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Riluzole increases the amount of latent HSF1 for an amplified heat shock response and cytoprotection
- Source :
- PLoS ONE, Vol 3, Iss 8, p e2864 (2008), PLoS ONE
- Publication Year :
- 2008
- Publisher :
- Public Library of Science (PLoS), 2008.
-
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 mRNA(hsf1) by RT-PCR showed no effect of either heat shock or riluzole treatment; riluzole also increased the expression of HSF1 from a CMV-promoter; analysis of the turnover of HSF1 by pulse chase and immunoprecipitation show that riluzole slowed the decay of [(35)S]labeled-HSF1. The effect of riluzole on HSF1 was qualitatively different from that of MG132 and chloroquine, inhibitors of the proteasome and lysosome, respectively, and appeared to involve the chaperone-mediated autophagy pathway as RNAi-mediated knockdown of CMA negated its effect. CONCLUSION/SIGNIFICANCE: We show that riluzole increased the amount of HSF1 to amplify the HSR for cytoprotection. Our study provides novel insight into the mechanism that regulates HSF1 turnover, and identifies the degradation of HSF1 as a target for therapeutics intervention.
- Subjects :
- Hot Temperature
Cell Survival
lcsh:Medicine
Biology
Biochemistry/Protein Folding
03 medical and health sciences
0302 clinical medicine
Heat Shock Transcription Factors
Genes, Reporter
Heat shock protein
Excitatory Amino Acid Agonists
medicine
Humans
Heat shock
Luciferases
HSF1
lcsh:Science
Cell Biology/Gene Expression
030304 developmental biology
Neurons
0303 health sciences
Gene knockdown
Riluzole
Multidisciplinary
fungi
lcsh:R
Neurodegenerative Diseases
Cell Biology/Cellular Death and Stress Responses
Cytoprotection
Molecular biology
3. Good health
Cell biology
DNA-Binding Proteins
Heat shock factor
Spinal Cord
Proteasome
lcsh:Q
Biochemistry/Drug Discovery
Neuroscience/Neurobiology of Disease and Regeneration
030217 neurology & neurosurgery
Research Article
Pharmacology/Drug Development
HeLa Cells
Transcription Factors
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 3
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....9494ac3521f8b8ea88ba0a7a57024eb3