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Volume 17, Number 5,
Issue of March 1, 1997
pp. 1561-1569
Copyright ©1997 Society for Neuroscience
Cloning and Expression of a Rat Brain Interleukin-1 -Converting
Enzyme (ICE)-Related Protease (IRP) and Its Possible Role in Apoptosis
of Cultured Cerebellar Granule Neurons
Received Sept. 17, 1996; revised Dec. 2, 1996; accepted Dec. 11, 1996.
Binhui Ni1, 4,
Xin Wu1,
Yansheng Du1,
Yuan Su1,
Elizabeth Hamilton-Byrd1, 3,
Pamela K. Rockey1,
Paul Rosteck Jr.1,
Guy G. Poirier2, and
Steven M. Paul1, 3, 4
1 Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, Indiana 46285, 2 Poly (ADP-Ribose) Polymerase
Metabolism Group, Laboratory of Molecular Endocrinology, Centre
Hospitalier de l'Université Laval Research Center and Laval
University, Sainte-Foy, Québec, Canada, G1V 4G2, and Departments
of 3 Pharmacology and Toxicology and
4 Psychiatry, School of Medicine, Indiana University,
Indianapolis, Indiana 46202
Several members of the IL-1 -converting enzyme (ICE) family of
proteases recently have been implicated in the intracellular cascade
mediating the apoptotic death of various cell types. It is unclear,
however, whether ICE-related proteases are involved in apoptosis of
mammalian neurons and, if so, how they are activated. Here we report
the cloning of an ICE-related protease (IRP) from rat brain, which
displays strong sequence identity to human CPP32. In
situ hybridization histochemistry reveals that this IRP mRNA is
expressed in neuron-enriched regions of the developing and adult rat
brain but is profoundly downregulated in the adult (compared with
developing) brain. To investigate whether this IRP is involved in the
death of neurons in the developing brain, we studied IRP expression in
cultured cerebellar granule neurons. In cultured cerebellar granule
neurons, reduction of extracellular K+ reliably induces
apoptosis and stimulates overexpression of IRP mRNA. The latter is
especially prominent 4 hr after switching from high K+ to
low K+ medium. The expression of IRP mRNA was maintained at
this level for at least 8 hr and was followed by apoptotic death of
these neurons. Induction of IRP mRNA and cell death are blocked
completely by adding depolarizing concentrations of K+  90
min after switching to low K+ medium (i.e., before the
commitment point for apoptosis) and partially blocked by brain-derived
neurotrophic factor (BDNF), which also partially rescues granule
neurons from low K+-induced apoptosis. In addition,
overexpression of IRP cDNA in HeLa cells results in cell death
accompanied by strong internucleosomal cleavage of DNA, a typical
feature of apoptosis. Finally, we detected cleavage of the putative
death substrate poly (ADP-ribose) polymerase (PARP), beginning 8 hr
after changing from high K+ to low K+ medium,
coinciding with the time course of induced expression of the IRP gene.
Our data suggest that transcriptional activation of IRP could be one of
the mechanisms involved in the apoptotic death of cerebellar granule
neurons.
Key words:
ICE-related protease;
CPP32/YAMA/apopain;
neuronal
apoptosis;
molecular cloning;
cerebellar granule neurons
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