title: Molecular basis for antagonism between PDGF and the TGFbeta family of signalling pathways by control of miR-24 expression.
abstract: Modulation of the vascular smooth-muscle-cell (vSMC) phenotype from a quiescent 'contractile' phenotype to a proliferative 'synthetic' phenotype has been implicated in vascular injury repair, as well as pathogenesis of vascular proliferative diseases. Both bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta)-signalling pathways promote a contractile phenotype, while the platelet-derived growth factor-BB (PDGF-BB)-signalling pathway promotes a switch to the synthetic phenotype. Here we show that PDGF-BB induces microRNA-24 (miR-24), which in turn leads to downregulation of Tribbles-like protein-3 (Trb3). Repression of Trb3 coincides with reduced expression of Smad proteins and decrease in BMP and TGFbeta signalling, promoting a synthetic phenotype in vSMCs. Inhibition of miR-24 by antisense oligonuclotides abrogates the downregulation of Trb3 as well as pro-synthetic activity of the PDGF-signalling pathway. Thus, this study provides a molecular basis for the antagonism between the PDGF and TGFbeta pathways, and its effect on the control of the vSMC phenotype.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Mun Chun
authors.initials: MC
authors.lastname: Chan
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Hilyard
authors.forename: Connie
authors.initials: C
authors.lastname: Wu
authors.forename: Brandi N
authors.initials: BN
authors.lastname: Davis
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Hill
authors.forename: Ashish
authors.initials: A
authors.lastname: Lal
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lagna
authors.forename: Akiko
authors.initials: A
authors.lastname: Hata
mesh_terms: D000818:Animals; D000077214:Becaplermin; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004336:Drug Antagonism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008907:Mink; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology
chemical_list: C543845:MIRN24 microRNA, human; C574736:MIRN24 microRNA, rat; D035683:MicroRNAs; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; C502443:Trib3 protein, rat; D000077214:Becaplermin; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases