Smad3-mediated Myocardin Silencing

Xie, Wei Bing; Li, Zuguo; Miano, Joseph M.; Long, Xiaochun; Chen, Shiyou

doi:10.1074/jbc.m110.202747

Cited by 45 publications

(20 citation statements)

References 44 publications

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“…MYOCD, which encodes a SRF co-transcriptional factor, was identified as the most significantly induced one among these markers, consistent with a previous observation in HMSCs and a mouse EC coculture model [17]. SRF-MYOCD was the master transcriptional factor activating the myogenic genes [63][64][65], which in the upstream were regulated by RhoA/ ROCK signaling [41,42,44]. We hypothesized that the coculture stimulated the secretion of signaling factors and the remodeling of extracellular matrix, which collectively activated the RhoA/ROCK-dependent myogenic differentiation.…”

Section: Discussionsupporting

confidence: 72%

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

LiJunxiang

MaYing

TengRuifang

et al. 2015

Stem Cells and Development

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Mesenchymal stem cells (MSCs) show great promise in blood vessel restoration and vascularization enhancement in many therapeutic situations. Typically, the co-implantation of MSCs with vascular endothelial cells (ECs) is effective for the induction of functional vascularization in vivo, indicating its potential applications in regenerative medicine. The effects of MSCs-ECs-induced vascularization can be modeled in vitro, providing simplified models for understanding their underlying communication. In this article, a contact coculture model in vitro and an RNA-seq approach were employed to reveal the active crosstalk between MSCs and ECs within a short time period at both morphological and transcriptional levels. The RNA-seq results suggested that angiogenic genes were significantly induced upon coculture, and this prevascularization commitment might require the NF-kB signaling. NF-kB blocking and interleukin (IL) neutralization experiments demonstrated that MSCs potentially secreted IL factors including IL1b and IL6 to modulate NF-kB signaling and downstream chemokines during coculture. Conversely, RNA-seq results indicated that the MSCs were regulated by the coculture environment to a smooth muscle commitment within this short period, which largely induced myocardin, the myogenic co-transcriptional factor. These findings demonstrate the mutual molecular mechanism of MSCs-ECs-induced prevascularization commitment in a quick response.

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Section: Discussionsupporting

confidence: 72%

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

LiJunxiang

MaYing

TengRuifang

et al. 2015

Stem Cells and Development

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“…Recently, slow induction of Myocd mRNA by TGF-␤ (Ͼ18 h after TGF-␤ stimulation) is reported in mouse mesenchymal C3H10T1/2 cells (55). This induction is mediated by PI3K signaling, which activates the Myocd promoter through induction of Nkx2.5 (55). Interestingly, in this report Smad4 acts to inhibit Nkx2.5 activity.…”

Section: Discussionmentioning

confidence: 81%

Down-regulation of Krüppel-like Factor-4 (KLF4) by MicroRNA-143/145 Is Critical for Modulation of Vascular Smooth Muscle Cell Phenotype by Transforming Growth Factor-β and Bone Morphogenetic Protein 4

