Molecular basis for antagonism between PDGF and the TGFbeta family of signalling pathways by control of miR-24 expression.
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.
Chan
Mun Chun
MC
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Hilyard
Aaron C
AC
Wu
Connie
C
Davis
Brandi N
BN
Hill
Nicholas S
NS
Lal
Ashish
A
Lieberman
Judy
J
Lagna
Giorgio
G
Hata
Akiko
A
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
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