Clusterin is a secreted protein chaperone up-regulated in several pathologies, including cancer and neurodegenerative diseases. The present study shows that accumulation of aberrant proteins, caused by the proteasome inhibitor MG132 or the incorporation of the amino acid analogue AZC (L-azetidine-2-carboxylic acid), increased both clusterin protein and mRNA levels in the human glial cell line U-251 MG. Consistently, MG132 treatment was capable of stimulating a 1.3 kb clusterin gene promoter. Promoter deletion and mutation studies revealed a critical MG132-responsive region between −218 and −106 bp, which contains a particular heat-shock element, named CLE for ‘clusterin element’. Gel mobility-shift assays demonstrated that MG132 and AZC treatments induced the formation of a protein complex that bound to CLE. As shown by supershift and chromatin-immunoprecipitation experiments, CLE is bound by HSF1 (heat-shock factor 1) and HSF2 upon proteasome inhibition. Furthermore, co-immunoprecipitation assays indicated that these two transcription factors interact. Gel-filtration analyses revealed that the HSF1–HSF2 heterocomplexes bound to CLE after proteasome inhibition have the same apparent mass as HSF1 homotrimers after heat shock, suggesting that HSF1 and HSF2 could heterotrimerize. Therefore these studies indicate that the clusterin is a good candidate to be part of a cellular defence mechanism against neurodegenerative diseases associated with misfolded protein accumulation or decrease in proteasome activity.
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Research Article|
March 15 2006
Up-regulation of the clusterin gene after proteotoxic stress: implication of HSF1–HSF2 heterocomplexes
Fabien Loison;
Fabien Loison
1Information et Programmation Cellulaire, UMR CNRS 6026, Interactions Cellulaires et Moléculaires, IFR 140 – Génétique Fonctionnelle Agronomie et Santé, Université de Rennes 1, France
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Laure Debure;
Laure Debure
1Information et Programmation Cellulaire, UMR CNRS 6026, Interactions Cellulaires et Moléculaires, IFR 140 – Génétique Fonctionnelle Agronomie et Santé, Université de Rennes 1, France
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Philippe Nizard;
Philippe Nizard
1Information et Programmation Cellulaire, UMR CNRS 6026, Interactions Cellulaires et Moléculaires, IFR 140 – Génétique Fonctionnelle Agronomie et Santé, Université de Rennes 1, France
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Pascale le Goff;
Pascale le Goff
1Information et Programmation Cellulaire, UMR CNRS 6026, Interactions Cellulaires et Moléculaires, IFR 140 – Génétique Fonctionnelle Agronomie et Santé, Université de Rennes 1, France
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Denis Michel;
Denis Michel
1Information et Programmation Cellulaire, UMR CNRS 6026, Interactions Cellulaires et Moléculaires, IFR 140 – Génétique Fonctionnelle Agronomie et Santé, Université de Rennes 1, France
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Yves le Dréan
Yves le Dréan
1
1Information et Programmation Cellulaire, UMR CNRS 6026, Interactions Cellulaires et Moléculaires, IFR 140 – Génétique Fonctionnelle Agronomie et Santé, Université de Rennes 1, France
1To whom correspondence should be addressed (email Yves.Le-Drean@univ-rennes1.fr).
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Publisher: Portland Press Ltd
Received:
July 22 2005
Revision Received:
December 05 2005
Accepted:
December 09 2005
Accepted Manuscript online:
December 09 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 395 (1): 223–231.
Article history
Received:
July 22 2005
Revision Received:
December 05 2005
Accepted:
December 09 2005
Accepted Manuscript online:
December 09 2005
Connected Content
A commentary has been published:
Clustering of heat-shock factors
Citation
Fabien Loison, Laure Debure, Philippe Nizard, Pascale le Goff, Denis Michel, Yves le Dréan; Up-regulation of the clusterin gene after proteotoxic stress: implication of HSF1–HSF2 heterocomplexes. Biochem J 1 April 2006; 395 (1): 223–231. doi: https://doi.org/10.1042/BJ20051190
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