Effects of ICE-like protease and calpain inhibitors on neuronal apoptosis

Nath, Rathna; Raser, Kadee J.; McGinnis, Kim M.; Nadimpalli, Ravi; Stafford, Daniel; Wang, Kevin

doi:10.1097/00001756-199612200-00050

Cited by 117 publications

(90 citation statements)

References 9 publications

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“…However, calpain inhibition had no protective effect in the excess Ca2+e-induced cell death in SH-SYSY cells. Calpain inhibition can, however, attenuate hypoxichypoglycemic injury to cerebrocortical neurons in culture and excitotoxic injury to Purkinje cells in cerebellar slices (Wang et al, 1996~).…”

Section: Cu2+ -Mediated Cell Death and Protease Activationmentioning

confidence: 97%

“…Calpain is activated during necrosis (Wang et al, 199627) and in many cell types undergoing apoptosis (Sarin et al, 1993;Squier et al, 1994) including SH-SY5Y cells . Calpain inhibitors have exhibited protective effects against apoptotic death in cultured cerebellar granule neurons (Nath et al, 1 9 9 6~) and against excitotoxic injury to Purkinje cells in cerebellar slices (Wang et al, 1996~).…”

Section: K M Mcginnis Et Almentioning

confidence: 99%

“…Calpain is activated in staurosporine-induced apoptosis in SH-SYSY cells and cerebellar granule cells in which apoptosis is induced by removal of high K+. It is interesting that calpain inhibitors were able to provide protection against low K+-induced apoptosis in cerebellar granule cells but provided only minimal protection against staurosporineinduced apoptosis in SH-SYSY cells (Nath et al, 1996~). This suggests that a role for calpain in mediating or contributing to apoptotic cell death is likely cell-type specific.…”

Section: Cu2+ -Mediated Cell Death and Protease Activationmentioning

confidence: 99%

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Alterations of Extracellular Calcium Elicit Selective Modes of Cell Death and Protease Activation in SH‐SY5Y Human Neuroblastoma Cells

McGinnis¹,

Wang²,

Gnegy³

1999

Journal of Neurochemistry

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Abstract:The role of intracellular Ca2+ homeostasis in mechanisms of neuronal cell death and cysteine protease activation was investigated in SH-SY5Y human neuroblastoma cells. Cells were incubated in 2 mM EGTA to lower intracellular Ca2+ or 5 mM CaCI, to raise it. Cell death and activation of calpain and caspase-3 were measured. Both EGTA and excess CaCI, elicited cell death. EGTA induced DNA laddering and an increase in caspase-3-like, but not calpain, activity. Pan-caspase inhibitors protected against EGTA-, but not CaCI,-, induced cell death. Conversely, excess Ca2+ elicited necrosis and activated calpain but not caspase-3. