scholarly journals MRTF: Basic Biology and Role in Kidney Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6040
Author(s):  
Maria Zena Miranda ◽  
Zsuzsanna Lichner ◽  
Katalin Szászi ◽  
András Kapus
Keyword(s):  
Kidney Disease ◽  
Actin Polymerization ◽  
Serum Response Factor ◽  
Inflammatory Responses ◽  
Regulation Of Gene Expression ◽  
Rho Family Gtpases ◽  
Epithelial Phenotype ◽  
Related Transcription Factor ◽  
Cytoskeleton Remodeling ◽  
Basic Biology

A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these is myocardin-related transcription factor (MRTF), which upon actin polymerization translocates to the nucleus and binds to its cognate partner, serum response factor (SRF). The MRTF/SRF complex then drives a large cohort of genes involved in cytoskeleton remodeling, contractility, extracellular matrix organization and many other processes. Accordingly, MRTF, activated by a variety of mechanical and chemical stimuli, affects a plethora of functions with physiological and pathological relevance. These include cell motility, development, metabolism and thus metastasis formation, inflammatory responses and—predominantly-organ fibrosis. The aim of this review is twofold: to provide an up-to-date summary about the basic biology and regulation of this versatile transcriptional coactivator; and to highlight its principal involvement in the pathobiology of kidney disease. Acting through both direct transcriptional and epigenetic mechanisms, MRTF plays a key (yet not fully appreciated) role in the induction of a profibrotic epithelial phenotype (PEP) as well as in fibroblast-myofibroblast transition, prime pathomechanisms in chronic kidney disease and renal fibrosis.

scholarly journals Enhancement of mDia2 activity by Rho-kinase-dependent phosphorylation of the diaphanous autoregulatory domain

2011 ◽  
Vol 439 (1) ◽  
pp. 57-65 ◽  
Author(s):  
Dean P. Staus ◽  
Joan M. Taylor ◽  
Christopher P. Mack
Keyword(s):  
Smooth Muscle ◽  
Actin Polymerization ◽  
Serum Response Factor ◽  
Rho Kinase ◽  
Specific Gene ◽  
Related Transcription Factor ◽  
Inhibitory Domain ◽  
Serum Response ◽  
Acidic Region ◽  
Basic Region

It is clear that RhoA activates the DRF (diaphanous-related formin) mDia2 by disrupting the molecular interaction between the DAD (diaphanous autoregulatory domain) and the DID (diaphanous inhibitory domain). Previous studies indicate that a basic motif within the DAD contributes to mDia2 auto-inhibition, and results shown in the present study suggest these residues bind a conserved acidic region within the DID. Furthermore, we demonstrate that mDia2 is phosphorylated by ROCK (Rho-kinase) at two conserved residues (Thr1061 and Ser1070) just C-terminal to the DAD basic region. Phosphomimetic mutations to these residues in the context of the full-length molecule enhanced mDia2 activity as measured by increased actin polymerization, SRF (serum response factor)-dependent smooth muscle-specific gene transcription, and nuclear localization of myocardin-related transcription factor B. Biochemical and functional data indicate that the T1061E/S1070E mutation significantly inhibited the ability of DAD to interact with DID and enhanced mDia2 activation by RhoA. Taken together, the results of the present study indicate that ROCK-dependent phosphorylation of the mDia2 DAD is an important determinant of mDia2 activity and that this signalling mechanism affects actin polymerization and smooth muscle cell-specific gene expression.

scholarly journals Loss of γ-cytoplasmic actin triggers myofibroblast transition of human epithelial cells

2014 ◽  
Vol 25 (20) ◽  
pp. 3133-3146 ◽  
Author(s):  
Susana Lechuga ◽  
Somesh Baranwal ◽  
Chao Li ◽  
Nayden G. Naydenov ◽  
John F. Kuemmerle ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Actin Polymerization ◽  
Serum Response Factor ◽  
Rho Gtpase ◽  
Smooth Muscle Actin ◽  
Tissue Fibrosis ◽  
Cytoplasmic Actin ◽  
Epithelial Plasticity ◽  
Epithelial Phenotype ◽  
Serum Response

