Molecular Biology of the Cell Sign up for new MBC in Press e-TOCs!

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

MBC in Press, published online ahead of print July 25, 2007
Mol. Biol. Cell 10.1091/mbc.E07-05-0491

A more recent version of this article appeared on October 1, 2007
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
E07-05-0491v1
18/10/3903    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nadeau, P. J.
Right arrow Articles by Landry, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nadeau, P. J.
Right arrow Articles by Landry, J.

Submitted on May 24, 2007
Revised on July 9, 2007
Accepted on July 16, 2007

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H2O2-induced JNK Activation and Apoptosis

Philippe J. Nadeau,* Steve J. Charette,* Michel B. Toledano,{dagger} and Jacques Landry*

*Centre de Recherche en Cancérologie de l’Université Laval, L’Hôtel-Dieu de Québec, Québec, Canada, G1R 2J6; {dagger}Laboratoire Stress Oxydants et Cancer, Service de Biologie Moléculaire Systémique, DBJC, CEA-Saclay, 91191 Gif-sur-Yvette Cedex, France

Monitoring Editor: Carole Parent

Apoptosis signal regulated kinase-1 (Ask1) lies upstream of a major redox-sensitive pathway leading to the activation of Jun N-terminal kinase (JNK) and the induction of apoptosis. We found that cell exposure to H2O2 caused the rapid oxidation of Ask1 leading to its multimerization through the formation of interchain disulfide bonds. Oxidized Ask1 was fully reduced within minutes after induction by H2O2. During this reduction, the thiol-disulphide oxidoreductase thioredoxin-1 (Trx1) became covalently associated with Ask1. Overexpression of Trx1 accelerated the reduction of Ask1 and a redox-inactive mutant of Trx1 (C35S) remained trapped with Ask1 blocking its reduction. Preventing the oxidation of Ask1 by either overexpressing Trx1 or using an Ask1 mutant in which the sensitive cysteines were mutated (Ask1-{Delta}Cys), impaired the activation of JNK and the induction of apoptosis while having little effect on Ask1 activation. Those results indicate that Ask1 oxidation is required at a step subsequent to activation for signaling downstream of Ask1 after H2O2-treatment.

Address correspondence to: Jacques Landry (jacques.landry{at}med.ulaval.ca)






Home Help [Feedback] [For Subscribers] [Archive] [Search] --
Copyright © 2007 by The American Society for Cell Biology. Terms of copyright protection, warranties, and disclaimers.