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Originally published In Press as doi:10.1074/jbc.M207325200 on October 4, 2002
J. Biol. Chem., Vol. 277, Issue 51, 49220-49229, December 20, 2002
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.
*
This work was supported by the Association pour la Recherche
contre le Cancer (ARC grant n°5333), INSERM, and the CNRS.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a doctoral fellowship from La Ligue Nationale Contre
le Cancer. To whom correspondence should be addressed. Tel.: 33-2-99-54-37-37; Fax: 33-2-99-54-01-37; E-mail:
david.gilot@rennes.inserm.fr.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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