Transdifferentiation of epithelial cells into mesenchymal cells and myofibroblasts plays an important role in tumor progression and tissue fibrosis. Such epithelial plasticity is accompanied by dramatic reorganizations of the actin cytoskeleton, although mechanisms underlying cytoskeletal effects on epithelial transdifferentiation remain poorly understood. In the present study, we observed that selective siRNA-mediated knockdown of γ-cytoplasmic actin (γ-CYA), but not β-cytoplasmic actin, induced epithelial-to-myofibroblast transition (EMyT) of different epithelial cells. The EMyT manifested by increased expression of α-smooth muscle actin and other contractile proteins, along with inhibition of genes responsible for cell proliferation. Induction of EMyT in γ-CYA–depleted cells depended on activation of serum response factor and its cofactors, myocardial-related transcriptional factors A and B. Loss of γ-CYA stimulated formin-mediated actin polymerization and activation of Rho GTPase, which appear to be essential for EMyT induction. Our findings demonstrate a previously unanticipated, unique role of γ-CYA in regulating epithelial phenotype and suppression of EMyT that may be essential for cell differentiation and tissue fibrosis.

scholarly journals The actin-MRTF-SRF transcriptional circuit controls tubulin acetylation via α-TAT1 gene expression

2018 ◽  
Vol 217 (3) ◽  
pp. 929-944 ◽  
Author(s):  
Jaime Fernández-Barrera ◽  
Miguel Bernabé-Rubio ◽  
Javier Casares-Arias ◽  
Laura Rangel ◽  
Laura Fernández-Martín ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Actin Polymerization ◽  
Serum Response Factor ◽  
Cell Types ◽  
Mrna Levels ◽  
Tubulin Acetylation ◽  
Hereditary Disorders ◽  
Related Transcription Factor ◽  
Transcriptional Complex ◽  
Serum Response

The role of formins in microtubules is not well understood. In this study, we have investigated the mechanism by which INF2, a formin mutated in degenerative renal and neurological hereditary disorders, controls microtubule acetylation. We found that silencing of INF2 in epithelial RPE-1 cells produced a dramatic drop in tubulin acetylation, increased the G-actin/F-actin ratio, and impaired myocardin-related transcription factor (MRTF)/serum response factor (SRF)–dependent transcription, which is known to be repressed by increased levels of G-actin. The effect on tubulin acetylation was caused by the almost complete absence of α-tubulin acetyltransferase 1 (α-TAT1) messenger RNA (mRNA). Activation of the MRTF-SRF transcriptional complex restored α-TAT1 mRNA levels and tubulin acetylation. Several functional MRTF-SRF–responsive elements were consistently identified in the α-TAT1 gene. The effect of INF2 silencing on microtubule acetylation was also observed in epithelial ECV304 cells, but not in Jurkat T cells. Therefore, the actin-MRTF-SRF circuit controls α-TAT1 transcription. INF2 regulates the circuit, and hence microtubule acetylation, in cell types where it has a prominent role in actin polymerization.

scholarly journals Nucleoskeletal regulation of transcription: Actin on MRTF

2019 ◽  
Vol 244 (15) ◽  
pp. 1372-1381 ◽  
Author(s):  
Ekaterina Sidorenko ◽  
Maria K Vartiainen
Keyword(s):  
Gene Expression ◽  
Serum Response Factor ◽  
Regulation Of Gene Expression ◽  
Dynamic Network ◽  
Nuclear Lamina ◽  
Fine Tuning ◽  
Regulation Of Transcription ◽  
Associated Proteins ◽  
Related Transcription Factor ◽  
Transcriptional Complex

