Targeting the Myofibroblast Genetic Switch: Inhibitors of Myocardin-Related Transcription Factor/Serum Response Factor–Regulated Gene Transcription Prevent Fibrosis in a Murine Model of Skin Injury

Haak, Andrew J.; Tsou, Pei Suen; Amin, M. Asif; Ruth, Jeffrey H.; Campbell, Phillip L.; Fox, David A.; Khanna, Dinesh; Larsen, Scott D.; Neubig, Richard R.

doi:10.1124/jpet.114.213520

Cited by 92 publications

(101 citation statements)

References 40 publications

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“…The implication that MRTF-A activation drives fibrosis in the heart is complemented by work in other systems. Studies using the MRTF-A inhibitor developed in the Neubig laboratory demonstrated a role for MRTF-A in fibrosis associated with a bleomycin-induced skin injury (Haak et al, 2014). In this model, MRTF-A also mediates increases in a-SMA expression, which is consistent with its role in mediating a fibroblast to myofibroblast transition.…”

Section: Pathophysiological Consequences Of Gpcr-and Rhoa-mediated Trsupporting

confidence: 65%

“…Recent studies using LPA and the TCFindependent SRE luciferase construct to carry out chemical screens identified CCG-1423 [N-[2-[4(4-chlorophenyl)amino]-1-methyl-2-oxoethoxy]-3,5-bis(trifluoromethyl)-benzamide], a compound that potently and selectively inhibits MRTF-A signaling (Evelyn et al, 2007). This inhibitor and another subsequently identified inhibitor with higher potency have been used to block and thereby identify downstream MRTF-Amediated cellular responses (Haak et al, 2014;Zhao et al, 2014).…”

Section: Gpcr and Rhoa Regulation Of Mrtf-amentioning

confidence: 99%

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G Protein–Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation

Brown

2015

Mol Pharmacol

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The low molecular weight G protein RhoA (rat sarcoma virus homolog family member A) serves as a node for transducing signals through G protein-coupled receptors (GPCRs). Activation of RhoA occurs through coupling of G proteins, most prominently, G 12/13 , to Rho guanine nucleotide exchange factors. The GPCR ligands that are most efficacious for RhoA activation include thrombin, lysophosphatidic acid, sphingosine-1-phosphate, and thromboxane A2. These ligands also stimulate proliferation, differentiation, and inflammation in a variety of cell and tissues types. The molecular events underlying these responses are the activation of transcription factors, transcriptional coactivators, and downstream gene programs. This review describes the pathways leading from GPCRs and RhoA to the regulation of activator protein-1, NFkB (nuclear factor k-light-chain-enhancer of activated B cells), myocardin-related transcription factor A, and Yes-associated protein. We also focus on the importance of two prominent downstream transcriptional gene targets, the inflammatory mediator cyclooxygenase 2, and the matricellular protein cysteine-rich angiogenic inducer 61 (CCN1). Finally, we describe the importance of GPCR-induced activation of these pathways in the pathophysiology of cancer, fibrosis, and cardiovascular disease.

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Section: Pathophysiological Consequences Of Gpcr-and Rhoa-mediated Trsupporting

confidence: 65%

Section: Gpcr and Rhoa Regulation Of Mrtf-amentioning

confidence: 99%

G Protein–Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation

Brown

2015

Mol Pharmacol

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“…At the same time, we examined three other genes, encoding alpha-smooth muscle actin (ACTA2), connective tissue growth factor (CTGF), and ankyrin repeat domain-containing protein 1 (ANKRD1), all of which are established MRTF-A-and YAP-regulated genes (7,31,(36)(37)(38)(39)(40). Knockdown of either YAP or MRTF-A fully abolished S1P-induced mRNA increases for all four of the genes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Myocardin-Related Transcription Factor A and Yes-Associated Protein Exert Dual Control in G Protein-Coupled Receptor- and RhoA-Mediated Transcriptional Regulation and Cell Proliferation

