Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription.
During the onset and progression of atherosclerosis, the vascular smooth muscle cell (VSMC) phenotype changes from differentiated to dedifferentiated, and in some cases, this change is accompanied by osteogenic transition, resulting in vascular calcification. One characteristic of dedifferentiated VSMCs is the down-regulation of smooth muscle cell (SMC) marker gene expression. Bone morphogenetic proteins (BMPs), which are involved in the induction of osteogenic gene expression, are detected in calcified vasculature. In this study, we found that the BMP2-, BMP4-, and BMP6-induced expression of Msx transcription factors (Msx1 and Msx2) preceded the down-regulation of SMC marker expression in cultured differentiated VSMCs. Either Msx1 or Msx2 markedly reduced the myocardin-dependent promoter activities of SMC marker genes (SM22alpha and caldesmon). We further investigated interactions between Msx1 and myocardin/serum response factor (SRF)/CArG-box motif (cis element for SRF) using coimmunoprecipitation, gel-shift, and chromatin immunoprecipitation assays. Our results showed that Msx1 or Msx2 formed a ternary complex with SRF and myocardin and inhibited the binding of SRF or SRF/myocardin to the CArG-box motif, resulting in inhibition of their transcription.
Hayashi
Ken'ichiro
K
Department of Neuroscience (D13), Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.
Nakamura
Seiji
S
Nishida
Wataru
W
Sobue
Kenji
K
D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051957:MSX1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D051381:Rats; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D000099251:Myocardin
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; D009687:Nuclear Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin; C084119:MSX2 protein; C497998:Msx1 protein, rat