Myocardin-related transcription factor A (MRTF-A) and serum response factor (SRF) form an essential transcriptional complex that regulates the expression of many cytoskeletal genes in response to dynamic changes in the actin cytoskeleton. The nucleoskeleton, a “dynamic network of networks,” consists of numerous proteins that contribute to nuclear shape and to its various functions, including gene expression. In this review, we will discuss recent work that has identified many nucleoskeletal proteins, such as nuclear lamina and lamina-associated proteins, nuclear actin, and the linker of the cytoskeleton and nucleoskeleton complex as important regulators of MRTF-A/SRF transcriptional activity, especially in the context of mechanical control of transcription. Impact statement Regulation of gene expression is a fundamental cellular process that ensures the appropriate response of a cell to its surroundings. Alongside biochemical signals, mechanical cues, such as substrate rigidity, have been recognized as key regulators of gene expression. Nucleoskeletal components play an important role in mechanoresponsive transcription, particularly in controlling the activity of MRTF-A/SRF transcription factors. This ensures that the cell can balance the internal and external mechanical forces by fine-tuning the expression of cytoskeletal genes.

scholarly journals The nature and intensity of mechanical stimulation drive different dynamics of MRTF-A nuclear redistribution after actin remodeling in myoblasts

2018 ◽  
Author(s):  
Lorraine Montel ◽  
Athanassia Sotiropoulos ◽  
Sylvie Hénon
Keyword(s):  
Mechanical Stimulation ◽  
Actin Polymerization ◽  
Target Genes ◽  
Serum Response Factor ◽  
Magnetic Tweezers ◽  
Point Of View ◽  
Nuclear Accumulation ◽  
Related Transcription Factor ◽  
Global Increase ◽  
Serum Response

AbstractSerum response factor and its cofactor myocardin-related transcription factor (MRTF) are key elements of muscle-mass adaptation to workload. The transcription of target genes is activated when MRTF is present in the nucleus. The localization of MRTF is controlled by its binding to G-actin. Thus, the pathway can be mechanically activated through the mechanosensitivity of the actin cytoskeleton. The pathway has been widely investigated from a biochemical point of view, but its mechanical activation and the timescales involved are poorly understood. Here, we applied local and global mechanical cues to myoblasts through two custom-built set-ups, magnetic tweezers and stretchable substrates. Both induced nuclear accumulation of MRTF-A. However, the dynamics of the response varied with the nature and level of mechanical stimulation and correlated with the polymerization of different actin sub-structures. Local repeated force induced local actin polymerization and nuclear accumulation of MRTF-A by 30 minutes, whereas a global static strain induced both rapid (minutes) transient nuclear accumulation, associated with the polymerization of an actin cap above the nucleus, and long-term (hours) accumulation, with a global increase in polymerized actin. Conversely, high strain induced actin depolymerization at intermediate times, associated with cytoplasmic MRTF accumulation.

scholarly journals APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

2019 ◽  
Vol 316 (1) ◽  
pp. F1-F8 ◽  
Author(s):  
Leslie A. Bruggeman ◽  
John F. O’Toole ◽  
John R. Sedor
Keyword(s):  
Kidney Disease ◽  
Human Genetics ◽  
Disease Risk ◽  
Kidney Diseases ◽  
Expression Patterns ◽  
Model Systems ◽  
Recessive Trait ◽  
Loss Of Function ◽  
Allele Expression ◽  
Basic Biology

The mechanism that explains the association of APOL1 variants with nondiabetic kidney diseases in African Americans remains unclear. Kidney disease risk is inherited as a recessive trait, and many studies investigating the intracellular function of APOL1 have indicated the APOL1 variants G1 and G2 are associated with cytotoxicity. Whether cytotoxicity results from the absence of a protective effect conferred by the G0 allele or is induced by a deleterious effect of variant allele expression has not be conclusively established. A central issue hampering basic biology studies is the lack of model systems that authentically replicate APOL1 expression patterns. APOL1 is present in humans and a few other primates and appears to have important functions in the kidney, as the kidney is the primary target for disease associated with the genetic variance. There have been no studies to date assessing the function of untagged APOL1 protein under native expression in human or primate kidney cells, and no studies have examined the heterozygous state, a disease-free condition in humans. A second major issue is the chronic kidney disease (CKD)-associated APOL1 variants are conditional mutations, where the disease-inducing function is only evident under the appropriate environmental stimulus. In addition, it is possible there may be more than one mechanism of pathogenesis that is dependent on the nature of the stressor or other genetic variabilities. Studies addressing the function of APOL1 and how the CKD-associated APOL1 variants cause kidney disease are challenging and remain to be fully investigated under conditions that faithfully model known human genetics and physiology.

