Smooth muscle cell-specific transcription is regulated by nuclear localization of the myocardin-related transcription factors

Hinson, Jeremiah S.; Medlin, Matthew D.; Lockman, Kashelle; Taylor, Joan M.; Mack, Christopher P.

doi:10.1152/ajpheart.00864.2006

Cited by 91 publications

(99 citation statements)

References 53 publications

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“…In addition, NF-kB has been shown to program macrophage polarization, favoring a proinflammatory M1 phenotype (Tugal et al, 2013). Mounting evidence supports a role for MRTF-A in directing differentiation/trans-differentiation in smooth muscle cells (Hinson et al, 2007), skeletal muscle cells , epithelial cells (Morita et al, 2007), megakaryocytes (Gilles et al, 2009) and fibroblast cells (Crider et al, 2011). We therefore speculate that MRTF-A deficiency could potentially skew the macrophages to an antiinflammatory M2 phenotype.…”

Section: Discussionmentioning

confidence: 87%

MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex

Weng

Peng

et al. 2014

Journal of Cell Science

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Chronic inflammation underscores the pathogenesis of a range of human diseases. Lipopolysaccharide (LPS) elicits strong pro-inflammatory response in macrophages via the transcription factor NF-κB. The epigenetic mechanism underlying LPS-induced pro-inflammatory transcription is not completely appreciated. Herein we describe a role for myocardin related transcription factor A, or MRTF-A, in this process. MRTF-A over-expression potentiated while MRTF-A silencing dampened NF-κB dependent pro-inflammatory transcription. MRTF-A deficiency also alleviated the synthesis of pro-inflammatory mediators in a mouse model of colitis. LPS promoted the recruitment of MRTF-A to the promoters of pro-inflammatory genes in a NF-κB dependent manner. Reciprocally, MRTF-A influenced the nuclear enrichment and target binding of NF-κB. Mechanistically, MRTF-A was necessary for the accumulation of active histone modifications on NF-κB target promoters by communicating with the histone H3K4 methyltransferase complex (COMPASS). Silencing of individual members of COMPASS, including ASH2, WDR5, and SET1, down-regulated the production of pro-inflammatory mediators and impaired the NF-κB kinetics. In summary, our work has uncovered a previously unknown function for MRTF-A and provided insights into the rationalized development of anti-inflammatory therapeutic strategies.

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Section: Discussionmentioning

confidence: 87%

MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex

Weng

Peng

et al. 2014

Journal of Cell Science

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“…7-13). Among these predicted targets are the zinc finger proteins; Kruppel-like factor 4 (KLF4) and KLF5, which repress SRF activity and either promote or inhibit SMC phenotypic switching (Nagai et al 2005;C Wang et al 2008;Yoshida et al 2008;Suzuki et al 2009); Slit-Robo GTPase-activating protein 1 (Srgap1) and Srgap2, which function as negative regulators of actin polymerization (Wong et al 2001); Adducin-3 (Add3), an F-actin capping protein involved in cell migration (Barkalow et al 2003); Sling-shot 2 (Ssh2) phosphatase, which stimulates the activity of the actin depolymerizing factor cofilin (San Martin et al 2008;Eiseler et al 2009); and MRTF-B, an actin-regulated coactivator of SRF (Kuwahara et al 2005;Hinson et al 2007;Parmacek 2007).…”

Section: Mir-143 and Mir-145 Target Multiple Regulators Of Actin Dynamentioning

confidence: 99%

MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury

Xin¹,

et al. 2009

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Vascular injury triggers dedifferentiation and cytoskeletal remodeling of smooth muscle cells (SMCs), culminating in vessel occlusion. Serum response factor (SRF) and its coactivator, myocardin, play a central role in the control of smooth muscle phenotypes by regulating the expression of cytoskeletal genes. We show that SRF and myocardin regulate a cardiovascular-specific microRNA (miRNA) cluster encoding miR-143 and miR-145. To assess the functions of these miRNAs in vivo, we systematically deleted them singly and in combination in mice. Mice lacking both miR-143 and miR-145 are viable and do not display overt abnormalities in smooth muscle differentiation, although they show a significant reduction in blood pressure due to reduced vascular tone. Remarkably, however, neointima formation in response to vascular injury is profoundly impeded in mice lacking these miRNAs, due to disarray of actin stress fibers and diminished migratory activity of SMCs. These abnormalities reflect the regulation of a cadre of modulators of SRF activity and actin dynamics by miR-143 and miR-145. Thus, miR-143 and miR-145 act as integral components of the regulatory network whereby SRF controls cytoskeletal remodeling and phenotypic switching of SMCs during vascular disease.

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“…Nuclear MRTF forms a complex with serum response factor (SRF) activating transcription of cytoskeletal genes associated with EMT, including αSMA (34,(40)(41)(42). Indeed, TGFβ has been shown to stimulate nuclear accumulation of MRTF-A in several organ fibrosis models (38,43,44), including in recent work from our group showing TGFβ-induced nuclear localization of MRTF-A in lens epithelial cells (39). However, whether TGFβ-induced changes in MTRF-A in the lens are ROCK-dependent is not known.…”

Section: Introductionmentioning

confidence: 99%

RhoA/ROCK Signaling Regulates TGFβ-Induced Epithelial-Mesenchymal Transition of Lens Epithelial Cells through MRTF-A

Korol

Taiyab

West‐Mays

2016

Mol Med

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Transforming growth factor (TGF)-β-induced epithelial-mesenchymal transition (EMT) leads to the formation of ocular fibrotic pathologies, such as anterior subcapsular cataract and posterior capsule opacification. Remodeling of the actin cytoskeleton, mediated by the Rho family of GTPases, plays a key role in EMT. However, how actin dynamics affect downstream markers of EMT has not been fully determined. Our previous work suggests that myocardin-related transcription factor A (MRTF-A), an actin-binding protein, might be an important mediator of TGFβ-induced EMT in lens epithelial cells. The aim of the current study was to determine the requirement of RhoA/ROCK signaling in mediating TGFβ-induced nuclear accumulation of MRTF-A and ultimate expression of α-smooth muscle actin (αSMA), a marker of a contractile myofibroblast phenotype. Using rat lens epithelial explants, we demonstrate that ROCK inhibition using Y-27632 prevents TGFβ-induced nuclear accumulation of MRTF-A, Ecadherin/β-catenin complex disassembly, and αSMA expression. Using a novel inhibitor specifically targeting MRTF-A signaling, CCG-203971, we further demonstrate the requirement of MRTF-A nuclear localization and activity in the induction of αSMA expression. Overall, our findings suggest that TGFβ-induced cytoskeletal reorganization through RhoA/ROCK/MRTF-A signaling is critical to EMT of lens epithelial cells.

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Smooth muscle cell-specific transcription is regulated by nuclear localization of the myocardin-related transcription factors

Cited by 91 publications

References 53 publications

MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex

MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex

MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury

RhoA/ROCK Signaling Regulates TGFβ-Induced Epithelial-Mesenchymal Transition of Lens Epithelial Cells through MRTF-A

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