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1.
Am J Respir Cell Mol Biol ; 67(1): 36-49, 2022 07.
Article in English | MEDLINE | ID: mdl-35377835

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFß (Transforming Growth Factor ß) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity.


Subject(s)
Aurora Kinase A , Idiopathic Pulmonary Fibrosis , Adaptor Proteins, Signal Transducing/metabolism , Animals , Aurora Kinase A/metabolism , Cell Cycle Proteins/metabolism , Fibroblasts/metabolism , Humans , Idiopathic Pulmonary Fibrosis/pathology , Mice , Transforming Growth Factor beta/metabolism , YAP-Signaling Proteins
2.
Am J Respir Cell Mol Biol ; 62(4): 479-492, 2020 04.
Article in English | MEDLINE | ID: mdl-31944822

ABSTRACT

Idiopathic pulmonary fibrosis is a lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. In this study, we developed a high-throughput small-molecule screen for YAP inhibitors in primary human lung fibroblasts. Multiple HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase inhibitors (statins) were found to inhibit YAP nuclear localization via induction of YAP phosphorylation, cytoplasmic retention, and degradation. We further show that the mevalonate pathway regulates YAP activation, and that simvastatin treatment reduces fibrosis markers in activated human lung fibroblasts and in the bleomycin mouse model of pulmonary fibrosis. Finally, we show that simvastatin modulates YAP in vivo in mouse lung fibroblasts. Our results highlight the potential of small-molecule screens for YAP inhibitors and provide a mechanism for the antifibrotic activity of statins in idiopathic pulmonary fibrosis.


Subject(s)
Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Cell Cycle Proteins/antagonists & inhibitors , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Pulmonary Fibrosis/drug therapy , Acyl Coenzyme A/metabolism , Animals , Biomarkers/metabolism , Bleomycin/pharmacology , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cytoplasm/drug effects , Cytoplasm/metabolism , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Mevalonic Acid/metabolism , Mice , Phosphoproteins/metabolism , Pulmonary Fibrosis/metabolism , Signal Transduction/drug effects , Simvastatin/pharmacology , Small Molecule Libraries/pharmacology , YAP-Signaling Proteins
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