预约演示

更新于：2025-05-07

MRTFB x MRTFA

更新于：2025-05-07

基本信息

关联

项与 MRTFB x MRTFA 相关的药物

MRTF inhibitor(Michigan State University)

靶点

MRTFA x MRTFB

作用机制

MRTFA inhibitors [+1]

在研机构-

原研机构

Michigan State University

在研适应症-

非在研适应症

黑色素瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MRTFB x MRTFA 相关的临床结果

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100 项与 MRTFB x MRTFA 相关的转化医学

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0 项与 MRTFB x MRTFA 相关的专利（医药）

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项与 MRTFB x MRTFA 相关的文献（医药）

2025-03-14·Cancer Research

MICAL2 Promotes Pancreatic Cancer Growth and Metastasis

Article

作者: Commisso, Cosimo ; Gallinger, Steven ; Sheik Pran Babu, Deepa ; Tamayo, Pablo ; Jang, Gun Ho ; Courelli, Asimina S. ; Sood, Divya ; Garg, Bharti ; Martsinkovskiy, Alexei ; Aggarwal, Neetu ; Goodfellow, Elliot ; D’Ippolito, Anthony ; Lambies, Guillem ; Johnston, Brian ; Tiriac, Hervé ; Lowy, Andrew M. ; Brodt, Pnina ; Wenzel, Alexander T. ; Jaque, Katelin ; Gulay, Kevin Christian Montecillo ; Sharma, Shweta ; Mesirov, Jill P. ; Patel, Jay ; Esparza, Edgar ; Khan, Sohini ; Austgen, Kathryn ; Rajbhandari, Nirakar ; Orlando, David A. ; Panneerpandian, Ponmathi ; Mose, Evangeline S. ; Jaquish, Dawn

AbstractPancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super-enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as an SE-associated gene in human PDAC, which encodes the flavin monooxygenase enzyme that induces actin depolymerization and indirectly promotes serum response factor transcription by modulating the availability of serum response factor coactivators such as myocardin-related transcription factors (MRTF-A and MRTF-B). MICAL2 was overexpressed in PDAC, and high-MICAL2 expression correlated with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and epithelial–mesenchymal transition signaling pathways, contributing to tumor growth and metastasis. In loss- and gain-of-function experiments in human and mouse PDAC cells, MICAL2 promoted both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 also inhibited macropinocytosis. MICAL2, MRTF-A, and MRTF-B influenced PDAC cell proliferation and migration and promoted cell-cycle progression in vitro. Importantly, MICAL2 supported in vivo tumor growth and metastasis. Interestingly, MRTF-B, but not MRTF-A, phenocopied MICAL2-driven phenotypes in vivo. This study highlights the multiple ways in which MICAL2 affects PDAC biology and provides a foundation for future investigations into the potential of targeting MICAL2 for therapeutic intervention.Significance: Characterization of the epigenomic landscape of pancreatic cancer to identify early drivers of tumorigenesis uncovered MICAL2 as a super-enhancer–associated gene critical for tumor progression that represents a potential pharmacologic target.

2024-10-01·Journal of Medical Virology

Exploring the effects of Merkel cell polyomavirus T antigens expression in REH and MCC13 cells by methylome and transcriptome profiling

Article

作者: Borman, Felix ; Liu, Dan ; van den Oord, Joost ; Färber, Martina ; Klufah, Faisal ; Macamo, Amanda ; Winnepenninckx, Véronique ; Chteinberg, Emil ; zur Hausen, Axel

AbstractMerkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a tripled incidence in the US and Europe over the past decade. Around 80% of MCC is linked to Merkel cell polyomavirus, but the cell of origin remains unknown. We stably introduced Merkel cell polyomavirus (MCPyV)‐sT) and LT antigens to MCC13 and REH cell lines, analyzing DNA methylation and gene transcriptional regulation. Gene ontology analysis assessed MCPyV effects, and integrative analysis correlated gene expression and methylation. Expression patterns were compared with 15 previously sequenced primary MCCs. We found that MCPyV‐LT induces DNA methylation changes in both cell lines, while MCPyV‐sT only affected REH cells. Greater gene expression changes are observed in MCC13 cells, with upregulated genes associated with cellular components and downregulated genes related to biological processes. Integrative analysis of differentially expressed genes (DEG) and differentially methylated regions (DMR) of REH cell lines revealed that no genes were commonly methylated and differentially expressed. The study compared DEGs and DMG in MCC13 and REH cells to overlapping genes in MCPyV‐positive cell lines (MKL1, MKL2, and WaGa), identifying hypomethylated genes in the gene body and hypermethylated genes at TSS1500. GO analysis of the two cell lines showed that MCPyV‐TAs can downregulate genes in MHC‐I pathways; this downregulation offers a target that can be used to create novel and efficient MCC immunotherapy approaches. Finally, it was confirmed that MCPyV‐LT controls gene expression in MCC tissues using an integrative investigation of DNA methylation and gene expression.

2023-09-29·bioRxiv : the preprint server for biology

Myocardin-related transcription factors regulate morphogenetic events in vertebrate embryos by controlling F-actin organization and apical constriction.

作者: Sokol, Sergei Y ; Itoh, Keiji ; Ossipova, Olga ; Matsuda, Miho

Myocardin-related transcription factors (Mrtfa and Mrtfb), also known as megakaryoblastic leukemia proteins (Mkl1/MAL and Mkl2), associate with serum response factor (Srf) to regulate transcription in response to actin dynamics, however, the functions of Mrtfs in early vertebrate embryos remain largely unknown. Here we document the requirement of Mrtfs for blastopore closure at gastrulation and neural plate folding in Xenopus early embryos. Both stimulation and inhibition of Mrtf activity caused similar gross morphological phenotypes, yet the effects on F-actin distribution and cell behavior were different. Suppressing Mrtf-dependent transcription reduced overall F-actin levels and inhibited apical constriction during gastrulation and neurulation. By contrast, constitutively active Mrtf caused tricellular junction remodeling and induced apical constriction in superficial ectoderm. The underlying mechanism appeared distinct from the one utilized by known apical constriction inducers. We propose that the regulation of apical constriction is among the primary cellular responses to Mrtf. Our findings highlight a dedicated role of specific transcription factors, Mrtfs, in early morphogenetic processes.

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