MKL1 mediates TGF‐β‐induced CTGF transcription to promote renal fibrosis

Mao, Lei; Liu, Li; Zhang, Tianyi; Wu, Xiaoyan; Zhang, Tao; Xu, Yong

doi:10.1002/jcp.29356

Cited by 35 publications

(29 citation statements)

References 61 publications

(79 reference statements)

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“…Here we provide examples of “famous” target genes that were shown to be (a) MRTF-dependent in kidney cells and/or (b) directly related to renal pathologies. These include the contractility protein myosin [ 16 , 141 ], the myofibroblast hallmark α-SMA [ 16 , 20 , 104 , 142 , 143 ], actin-severing (cofilin), capping (CapZ) [ 20 ]) and bundling (filamin) [ 144 ]) proteins; focal adhesion and cell-matrix components (α and β integrins [ 145 ]), tenascin [ 144 , 146 ]); extracellular matrix proteins (collagen [ 62 , 147 ], CTGF [ 124 , 148 , 149 , 150 ]); caveolar proteins (caveolin 1 [ 144 , 151 ]), fibrogenic cytokines (TGFβ [ 124 ]), cell cycle regulators (p21 [ 152 ]), NADPH oxidases [ 153 , 154 ]; and transcription factors, encompassing SRF itself [ 20 ], the EMT drivers Snai1/2 and ZEB2 [ 155 , 156 , 157 ] and the Hippo effector TAZ [ 22 , 95 ]. Moreover, SRF/MRTF-targeted CArG motifs are frequently located in the vicinity of AP1 and TEAD sites (that are activated by YAP/TAZ), showing that these TFs often regulate the same genes, and may act synergistically with MRTF [ 23 ].…”

Section: Targets Functions Actionsmentioning

confidence: 99%

MRTF: Basic Biology and Role in Kidney Disease

Miranda

Lichner

Szászi

et al. 2021

IJMS

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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.

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Section: Targets Functions Actionsmentioning

confidence: 99%

MRTF: Basic Biology and Role in Kidney Disease

Miranda

Lichner

Szászi

et al. 2021

IJMS

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“…Whole-cell lysates were obtained by re-suspending cell pellets in RIPA buffer (50 mM Tris pH7.4, 150 mM NaCl, 1% Triton X-100) with freshly added protease inhibitor (Roche) as previously described [55][56][57][58][59] . Specific antibodies or pre-immune IgGs (P.I.I.)…”

Section: Protein Extraction Immunoprecipitation and Western Blotmentioning

confidence: 99%

Epigenetic activation of the small GTPase TCL contributes to colorectal cancer cell migration and invasion

et al. 2020

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TC10-like (TCL) is a small GTPase that has been implicated in carcinogenesis. Elevated TCL expression has been observed in many different types of cancers although the underlying epigenetic mechanism is poorly understood. Here we report that TCL up-regulation was associated with high malignancy in both human colorectal cancer biopsy specimens and in cultured colorectal cancer cells. Hypoxia, a pro-metastatic stimulus, up-regulated TCL expression in HT-29 cells. Further studies revealed that myocardin-related transcription factor A (MRTF-A) promoted migration and invasion of HT-29 cells in a TCL-dependent manner. MRTF-A directly bound to the proximal TCL promoter in response to hypoxia to activate TCL transcription. Chromatin immunoprecipitation (ChIP) assay showed that hypoxia stimulation specifically enhanced acetylation of histone H4K16 surrounding the TCL promoter, which was abolished by MRTF-A depletion or inhibition. Mechanistically, MRTF-A interacted with and recruited the H4K16 acetyltransferase hMOF to the TCL promoter to cooperatively regulate TCL transcription. hMOF depletion or inhibition attenuated hypoxia-induced TCL expression and migration/invasion of HT-29 cells. In conclusion, our data identify a novel MRTF-A-hMOF-TCL axis that contributes to colorectal cancer metastasis.

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“…Histological analyses were performed essentially as previously described ( Zhao et al, 2019 ; Dong et al, 2020 ; Mao et al, 2020 ). Paraffin sections of heart tissue from the mice receiving different treatments were incubated with anti-MRTF-A primary antibody (1:100 dilution, Proteintech, China) and anti-actinin primary antibody (1:100 dilution, Abcam, United Kingdom) overnight at 4°C, then incubated with af594-labeled secondary antibody (1:100 dilution, Life Technologies, United States) for actinin and AF488-labeled secondary antibody (1:100 dilution, Life Technologies, United States) for MRTF-A at room temperature for 1 h. After stained with 4′,6-diamidino-2-phenylindole (DAPI) to label nuclei, the samples were observed under a confocal microscope (LSM 710, Zeiss, Germany).…”

Section: Methodsmentioning

confidence: 99%

An MRTF-A–Sp1–PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy

Wang

Xin

et al. 2020

Front. Cell Dev. Biol.

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Cardiac hypertrophy is a critical intermediate step in the pathogenesis of heart failure. A myriad of signaling networks converge on cardiomyocytes to elicit hypertrophic growth in response to various injurious stimuli. In the present study, we investigated the cardiomyocyte-specific role of myocardin-related transcription factor A (MRTF-A) in angiotensin-II (Ang-II)-induced cardiac hypertrophy and the underlying mechanism. We report that conditional MRTF-A deletion in cardiomyocytes attenuated Ang-II-induced cardiac hypertrophy in mice. Similarly, MRTF-A knockdown or inhibition suppressed Ang-II-induced prohypertrophic response in cultured cardiomyocytes. Of note, Ang II treatment upregulated expression of phosphodiesterase 5 (PDE5), a known mediator of cardiac hypertrophy and heart failure, in cardiomyocytes, which was blocked by MRTF-A depletion or inhibition. Mechanistically, MRTF-A activated expression of specificity protein 1 (Sp1), which in turn bound to the PDE5 promoter and upregulated PDE5 transcription to promote hypertrophy of cardiomyocytes in response to Ang II stimulation. Therefore, our data unveil a novel MRTF-A-Sp1-PDE5 axis that mediates Ang-II-induced hypertrophic response in cardiomyocytes. Targeting this newly identified MRTF-A-Sp1-PDE5 axis may yield novel interventional solutions against heart failure.

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MKL1 mediates TGF‐β‐induced CTGF transcription to promote renal fibrosis

Abstract: Aberrant fibrogenesis impairs the architectural and functional homeostasis of the kidneys. It also predicts poor diagnosis in patients with end-stage renal disease (ESRD). Renal tubular epithelial cells (RTEC) can trans-differentiate into myofibro-

Cited by 35 publications

References 61 publications

MRTF: Basic Biology and Role in Kidney Disease

MRTF: Basic Biology and Role in Kidney Disease

Epigenetic activation of the small GTPase TCL contributes to colorectal cancer cell migration and invasion

An MRTF-A–Sp1–PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy

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