Davis‐Dusenbery

Chan

Reno

et al. 2011

Journal of Biological Chemistry

226

196

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Vascular smooth muscle cells (VSMCs) 3 are highly plastic cells that undergo phenotype modulation in response to physiological and pathological cues (1). In response to vascular injury or growth factors, such as platelet-derived growth factor (PDGF) (2), VSMCs dedifferentiate and adopt a highly migratory, proliferative phenotype known as a "synthetic" phenotype that is required for vascular injury repair or during angiogenesis (1). However, prolonged or deregulated dedifferentiation can cause occlusion of the vasculature and contributes to development of vascular proliferative disorders, such as atherosclerosis, restenosis following angioplasty, as well as both systemic and pulmonary hypertension (1). Unlike PDGF, the TGF-␤ family of growth factors, including TGF-␤ and BMP4, promote a less migratory and proliferative phenotype known as the "contractile" phenotype (3). Contractile VSMC phenotype is characterized by alterations in the gene expression profile of VSMC. In particular, high expression of VSMC-specific genes, such as smooth muscle ␣-actin (SMA), calponin1 (CNN), and SM22␣ (SM22) are associated with the contractile VSMC phenotype. Transcription of contractile genes is regulated by SRF through a DNA sequence motif known as the CArG box (CC(A/T) 6 GG), which is present in the promoters of VSMC-specific genes (1). A coactivator of SRF, Myocd, interacts with SRF and activates VSMC expression of contractile genes (4 -6). Similarly, the Myocd-related transcription factor (MRTF) family of proteins, MRTF-A and MRTF-B, are also involved in the transcriptional regulation of contractile gene markers as coactivators of SRF (7,8). Myocd is constitutively localized to the nucleus and its activity is regulated primarily at the level of expression. Conversely, MRTFs are sequestered in the cytoplasm through interaction with monomeric G-actin (9, 10). In response to BMP4 or other stimuli, Rho signaling promotes actin polymerization and MRTF translocation into the nucleus where MRTFs associate with SRF (3), resulting in the activation of contractile gene transcription. Unlike BMP4, TGF-␤ does not activate Rho signal-* This work was supported, in whole or in part, by National Institutes of Health 3 The abbreviations used are: VSMC, vascular smooth muscle cell; TGF-{␤}, transforming growth factor-{␤}; PDGF, platelet-derived growth factor; PAI-1, plasminogen activator inhibitor-1; PDCD4, programed cell death 4; BMP, bone morphogenetic protein; MRTF, Myocd-related transcription factor; PASMC, pulmonary artery smooth muscle cell; ESC, embryonic stem cell; SRF, serum response factor; Myocd, myocardin; miRNA, microRNA; pri-miRNA; primary miRNA; SBE, Smad-binding element; rAoSMC, rat aortic SMC; qRT, quantitative reverse transcriptase.

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“…Overexpression of Smad3, but not Smad2, inhibited Myocardin promoter activity [9]. In our study, luciferase assays determine that Smad2 significantly activated myocardin promoter, but Smad3 suppressed activity of the myocardin promoter at 18h.…”

Section: Discussionmentioning

confidence: 94%

Construction and function analysis of luciferase reporter plasmid with myocardin gene promoter

Qiang

Wang

et al. 2011

2011 4th International Conference on Biomedical Engineering and Informatics (BMEI)

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Myocardin is a potent coactivator of SRF and expressed mainly in cardiomyocytes and smooth muscle cells (SMCs), Myocardin is important for SMC differentiation, but its precise role in regulating the initiation of SMC development is less clear. Constuction and function analysis of myocardin promoter luciferase reporter plasmid will provide the theory basis for researching the function of myocardin in SMC differentiation. In this study, a mouse myocardin promoter luciferase reporter construct was successfully constructed. To determine whether myocardin transcription activity were regulated by several factors, which play important roles in SMC differentiation, luciferase repoeter assays were performed in COS-7 cells and vascular smooth muscle cells (VSMCs). The results illustrated that Smad2 significantly activated myocardin promoter, but Smad3 signaling was inhibitory to myocardin expression at 18h. Myocardin promoter transactivity was inhibited by estrogen receptor α (ERα), and enhanced by p300. These findings indicated myocardin might be regulated by multi-signals and these factors might affect SMC differentiation through activating or inhibiting myocardin transcription.

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Smad3-mediated Myocardin Silencing

Cited by 45 publications

References 44 publications

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

Down-regulation of Krüppel-like Factor-4 (KLF4) by MicroRNA-143/145 Is Critical for Modulation of Vascular Smooth Muscle Cell Phenotype by Transforming Growth Factor-β and Bone Morphogenetic Protein 4

Construction and function analysis of luciferase reporter plasmid with myocardin gene promoter

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