Last update 01 Nov 2024

NF-κB x MRTFA

Last update 01 Nov 2024

Basic Info

Related Targets

NF-κBMRTFA

Drugs associated with NF-κB x 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

100 Clinical Results associated with NF-κB x MRTFA

100 Translational Medicine associated with NF-κB x MRTFA

0 Patents (Medical) associated with NF-κB x MRTFA

Literatures (Medical) associated with NF-κB x MRTFA

04 Jul 2023·Circulation

INKILN is a Novel Long Noncoding RNA Promoting Vascular Smooth Muscle Inflammation via Scaffolding MKL1 and USP10

Article

Author: Gao, Ping ; Bryant, William B ; Kempf, Wolfgang ; Lu, Yao Wei ; Shan, Shengshuai ; Long, Xiaochun ; Warthi, Ganesh ; Choi, Mihyun ; Weintraub, Neal L ; Lyu, Qing ; Zhang, Wei ; Kim, David ; Baker, Andrew H ; Kim, Ha Won ; Deng, Lin ; Ishimwe, Nestor ; Pauli, Jessica ; Bennett, Matthew ; Ballantyne, Margaret D ; Rodor, Julie ; Miller, Clint L ; Barroso, Margarida M ; Miano, Joseph M ; Maegdefessel, Lars ; Wu, Wen ; Zhao, Jinjing ; Turner, Adam W

Background:Activation of vascular smooth muscle cell (VSMC) inflammation is vital to initiate vascular disease. The role of human-specific long noncoding RNAs in VSMC inflammation is poorly understood.Methods: Bulk RNA sequencing in differentiated human VSMCs revealed a novel human-specific long noncoding RNA called inflammatory MKL1 (megakaryoblastic leukemia 1) interacting long noncoding RNA ( INKILN ). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation as well as human atherosclerosis and abdominal aortic aneurysm. The transcriptional regulation of INKILN was verified through luciferase reporter and chromatin immunoprecipitation assays. Loss-of-function and gain-of-function studies and multiple RNA–protein and protein–protein interaction assays were used to uncover a mechanistic role of INKILN in the VSMC proinflammatory gene program. Bacterial artificial chromosome transgenic mice were used to study INKILN expression and function in ligation injury–induced neointimal formation. Results:INKILN expression is downregulated in contractile VSMCs and induced in human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB (nuclear factor kappa B) site within its proximal promoter. INKILN activates proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway. INKILN depletion blocks interleukin-1β–induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1 and the luciferase activity of an NF-κB reporter. Furthermore, INKILN knockdown enhances MKL1 ubiquitination through reduced physical interaction with the deubiquitinating enzyme USP10 (ubiquitin-specific peptidase 10). INKILN is induced in injured carotid arteries and exacerbates ligation injury–induced neointimal formation in bacterial artificial chromosome transgenic mice. Conclusions: These findings elucidate an important pathway of VSMC inflammation involving an INKILN /MKL1/USP10 regulatory axis. Human bacterial artificial chromosome transgenic mice offer a novel and physiologically relevant approach for investigating human-specific long noncoding RNAs under vascular disease conditions.

01 Dec 2021·BMC CancerQ2 · MEDICINE

MKL1 regulates hepatocellular carcinoma cell proliferation, migration and apoptosis via the COMPASS complex and NF-κB signaling

Q2 · MEDICINE

ArticleOA

Author: Sun, Jiuzheng ; Liu, Zhao ; Xu, Liyou ; Li, Chuanzhi ; Liu, Jun

AbstractBackgroundHistone modification plays essential roles in hepatocellular carcinoma (HCC) pathogenesis, but the regulatory mechanisms remain poorly understood. In this study, we aimed to analyze the roles of Megakaryoblastic leukemia 1 (MKL1) and its regulation of COMPASS (complex of proteins associated with Set1) in HCC cells.MethodsMKL1 expression in clinical tissues and cell lines were detected by bioinformatics, qRT-PCR and western blot. MKL1 expression in HCC cells were silenced with siRNA, followed by cell proliferation evaluation via Edu staining and colony formation, migration and invasion using the Transwell system, and apoptosis by Hoechst staining. HCC cell tumorigenesis was assessed by cancer cell line-based xenograft model, combined with H&E staining and IHC assays.ResultsMKL1 expression was elevated in HCC cells and clinical tissues which was correlated with poor prognosis. MKL1 silencing significantly repressed proliferation, migration, invasion and colony formation but enhanced apoptosis in HepG2 and Huh-7 cells. MKL1 silencing also inhibited COMPASS components and p65 protein expression in HepG2 and Huh-7 cells. HepG2 cell tumorigenesis in nude mice was severely impaired by MKL1 knockdown, resulted into suppressed Ki67 expression and cell proliferation.ConclusionMKL1 promotes HCC pathogenesis by regulating hepatic cell proliferation, migration and apoptosis via the COMPASS complex and NF-κB signaling.

01 Oct 2021·Human & Experimental ToxicologyQ4 · MEDICINE

Therapeutic effects of myocardin-related transcription factor A (MRTF-A) knockout on experimental mice with nonalcoholic steatohepatitis induced by high-fat diet

Q4 · MEDICINE

Article

Author: Cui, Xiao-Chun ; Li, Hua-Long ; Zhang, Lei ; Zhang, Ding-Ding

Objective: To explore the effects of myocardin-related transcription factor A (MRTF-A) knockout on mice with nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD). Methods: Normal-fat diet (NFD) or HFD was fed to MRTF-A-knockout (MRTF-A−/−) and wild-type (WT) mice for 16 weeks. Liver histopathological status was observed using Hematoxylin and Eosin (HE) staining, Oil Red O staining, Sirius Red staining, and Immunohistochemical staining. The mRNA and protein levels in liver tissues were measured through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Results: Compared with WT + HFD group, mice in MRTF-A−/− + HFD group were decreased in body weight, blood glucose, plasma insulin, liver TG and NAFLD activity score (NAS), with liver function recovery. Besides, compared with HFD-fed WT mice, HFD-fed MRTF-A−/− mice were improved in hepatic fibrosis, accompanied by decreased collagen content (%) and down-regulated expressions of α-SMA, COL1A2, TGFβ1, and SMAD3. In mice fed with HFD, the expression of MCP-1, CCR2, F4/80 and CD68 declined in liver tissues of MRTF-A−/− mice as compared with WT mice. Besides, in hepatic macrophages isolated from HFD-fed mice, the observed increased expression of TNF-α, IL-1β, MCP-1, as well as decreased expression of CCR2. Compared with WT + HFD group, MRTF-A−/− + HFD group mice were decreased regarding NF-κB p65 in liver tissues. Conclusion: MRTF-A knockout reduced macrophage infiltration, down-regulated NF-κB p65 expression, and ameliorated inflammation and fibrosis of liver tissues in mice, thereby becoming a potential therapeutic target for NASH treatment.

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