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A high throughput screening platform targeting PDLIM5 for pulmonary hypertension

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Title: A high throughput screening platform targeting PDLIM5 for pulmonary hypertension
Author(s): Zhou, G.A.; Rong, L.; Khatib, N.; Huang, J.B.; Zhou, Q.; Park, D.; Tor, M.; Chen, T.; Cheng, H.
Subject(s): TGF/Smad PDLIM5 luciferase reporter assay high-throughput screening
Abstract: Pulmonary arterial hypertension is a complex disease with multiple etiologic factors. PDLIM5, a member of the Enigma subfamily of PDZ and LIM domain protein family, contains an N-terminal PDZ domain and three LIM domains at its C-terminus. We have previously shown that overexpression of PDLIM5 prevents hypoxia-induced pulmonary hypertension (PH), and deletion of PDLIM5 in smooth muscle cells enhances hypoxia-induced PH in vivo. These results suggest that PDLIM5 may be a novel therapeutic target of PH. In this study, we aim to establish a high-throughput screening platform for PDLIM5-targeted drug discovery. We generated a stable mink lung epithelial cell line (MLEC) containing a transforming growth factor-β/Smad luciferase reporter with lentivirus-mediated suppression of PDLIM5 (MLEC-shPDLIM5) and measured levels of Smad2/3 and pSmad2/3. We found that in MLEC, suppression of PDLIM5 decreased Smad-dependent luciferase activity, Smad3, and pSmad3. We used MLEC-shPDLIM5 and a control cell line (MLEC-shCTL) to screen the Prestwick library (1200 compounds) and identified and validated paclitaxel as a PDLIM5 inhibitor in MLEC. Furthermore, we showed that paclitaxel inhibited Smad2 expression and Smad3 phosphorylation in A549 cells. Our study suggests that this system is robust and suitable for PDLIM5-targeted drug discovery.
Issue Date: 2016-04
Publisher: SAGE Publications
Citation Info: Cheng, H., Chen, T., Tor, M., Park, D., Zhou, Q., Huang, J. B., Khatib, N., Rong, L. and Zhou, G. A High-Throughput Screening Platform Targeting PDLIM5 for Pulmonary Hypertension. Journal of Biomolecular Screening. 2016. 21(4): 333-341. DOI: 10.1177/1087057115625924.
Type: Article
Description: This is a copy of an article published in the Journal of Biomolecular Screening © 2015 SAGE Publications.
URI: http://hdl.handle.net/10027/20672
ISSN: 1087-0571
Sponsor: American Lung Association Biomedical Research Grant, a Pulmonary Hypertension Association/Pfizer Proof-of-Concept award (in which American Thoracic Society provides administrative support), an Inception Grant Arm 1 from UIC CCTS and UICentre, a Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension award (G Zhou), and NIH R01HL123804 (G Zhou).
Date Available in INDIGO: 2017-04-02
 

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