Molecular basis for antagonism between PDGF and the TGFβ family of signalling pathways by control of miR‐24 expression |
| |
| Authors: | Mun Chun Chan Aaron C Hilyard Connie Wu Brandi N Davis Nicholas S Hill Ashish Lal Judy Lieberman Giorgio Lagna Akiko Hata |
| |
| Institution: | 1. Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA;2. Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA;3. Pulmonary, Critical Care, and Sleep Division, Tufts Medical Center, Boston, MA, USA;4. Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, 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‐β (TGFβ)‐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 TGFβ 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 TGFβ pathways, and its effect on the control of the vSMC phenotype. |
| |
| Keywords: | BMP microRNA PDGF TGFβ vascular smooth‐muscle cell |
|
|
