|Author||Kawano S, Maruyama J, Nagashima S, Inami K, Qiu W, Iwasa H, Nakagawa K, Ishigami-Yuasa M, Kagechika H, Nishina H, Hata Y.|
|Title||A cell-based screening for TAZ activators identifies ethacridine, a widely used antiseptic and abortifacient, as a compound that promotes dephosphorylation of TAZ and inhibits adipogenesis in C3H10T1/2 cells.|
Transcriptional co-activator with PSD-95/Dlg-A/ZO-1 (PDZ)-binding motif (TAZ) regulates in cell proliferation and differentiation. In mesenchymal stem cells it promotes osteogenesis and myogenesis, and suppresses adipogenesis. TAZ activators are expected to prevent osteoporosis, obesity and muscle atrophy. TAZ activation induces epithelial-mesenchymal transition, confers stemness to cancer cells and leads to poor clinical prognosis in cancer patients. In this point of view, TAZ inhibitors should contribute to cancer therapy. Thus, TAZ attracts attention as a two-faced drug target. We screened for TAZ modulators by using human lung cancer A549 cells expressing the fluorescent reporter. Through this assay, we obtained TAZ activator candidates. We unexpectedly found that ethacridine, a widely used antiseptic and abortifacient, enhances the interaction of TAZ and protein phosphatases and increases unphosphorylated and nuclear TAZ. Ethacridine inhibits adipogenesis in mesenchymal C3H10T1/2 cells through the activation of TAZ. This finding suggests that ethacridine is a bona fide TAZ activator and supports that our assay is useful to discover TAZ activators.
|MeSH||Active Transport, Cell Nucleus / drug effects Adaptor Proteins, Signal Transducing / agonists Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism Adipogenesis / drug effects* Anti-Obesity Agents / pharmacology* Cell Line, Tumor Drug Evaluation, Preclinical Ethacridine / pharmacology* Genes, Reporter / drug effects HEK293 Cells Humans Intracellular Signaling Peptides and Proteins / agonists* Intracellular Signaling Peptides and Proteins / antagonists & inhibitors Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism Luminescent Proteins / genetics Luminescent Proteins / metabolism Mesenchymal Stem Cells / cytology Mesenchymal Stem Cells / drug effects* Mesenchymal Stem Cells / metabolism Phosphoproteins / agonists Phosphoproteins / genetics Phosphoproteins / metabolism Phosphorylation / drug effects Promoter Regions, Genetic / drug effects Protein Phosphatase 1 / chemistry Protein Phosphatase 1 / genetics Protein Phosphatase 1 / metabolism* Protein Phosphatase 2 / chemistry Protein Phosphatase 2 / genetics Protein Phosphatase 2 / metabolism* Protein Processing, Post-Translational / drug effects Protein-Serine-Threonine Kinases / antagonists & inhibitors Protein-Serine-Threonine Kinases / genetics Protein-Serine-Threonine Kinases / metabolism RNA Interference Recombinant Fusion Proteins / chemistry Recombinant Fusion Proteins / metabolism Transcription Factors Tumor Suppressor Proteins / antagonists & inhibitors Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism|
|WOS Category||BIOCHEMISTRY & MOLECULAR BIOLOGY|
|DNA material||pLL3.7 K122 FH-TAZ-ires-GFP-TEAD-responsive-H2B mCherry (RDB13967) pFLAG-human yes-associated protein (YAP)1 (RDB13968) pClneoMyc-LATS1 (RDB13969) pClneoMyc-LATS2 (RDB13970) pClneoLuc-PP1A (RDB13971) pClneoLuc-PP2A (RDB13972).|