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Volume 17, Number 2,
Issue of January 15, 1997
pp. 553-562
Copyright ©1997 Society for Neuroscience
Activation of the CED3/ICE-Related Protease CPP32 in Cerebellar
Granule Neurons Undergoing Apoptosis But Not Necrosis
Received Sept. 4, 1996; revised Oct. 17, 1996; accepted Oct. 23, 1996.
Robert C. Armstrong1,
Teresa J. Aja1,
Kim D. Hoang1,
Smita Gaur1,
Xu Bai1,
Emad S. Alnemri2,
Gerald Litwack2,
Donald S. Karanewsky1,
Lawrence C. Fritz1, and
Kevin J. Tomaselli1
1 IDUN Pharmaceuticals, Inc., La Jolla, California
92037, and 2 Jefferson Cancer Institute, Thomas Jefferson
University, Philadelphia, Pennsylvania 19107
Neuronal apoptosis occurs during nervous system development and
after pathological insults to the adult nervous system. Inhibition of
CED3/ICE-related proteases has been shown to inhibit neuronal apoptosis
in vitro and in vivo, indicating a role
for these cysteine proteases in neuronal apoptosis. We have studied the
activation of the CED3/ICE-related protease CPP32 in two in
vitro models of mouse cerebellar granule neuronal cell
death: K+/serum deprivation-induced apoptosis and
glutamate-induced necrosis. Pretreatment of granule neurons with a
selective, irreversible inhibitor of CED3/ICE family proteases,
ZVAD-fluoromethylketone, specifically inhibited granule neuron
apoptosis but not necrosis, indicating a selective role for CED3/ICE
proteases in granule neuron apoptosis. Extracts prepared from
apoptotic, but not necrotic, granule neurons contained a protease
activity that cleaved the CPP32 substrate Ac-DEVD-aminomethylcoumarin.
Induction of the protease activity was prevented by inhibitors of RNA
or protein synthesis or by the CED3/ICE protease inhibitor. Affinity
labeling of the protease activity with an irreversible CED3/ICE
protease inhibitor, ZVK(biotin)D-fluoromethylketone, identified two
putative protease subunits, p20 and p18, that were present in apoptotic but not necrotic granule neuron extracts. Western blotting with antibodies to the C terminus of the large subunit of mouse CPP32 (anti-CPP32) identified p20 and p18 as processed subunits of the CPP32
proenzyme. Anti-CPP32 specifically inhibited the DEVD-amc cleaving
activity, verifying the presence of active CPP32 protease in the
apoptotic granule neuron extracts. Western blotting demonstrated that
the CPP32 proenzyme was expressed in granule neurons before induction
of apoptosis. These results demonstrate that the CED3/ICE homolog CPP32
is processed and activated during cerebellar granule neuron apoptosis.
CPP32 activation requires macromolecular synthesis and CED3/ICE
protease activity. The lack of CPP32 activation during granule neuron
necrosis suggests that proteolytic processing and activation of
CED3/ICE proteases are specific biochemical markers of apoptosis.
Key words:
apoptosis;
necrosis;
cerebellar neurons;
CED3/ICE
proteases;
CPP32;
Caspase
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