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J. Biol. Chem., Vol. 278, Issue 16, 14162-14167, April 18, 2003
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From the Departments of Cross-talk between calpain and caspase
proteolytic systems has complicated efforts to determine their distinct
roles in apoptotic cell death. This study examined the effect of
overexpressing calpastatin, the specific endogenous calpain inhibitor,
on the activity of the two proteolytic systems following an apoptotic
stimulus. Human SH-SY5Y neuroblastoma cells were stably transfected
with full-length human calpastatin cDNA resulting in 20-fold
overexpression based on Western blot and 5-fold greater calpain
inhibitory activity in cell extracts. Wild type and calpastatin
overexpressing (CST1) cells were neuronally differentiated and
apoptosis-induced with staurosporine (0.1-1.0 µM).
Calpastatin overexpression decreased calpain activation, increased
caspase-3-like activity, and accelerated the appearance of
apoptotic nuclear morphology. Following 0.1-0.2 µM
staurosporine, plasma membrane integrity based on
calcein-acetoxymethyl fluorescence was significantly greater at
24 h in differentiated CST1 compared with differentiated wild type
cells. However, this protective effect was lost at higher staurosporine
doses (0.5-1.0 µM), which resulted in pronounced
caspase-mediated degradation of the overexpressed calpastatin. These
results suggest a dual role for calpains during neuronal apoptosis. In
the early execution phase, calpain down-regulates caspase-3-like
activity and slows progression of apoptotic nuclear morphology.
Subsequent calpain activity, facilitated by caspase-mediated
degradation of calpastatin, contributes to plasma membrane disruption
and secondary necrosis.
Cross-talk between Calpain and Caspase Proteolytic Systems During
Neuronal Apoptosis*
§,
,
,
Emergency Medicine and
Pharmacology, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania 19104 and the ¶ University of Kentucky
Center on Aging, Lexington, Kentucky 40536
*
This study was supported by grants from the American Heart
Association (9951263U), the W. W. Smith Foundation (H9902), and the Emergency Medicine Foundation.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.
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