Abstract 187: Regulation of Vascular Smooth Muscle Cell (VSMC) Inflammation and Migration by the Pro-resolving Lipid Mediator Maresin-1 (mar1)

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Anuran Chatterjee ◽  
Robert Toy ◽  
Giorgio Mottola ◽  
Mian Chen ◽  
Michael S Conte
Keyword(s):  
Actin Polymerization ◽  
Inflammatory Responses ◽  
Oxidant Stress ◽  
Lipid Mediator ◽  
Monocyte Adhesion ◽  
Inflammatory Gene Expression ◽  
New Class ◽  
Tnf Α ◽  
And Migration ◽  
Inflammatory Molecules

Introduction Resolution of acute inflammation is regulated by endogenous lipid mediators derived from polyunsaturated fatty acids such as docosahexaenoic acid (DHA), however little is known about mechanisms of resolution in vascular injury. We investigated the effects of the DHA-derived mediator Mar1 on VSMC phenotype responses. Methods Primary human VSMCs were obtained from saphenous vein. VSMC were pretreated with Mar1 (10-100nM) then exposed to TNF-α (10ng/ml), and inflammatory responses assessed using a monocyte adhesion (U937) assay, expression of cell adhesion molecules and pro-inflammatory molecules (qPCR, western blot, ELISA), and production of superoxide (DHE). VSMC migration was measured in a transwell assay with PDGF-AB as the agonist, and cyotskeletal changes were assessed by actin-phalloidin staining. Results Mar-1 (100 nM) reduced U937 adhesion to TNF-stimulated VSMC, VCAM-1, and pro-inflammatory cytokine (IL-6, IL-8) expression. Superoxide production measured by DHE fluorescence was reduced by 57% (p=0.002) and Nox4 expression was markedly attenuated (43%, p=0.01). Mar-1 (0.01-100nM) induced rapid cytoskeletal changes with increased cell area, and reduced VSMC migration (76%, p=0.004) to PDGF-AB (50ng/ml; Figure). Conclusions Mar-1 attenuates TNF-α inflammatory activation of VSMC, with reduction in pro-inflammatory gene expression, oxidant stress, and monocyte adhesion. Mar-1 reduces actin polymerization and inhibits VSMC chemotaxis to PDGF. Pro-resolving mediators may represent a new class of endogenous vascular therapeutics.

scholarly journals MRTFA augments megakaryocyte maturation by enhancing the SRF regulatory axis

2018 ◽  
Vol 2 (20) ◽  
pp. 2691-2703 ◽  
Author(s):  
Nur-Taz Rahman ◽  
Vincent P. Schulz ◽  
Lin Wang ◽  
Patrick G. Gallagher ◽  
Oleg Denisenko ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Serum Response Factor ◽  
Sequencing Data ◽  
Binding Motifs ◽  
Ets Proteins ◽  
Human Cd34 ◽  
Genomic Association ◽  
Hel Cells ◽  
Related Transcription Factor

Abstract Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds DNA at CArG (CC[A/T]6GG) domains in association with myocardin-family proteins (eg, myocardin-related transcription factor A [MRTFA]) or the ternary complex factor family of E26 transformation-specific (ETS) proteins. In primary hematopoietic cells, knockout of either SRF or MRTFA decreases megakaryocyte (Mk) maturation causing thrombocytopenia. The human erythroleukemia (HEL) cell line mimics the effects of MRTFA on Mk maturation, and MRTFA overexpression (MRTFAOE) in HEL cells enhances megakaryopoiesis. To identify the mechanisms underlying these effects, we performed integrated analyses of anti-SRF chromatin immunoprecipitation (ChIP) and RNA-sequencing data from noninduced and phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA])–induced HEL cells, with and without MRTFAOE. We found that 11% of genes were upregulated with TPA induction, which was enhanced by MRTFAOE, resulting in an upregulation of 25% of genes. MRTFAOE increased binding of SRF to genomic sites and enhanced TPA-induced expression of SRF target genes. The TPA-induced genes are predicted to be regulated by SRF and ETS factors, whereas those upregulated by TPA plus MRTFAOE lack ETS binding motifs, and MRTFAOE skews SRF binding to genomic regions with CArG sites in regions relatively lacking in ETS binding motifs. Finally, ChIP–polymerase chain reaction using HEL cells and primary human CD34+ cell–derived subpopulations confirms that both SRF and MRTFA have increased binding during megakaryopoiesis at upregulated target genes (eg, CORO1A). We show for the first time that MRTFA increases both the genomic association and activity of SRF and upregulates genes that enhance primary human megakaryopoiesis.

