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Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, Villejuif, France
Proteasomes and mitochondrial membrane changes are involved in
thymocyte apoptosis. The hierarchical relationship between protease
activation and mitochondrial alterations has been elusive. Here we show
that inhibition of proteasomes by two specific agents, lactacystin or
MG132, prevents all manifestations of thymocyte apoptosis induced by
the glucocorticoid receptor agonist dexamethasone or by the
topoisomerase II inhibitor etoposide. Lactacystin and MG132 prevent the
early disruption of the mitochondrial transmembrane potential
(
m), which precedes caspase activation,
exposure of phosphatidylserine, and nuclear DNA fragmentation. In
contrast, stabilization of the m using the
permeability transition pore inhibitor bongkrekic acid or inhibition of
caspases by
N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone does not
prevent the activation of proteasomes, as determined with the
fluorogenic substrate
N-succinyl-L-leucyl-L-leucyl-L-valyl-L-tyrosine-7-amido-4-methylcoumarin.
Thus, proteasome activation occurs upstream from mitochondrial changes
and caspase activation. Whereas the proteasome-specific agents
lactacystin and MG132 truly maintain thymocyte viability, a number of
protease inhibitors that inhibit nuclear DNA fragmentation
(acetyl-Asp-Glu-Val-Asp-fluoromethylketone;
N-Boc-Asp(OMe)-fluoromethylketone;
N-tosyl-L-Phe-chloromethylketone) do not
prevent the cytolysis induced by DEX or etoposide. These latter agents
fail to interfere with the preapoptotic m disruption.
Altogether, our data indicate that different proteases may be involved
in the pre- or postmitochondrial phase of apoptosis. Only those
protease inhibitors that interrupt the apoptotic process at the
premitochondrial stage can actually preserve cell viability.
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