Miyamoto

Brown

2016

Molecular and Cellular Biology

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The ability of a subset of G-protein coupled receptors (GPCRs) to activate RhoA endows them with unique growth regulatory properties. Two transcriptional pathways are activated through GPCRs and RhoA, one utilizing SRF and its transcriptional co-activator MRTF-A, the other, TEAD and its transcriptional co-activator YAP. These pathways have not been compared for their relative importance and potential interactions in RhoA target gene expression. GPCRs for thrombin and S1P on human glioblastoma cells robustly couple to RhoA and induce the matricelluar protein CCN1. Knockdown of either MRTF-A or YAP abrogates S1P stimulated CCN1 expression, demonstrating that both co-activators are required. MRTF-A and YAP are also both required for induction of other S1P regulated genes in various cell types and for S1P stimulated glioblastoma cell proliferation. Interactions between MRTF-A and YAP are indicated by their synergistic effects on SRE.L and TEAD-luciferase expression. Moreover, MRTF-A and YAP associate in co-IPs from S1P stimulated cells. ChIP analysis of the CCN1 promoter demonstrates that S1P increases co-activator binding at their canonical transcription factor sequences. Unexpectedly, SIP also enhances MRTF-A binding at TEA sites. Our findings reveal that GPCR and RhoA-regulated gene expression requires dual input and integration of two distinct transcriptional pathways.

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“…Harnessing the natural regenerative capacity of epicardium-derived cardiovascular progenitor cells by modulating MRTF activity presents an exciting therapeutic strategy. Unlike most transcription factors, which are difficult to target pharmacologically, affecting MRTF localization and activity has proven feasible (Evelyn et al, 2007;Haak et al, 2014;Velasquez et al, 2013). It is interesting to speculate that epicardium-derived progenitor cells might be manipulated to promote neoangiogenesis and cardiac repair at the expense of fibroblast accumulation and scar formation.…”

Section: Discussionmentioning

confidence: 99%

Myocardin-related transcription factors control the motility of epicardium-derived cells and the maturation of coronary vessels

et al. 2015

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An important pool of cardiovascular progenitor cells arises from the epicardium, a single layer of mesothelium lining the heart. Epicardiumderived progenitor cell (EPDC) formation requires epithelial-tomesenchymal transition (EMT) and the subsequent migration of these cells into the sub-epicardial space. Although some of the physiological signals that promote EMT are understood, the functional mediators of EPDC motility and differentiation are not known. Here, we identify a novel regulatory mechanism of EPDC mobilization. Myocardin-related transcription factor (MRTF)-A and MRTF-B (MKL1 and MKL2, respectively) are enriched in the perinuclear space of epicardial cells during development. Transforming growth factor (TGF)-β signaling and disassembly of cell contacts leads to nuclear accumulation of MRTFs and the activation of the motile gene expression program. Conditional ablation of Mrtfa and Mrtfb specifically in the epicardium disrupts cell migration and leads to subepicardial hemorrhage, partially stemming from the depletion of coronary pericytes. Using lineage-tracing analyses, we demonstrate that sub-epicardial pericytes arise from EPDCs in a process that requires the MRTF-dependent motile gene expression program. These findings provide novel mechanisms linking EPDC motility and differentiation, shed light on the transcriptional control of coronary microvascular maturation and suggest novel therapeutic strategies to manipulate epicardium-derived progenitor cells for cardiac repair.

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Targeting the Myofibroblast Genetic Switch: Inhibitors of Myocardin-Related Transcription Factor/Serum Response Factor–Regulated Gene Transcription Prevent Fibrosis in a Murine Model of Skin Injury

Cited by 92 publications

References 40 publications

G Protein–Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation

G Protein–Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation

Myocardin-Related Transcription Factor A and Yes-Associated Protein Exert Dual Control in G Protein-Coupled Receptor- and RhoA-Mediated Transcriptional Regulation and Cell Proliferation

Myocardin-related transcription factors control the motility of epicardium-derived cells and the maturation of coronary vessels

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