A Sphingosine-1-Phosphate Modulator Ameliorates Polycystic Kidney Disease in Han:SPRD Rats

2019 ◽  
Vol 51 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Xin Li ◽  
Ming Wu ◽  
Limin Chen ◽  
Junyan Lu ◽  
Guo Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Kidney Diseases ◽  
Cordyceps Sinensis ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Sphingosine 1 Phosphate

Background: Inflammation plays an important role in polycystic kidney disease (PKD). Cordyceps sinensis, a prized ­Chinese medicinal herb, exerts anti-tumor, anti-inflammatory and anti-metastatic effects and benefits patients with kidney diseases. The aim of this study was to test the efficacy of FTY720, an immunosuppressant derived from C. sinensis, in a rat cystic kidney disease model, and explore its underlining mechanism. Methods: Male wild type and Cy/+ Han:SPRD rats were treated with FTY720 at 3 and 10 mg/kg/day for 5 weeks and 12 weeks by gavage. Blood and kidney were collected for functional, morphological, RNA, and protein analysis. Results: Inflammation is activated in Cy/+ Han:SPRD rats. Inflammatory cytokines including interleukin 6 and tumor necrosis factor alpha were upregulated and inflammation-related pathways were activated, such as nuclear factor κB and signal transducer and activator of transcription 3 (STAT3) pathways. Furthermore, the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), a regulator of inflammation, was accumulated in the Cy/+ Han:SPRD rats. FTY720 significantly reduced cyst growth and delayed disease progression by reducing the accumulation of S1P, thereby inhibiting inflammatory responses. Conclusion: FTY720 treatment reduced the expression of inflammatory cytokines and attenuated the activation of NK-κB and STAT3 pathways in Cy/+ Han:SPRD rats. It suggests that FTY720 may serve as a therapeutic agent for clinical autosomal dominant PKD treatment.

scholarly journals Renal tubule Na,K-ATPase polarity in different animal models of polycystic kidney disease.

1995 ◽  
Vol 43 (8) ◽  
pp. 785-790 ◽  
Author(s):  
M R Ogborn ◽  
S Sareen ◽  
K Tomobe ◽  
H Takahashi ◽  
J F Crocker
Keyword(s):  
Kidney Disease ◽  
Animal Models ◽  
Polycystic Kidney Disease ◽  
Renal Tubule ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Epithelial Phenotype ◽  
Electrolyte Flux ◽  
Cyst Development

Apical mislocation of the ubiquitous transport enzyme Na,K-ATPase has been implicated as a feature of cyst development in in vitro studies of human polycystic kidney disease (PKD) epithelia. We undertook an immunohistochemical study of murine glucocorticoid-induced PKD, the pcy mouse, the cpk mouse, and the diphenylthiazole (DPT)-induced rat models of PKD to determine if this feature was common to these models of cyst development. Distribution of Na,K-ATPase was determined with a polyclonal anti-Na,K-ATPase antibody and a nickel-silver-enhanced peroxidase color development system. Results were documented objectively with densitometric techniques. Control animals appropriate to the age, strain, and species of the experimental groups demonstrated the expected polar distribution of Na,K-ATPase to the basolateral surface. This distribution was more marked in mature animals. Tubular dilatation and cystic change, however, were associated with increased apical Na,K-ATPase in all models. The murine models demonstrated decreased basolateral staining for Na,K-ATPase compared with controls, although this was not a feature of the DPT rat model. Abnormal location of Na,K-ATPase is a shared feature of a variety of animal models and human PKD. This may contribute to abnormal fluid and electrolyte flux favoring cyst formation or may represent expression of a less differentiated renal tubule epithelial phenotype.

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