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Volume 17, Number 16,
Issue of August 15, 1997
pp. 6105-6113
Copyright ©1997 Society for Neuroscience
The Role of CED-3-Related Cysteine Proteases in Apoptosis of
Cerebellar Granule Cells
Received Jan. 2, 1997; revised May 30, 1997; accepted June 4, 1997.
Basil A. Eldadah1, 2,
Alexander G. Yakovlev1, 3, and
Alan I. Faden1, 3
1 Georgetown Institute for Cognitive and Computational
Sciences, 2 Interdisciplinary Program in Neuroscience, and
3 Department of Neurology, Georgetown University Medical
Center, Washington, DC 20007
The CED-3-related cysteine proteases (CRCPs) have been implicated
as mediators of apoptosis, primarily in hematogenous cell systems, but
their role in neuronal apoptosis remains unclear. The present study
examined the role of two CRCP families CPP32- and interleukin-1
converting enzyme (ICE)-like cysteine proteasesin apoptosis of
cerebellar granule cells (CGCs) caused by withdrawal of serum and/or
potassium (K+). Serum deprivation potentiated
apoptosis caused by K+ withdrawal, reducing cell
viability by approximately one half of control values after 12 hr as
measured by calcein fluorescence. Cell death after
serum/K+ deprivation was significantly attenuated by
the CPP32-like inhibitor z-DEVD-fmk; however, the ICE-like inhibitor
z-YVAD-fmk had only slightly protective effects at the highest
concentration used. Both inhibitors reduced CPP32-like activity
directly in an in vitro fluorometric assay system,
although z-DEVD-fmk showed much greater potency. K+
and serum/K+ deprivation each were accompanied by
increased CPP32-like activity; however, ICE-like activity was absent
after 12 hr of serum and/or K+ deprivation. CPP32
mRNA levels were unchanged after K+ deprivation but
increased after serum and combined serum/K+
withdrawal as measured by reverse transcription-PCR (RT-PCR), with peak
values at 4 hr reaching 210 ± 37% and 269 ± 42% of
control levels, respectively. In contrast, ICE mRNA was undetectable by RT-PCR. These results are consistent with the hypothesis that CPP32-like proteases play an important role in apoptosis of CGCs caused
by deprivation of K+ or
serum/K+.
Key words:
CPP32;
ICE;
CED-3;
cerebellar granule cells;
RT-PCR;
protease activity;
calcein AM
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