Journalartikel

Jahr der Veröffentlichung: 2017

Zeitschrift: PLoS ONE

Bandnummer: 12

Heftnummer: 2

ISSN: 1932-6203

Open Access Status: Gold

DOI Link: https://doi.org/10.1371/journal.pone.0172116

Verlag: Public Library of Science

Abstract: 
A hallmark of acute respiratory distress syndrome (ARDS) is accumulation of protein-rich edema in the distal airspaces and its removal is critical for patient survival. Previous studies have shown a detrimental role of Glycogen Synthase Kinase (GSK) 3 beta during ARDS via inhibition of alveolar epithelial protein transport. We hypothesized that post-transcriptional regulation of GSK3 beta could play a functional role in ARDS resolution. To address this hypothesis, we performed an in silico analysis to identify regulatory genes whose expression correlation to GSK3 beta messenger RNA utilizing two lung cancer cell line array datasets. Among potential regulatory partners of GSK3 beta, these studies identified the RNA-binding protein ELAVL-1/HuR (Embryonic Lethal, Abnormal Vision, Drosophila-Like) as a central component in a likely GSK3 beta signaling network. ELAVL-1/HuR is a RNA-binding protein that selectively binds to AU-rich elements of mRNA and enhances its stability thereby increasing target gene expression. Subsequent studies with siRNA suppression of ELAVL-1/HuR demonstrated deceased GSK3 beta mRNA and protein expression and improved clearance of FITC-albumin in A549 cells. Conversely, stabilization of ELAVL-1/HuR with the proteasome inhibitor MG-132 resulted in induction of GSK3 beta at mRNA and protein level and attenuated FITC-albumin clearance. Utilizing ventilator-induced lung injury or intra-tracheal installation of hydrochloric acid to induce ARDS in mice, we observed increased mRNA and protein expression of ELAVL-1/HuR and GSK3 beta. Together, our findings indicate a previously unknown interaction between GSK3 beta and ELAV-1 during ARDS, and suggest the inhibition of the ELAV-1- GSK3 beta pathways as a novel ARDS treatment approach.

Harvard-Zitierstil: Hoffman, O., Burns, N., Vadasz, I., Eltzschig, H., Edwards, M. and Vohwinkel, C. (2017) Detrimental ELAVL-1/HuR-dependent GSK3β mRNA stabilization impairs resolution in acute respiratory distress syndrome, PLoS ONE, 12(2), Article e0172116. https://doi.org/10.1371/journal.pone.0172116

APA-Zitierstil: Hoffman, O., Burns, N., Vadasz, I., Eltzschig, H., Edwards, M., & Vohwinkel, C. (2017). Detrimental ELAVL-1/HuR-dependent GSK3β mRNA stabilization impairs resolution in acute respiratory distress syndrome. PLoS ONE. 12(2), Article e0172116. https://doi.org/10.1371/journal.pone.0172116