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J. Biol. Chem., Vol. 277, Issue 51, 49220-49229, December 20, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/51/49220    most recent M207325200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gilot, D. Articles by Guguen-Guillouzo, C. Search for Related Content PubMed PubMed Citation Articles by Gilot, D. Articles by Guguen-Guillouzo, C. Social Bookmarking                      What's this?

Liver Protection from Apoptosis Requires Both Blockage of Initiator Caspase Activities and Inhibition of ASK1/JNK Pathway via Glutathione S-Transferase Regulation^*

David Gilot, Pascal Loyer, Anne Corlu, Denise Glaise, Dominique Lagadic-Gossmann^§, Azeddine Atfi^¶, Fabrice Morel^§, Hidenori Ichijo, and Christiane Guguen-Guillouzo

From INSERM U522, Régulation des Equilibres fonctionnels du foie Normal et Pathologique, Avenue de la Bataille Flandre/Dunkerque, Hôpital Pontchaillou, 35033 Rennes, ^§ INSERM U456, Détoxication et Réparation Tissulaire, Faculté de Pharmacie, Avenue Léon Bernard, 35049 Rennes, France, ^¶ INSERM U482, 184 Rue du Faubourg Saint-Antoine, Hôpital St-Antoine, Paris 75571, and the  Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan

Hepatoprotection mediated by free radical scavenging molecules such as dimethyl sulfoxide (Me₂SO) arose the question as to whether this effect involved one or several anti-apoptotic signals. Here, using primary cultures of rat hepatocytes and in vivo thioacetamide-induced liver failure, we showed that Me₂SO failed to prevent any cleavage of initiator caspase-8 and -9 but constantly inhibited procaspase-3 maturation and apoptosis execution, pointing to an efficient inhibition of cleaved initiator caspase activities. Evidence was recently provided that apoptosis might require both caspase and ASK1/JNK-p38 activities. We demonstrated that this kinase pathway was strongly inhibited in the presence of Me₂SO whereas overexpression of ASK1 was able to restore caspase-3 activity and apoptosis. Interestingly, we also found that GST M1/2 and GST A1/2 dropped under apoptotic conditions; furthermore transfection of GST M1, A1, or P1 to cells overexpressing ASK1, abolished caspase-3 activity and restored viability. This role of GSTs was further assessed by showing that their high expression level was tightly associated with inhibition of ASK1 activity in Me₂SO-protected hepatocytes. Together, these results demonstrate that Me₂SO-mediated hepatoprotection involves a dual inhibition of cleaved initiator caspase and ASK1/JNK-p38 activities. Furthermore, in highlighting the control of apoptosis by GSTs, these data provide new insights for analyzing the complex mechanisms of hepatoprotection.

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