riluzole increases the amount of latent hsf1 for an amplified heat shock response and cytoprotection利鲁唑增加潜在hsf1的放大和cytoprotection热休克反应.pdfVIP

Riluzole Increases the Amount of Latent HSF1 for an Amplified Heat Shock Response and Cytoprotection 1 1 2 1 Jingxian Yang , Kristen Bridges , Kuang Yu Chen , Alice Y.-C. Liu * 1 Department of Cell Biology and Neuroscience, Rutgers State University of New Jersey, Piscataway, New Jersey, United States of America, 2 Department of Chemistry and Chemical Biology, Rutgers State University of New Jersey, Piscataway, New Jersey, United States of America Abstract Background: Induction of the heat shock response (HSR) and increased expression of the heat shock proteins (HSPs) provide mechanisms to ensure proper protein folding, trafficking, and disposition. The importance of HSPs is underscored by the understanding that protein mis-folding and aggregation contribute centrally to the pathogenesis of neurodegenerative diseases. Methodology/Principal Findings: We used a cell-based hsp70-luciferease reporter gene assay system to identify agents that modulate the HSR and show here that clinically relevant concentrations of the FDA-approved ALS drug riluzole significantly increased the heat shock induction of hsp70-luciferse reporter gene. Immuno-Western and -cytochemical analysis of HSF1 show that riluzole increased the amount of cytosolic HSF1 to afford a greater activation of HSF1 upon heat shock. The increased HSF1 contributed centrally to the cytoprotective activity of riluzole as hsf1 gene knockout negated the synergistic activity of riluzole and conditioning heat shock to confer cell survival under oxidative stress. Evidence of a post- transcriptional mechanism for the increase in HSF1 include: quantitation of mRNAhsf1 by RT-PCR showed no effect of either heat shock or riluzole tr