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.
Highlights
Yes-associated protein 1 (YAP1) was identified as a protein interacting with yes tyrosine kinase [1]
NheI/EcoRI fragment was isolated from pEGFP-C2 (Clontech Laboratories) and ligated into NheI/EcoRI sites of pCIneo (Promega) to generate pCIneoEGFPC2. pIRES2-EGFP (Clontech Laboratories) was cut with NotI, filled in, and digested with NheI. pLL3.7 vector was cut with EcoRI, filled in, and digested with NheI
We evaluated the effects of 47 compounds on a YAP1-depedent TEA-domain family proteins (TEAD) reporter assay in HEK293FT cells and YAP1 phosphorylation in ARPE-19 reporter cells
Summary
Yes-associated protein 1 (YAP1) was identified as a protein interacting with yes tyrosine kinase [1]. YAP1 is negatively regulated by the tumor suppressor Hippo pathway [7, 8]. The Hippo pathway is frequently deregulated and the YAP1 gene is amplified, so that YAP1 activity is enhanced [9]. Cancer cells with hyperactive YAP1 undergo epithelial–mesenchymal transition and acquire drug resistance [10]. Upon DNA damage, ABL1 phosphorylates YAP1 at tyrosine 357 and promotes the interaction with p73. We established a new cell-based assay, in which the YAP1-dependent TEAD-responsive reporter activity is monitored. We performed a small chemical compound library screening with the use of this assay and obtained candidate YAP1 activators. We characterized these compounds to examine whether they activate YAP1 and tested the idea that YAP1 activator can be used against MM and other blood cancer cells
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