC marker expression. SRF-depleted cells showed decreased levels of microRNA (miR)-143 and increased miR-21, which was sufficient to suppress PTEN. Increased miR-21 expression was dependent on induction of Fos related antigen (FRA)-1, which is a direct target of miR-143. Introducing miR-143 into SRF-depleted SMCs reduced FRA-1 expression and miR-21 levels and restored PTEN expression.
  
  
  CONCLUSIONS
  SRF regulates PTEN expression in SMCs through a miR network involving miR-143, targeting FRA-1, which regulates miR-21. Cross-talk between SRF and PTEN likely represents a critical axis in phenotypic remodeling of SMCs.
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Henrick N
authors.initials: HN
authors.lastname: Horita
authors.forename: Peter A
authors.initials: PA
authors.lastname: Simpson
authors.forename: Allison
authors.initials: A
authors.lastname: Ostriker
authors.forename: Seth
authors.initials: S
authors.lastname: Furgeson
authors.forename: Vicki
authors.initials: V
authors.lastname: Van Putten
authors.forename: Mary C M
authors.initials: MC
authors.lastname: Weiser-Evans
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D035683:MicroRNAs / Q000378:metabolism*; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000099169:Fos-Related Antigen 1
chemical_list: D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D016760:Proto-Oncogene Proteins c-fos; D026362:Serum Response Factor; D000099169:Fos-Related Antigen 1; C569508:MIRN143 microRNA, rat; C546082:mirn21 microRNA, rat