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1.
Mol Cancer Res ; 16(2): 197-211, 2018 02.
Article in English | MEDLINE | ID: mdl-29061667

ABSTRACT

Yes-associated protein 1 (YAP1) interacts with numerous transcription factors, including TEA-domain family proteins (TEAD) and p73. YAP1 is negatively regulated by the tumor suppressor Hippo pathway. In human cancers, the deregulation of the Hippo pathway and YAP1 gene amplification lead to the activation of YAP1, which induces epithelial-mesenchymal transition (EMT) and drug resistance. YAP1 inhibitors are expected to be useful in cancer therapy. On the other hand, in certain cancers, YAP1 upregulates p73-dependent gene transcription and behaves as a tumor suppressor. Moreover, as YAP1 regulates self-renewal and differentiation of tissue stem cells and plays an important role in tissue homeostasis, YAP1 activators may contribute to the regenerative medicine. With this in our mind, we screened for YAP1 activators by using human retinal pigment epithelial ARPE-19 cells expressing the TEAD-responsive fluorescence reporter under the coexpression of YAP1. From an extensive chemical compound library (n = 18,606) 47 candidate YAP1 activators were identified. These compounds were characterized to determine whether this assay provides bona fide YAP1 activators. Importantly, one YAP1 activator was effective against the human multiple myeloma IM-9 cells and chronic myeloid leukemia K562 cells.Implications: YAP1 activation limits growth, induces apoptosis, and may be useful at suppressing hematological cancers. Mol Cancer Res; 16(2); 197-211. ©2017 AACR.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Multiple Myeloma/drug therapy , Phosphoproteins/genetics , Phosphoproteins/metabolism , Small Molecule Libraries/administration & dosage , Transcriptional Activation , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Epithelial-Mesenchymal Transition/drug effects , Gene Expression Regulation, Neoplastic/drug effects , HEK293 Cells , Humans , K562 Cells , Mice , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Retinal Pigment Epithelium/cytology , Retinal Pigment Epithelium/drug effects , Retinal Pigment Epithelium/metabolism , Small Molecule Libraries/pharmacology , Transcription Factors/metabolism , Xenograft Model Antitumor Assays , YAP-Signaling Proteins
2.
J Biochem ; 158(5): 413-23, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25979969

ABSTRACT

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.


Subject(s)
Adipogenesis/drug effects , Anti-Obesity Agents/pharmacology , Ethacridine/pharmacology , Intracellular Signaling Peptides and Proteins/agonists , Mesenchymal Stem Cells/drug effects , Protein Phosphatase 1/metabolism , Protein Phosphatase 2/metabolism , Active Transport, Cell Nucleus/drug effects , Adaptor Proteins, Signal Transducing/agonists , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Cell Line, Tumor , Drug Evaluation, Preclinical , Genes, Reporter/drug effects , HEK293 Cells , Humans , 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/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 2/chemistry , Protein Phosphatase 2/genetics , 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 , Trans-Activators , Transcription Factors , Transcriptional Coactivator with PDZ-Binding Motif Proteins , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , YAP-Signaling Proteins
3.
Exp Cell Res ; 319(7): 931-45, 2013 Apr 15.
Article in English | MEDLINE | ID: mdl-23396260

ABSTRACT

The mammalian Hippo pathway comprises mammalian Ste20-like kinases (MST1/2) and large tumor suppressor kinases (LATS1/2). LATS1/2, which are activated by MST1/2, phosphorylate a transcriptional co-activator, yes-associated protein (YAP), and induce the recruitment of YAP by 14-3-3 to cytoplasm, so that the TEAD-dependent gene transcriptions are turned off. Although the core components of the Hippo pathway are well conserved in metazoans, it has been discussed that Caenorhabditis elegans lacks YAP ortholog, we found that F13E6.4 gene encodes a protein that shows sequence similarities to YAP in the N-terminal TEAD-binding domain and in the WW domain. We designated this gene as yap-1. YAP-1 is widely expressed in various cells such as epithelial cells, muscles, hypodermal cells, gonadal sheath cells, spermatheca, and hypodermal cells. YAP-1 is distributed in cytoplasm and nuclei. wts-1 (LATS ortholog) and ftt-2 (14-3-3 ortholog) knockdowns cause nuclear accumulation of YAP-1, supporting that the subcellular localization of YAP-1 is regulated in a similar way as that of YAP. Heat shock also causes the nuclear accumulation of YAP-1 but after heat shock, YAP-1 translocates to cytoplasm. Knockdowns of DAF-21 (HSP90 ortholog) and HSF-1block the nuclear export of YAP-1 during this recovery. YAP-1 overexpression is beneficial for thermotolerance, whereas YAP-1 hyperactivity induced by wts-1 and ftt-2 knockdowns is deleterious on thermal response and yap-1 deficiency promotes health aging. In short, YAP-1 partially shares basal characters with mammalian YAP and plays a role in thermal stress response and healthy aging.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Aging , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Phosphoproteins/metabolism , Active Transport, Cell Nucleus/physiology , Animals , Cytoplasm/metabolism , Humans , Protein Binding/physiology , Signal Transduction/physiology , Temperature , Transcription Factors/genetics , Transcription Factors/metabolism , YAP-Signaling Proteins
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