Last update 19 Sep 2024

MRTFA

Last update 19 Sep 2024

Basic Info

Synonyms

BSAC, KIAA1438, MAL

+ [9]

Introduction

Transcription coactivator that associates with the serum response factor (SRF) transcription factor to control expression of genes regulating the cytoskeleton during development, morphogenesis and cell migration (PubMed:26224645). The SRF-MRTFA complex activity responds to Rho GTPase-induced changes in cellular globular actin (G-actin) concentration, thereby coupling cytoskeletal gene expression to cytoskeletal dynamics. MRTFA binds G-actin via its RPEL repeats, regulating activity of the MRTFA-SRF complex. Activity is also regulated by filamentous actin (F-actin) in the nucleus.

Drugs associated with MRTFA

CCG-257081

Target

MRTFA x NF-κB

Mechanism

MRTFA inhibitors [+1]

Active Org.

Fibrosix, Inc.

Originator Org.

Fibrosix, Inc.

Active Indication

Pneumonia [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CCG-1423

Target

MRTFA x RHOA

Mechanism

MRTFA inhibitors [+1]

Active Org.

Kyoto University

Originator Org.

Kyoto University

Active Indication-

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MRTFA

100 Translational Medicine associated with MRTFA

0 Patents (Medical) associated with MRTFA

696

Literatures (Medical) associated with MRTFA

01 Sep 2024·American Journal of Obstetrics and Gynecology

Altered extracellular matrix–related pathways accelerate the transition from normal to prefibroid myometrium in Black women

Article

Author: Al-Hendy, Ayman ; Bariani, Maria Victoria ; Ali, Mohamed ; Grimm, Sandra L ; Coarfa, Cristian ; Velez Edwards, Digna R ; Yang, Qiwei ; Walker, Cheryl L

BACKGROUNDBlack women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive.OBJECTIVEThe aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women.STUDY DESIGNWe conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16).RESULTSThe transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women.CONCLUSIONThese findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences.

01 Aug 2024·British Journal of Pharmacology

The insulin‐like growth factor binding protein–microfibrillar associated protein–sterol regulatory element binding protein axis regulates fibroblast–myofibroblast transition and cardiac fibrosis

Article

Author: Zong, Genjie ; Xu, Yong ; Hong, Wenxuan ; Zhuo, Lili ; Huang, Shan ; Shao, Tinghui ; Zhao, Qianwen ; Zhang, Junjie

Background and PurposeExcessive fibrogenesis is associated with adverse cardiac remodelling and heart failure. The myofibroblast, primarily derived from resident fibroblast, is the effector cell type in cardiac fibrosis. Megakaryocytic leukaemia 1 (MKL1) is considered the master regulator of fibroblast–myofibroblast transition (FMyT). The underlying transcriptional mechanism is not completely understood. Our goal was to identify novel transcriptional targets of MKL1 that might regulate FMyT and contribute to cardiac fibrosis.Experimental ApproachRNA sequencing (RNA‐seq) performed in primary cardiac fibroblasts identified insulin‐like growth factor binding protein 5 (IGFBP5) as one of the genes most significantly up‐regulated by constitutively active (CA) MKL1 over‐expression. IGFBP5 expression was detected in heart failure tissues using RT‐qPCR and western blots.Key ResultsOnce activated, IGFBP5 translocated to the nucleus to elicit a pro‐FMyT transcriptional programme. Consistently, IGFBP5 knockdown blocked FMyT in vitro and dampened cardiac fibrosis in mice. Of interest, IGFBP5 interacted with nuclear factor of activated T‐cell 4 (NFAT4) to stimulate the transcription of microfibril‐associated protein 5 (MFAP5). MFAP5 contributed to FMyT and cardiac fibrosis by enabling sterol response element binding protein 2 (SREBP2)‐dependent cholesterol synthesis.Conclusions and ImplicationsOur data unveil a previously unrecognized transcriptional cascade, initiated by IGFBP5, that promotes FMyT and cardiac fibrosis. Screening for small‐molecule compounds that target this axis could yield potential therapeutics against adverse cardiac remodelling.

01 Aug 2024·Life Sciences

Macrophage MKL1 contributes to cardiac fibrosis in a mouse model of myocardial infarction

Article

Author: Kuai, Yameng ; Yu, Wenkui ; Cao, Ke ; Zhu, Yuwen ; Chen, Baoyu ; Zhao, Qianwen

AIMSCardiac fibrosis is characterized by aberrant collagen deposition in the heart. Macrophage polarization or infiltration is the main reason to accelerate the collagen deposition. We attempted to investigate the involvement of MKL1 in macrophages during the development of cardiac fibrosis.MATERIALS AND METHODSCardiac fibrosis is induced by myocardial infarction (MI). The MKL1^f/f mice were crossed to the Lyz2-cre mice to generate macrophage conditional MKL1 knockout mice (MKL1^ΔMφ). In addition, macrophage conditional MKL1 overexpression mice (MKL1^Mϕ-OE) were constructed by crossing Lyz2-cre mice to MKL1^{ΔN200-Rosa26} mice.KEY FINDINGSMKL1 expression was significantly increased in macrophages of both ischemic cardiomyopathy (ICM) patients and mice induced to develop myocardial infarction. Deletion of MKL1 in macrophages improved the heart function after MI-induced cardiac fibrosis. Consistently, MKL1^Mϕ-OE mice displayed more severe cardiac fibrosis and worsened heart function than the control mice after MI. Moreover, administration of a small-molecule MKL1 inhibitor CCG-1423 also decreased the collagen deposition after MI.SIGNIFICANCEOur data demonstrate that MKL1 in macrophages contributes to cardiac fibrosis pathogenesis and reinforce the notion that targeting MKL1 may yield effective antifibrotic therapeutics in the heart.

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MRTFA

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