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EMBO J. 2010 Feb 3;29(3):559-73. doi: 10.1038/emboj.2009.370. Epub 2009 Dec 17.

Molecular basis for antagonism between PDGF and the TGFbeta family of signalling pathways by control of miR-24 expression.

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1
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.

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.

PMID:
20019669
PMCID:
PMC2830697
DOI:
10.1038/emboj.2009.370
[Indexed for MEDLINE]
Free PMC Article

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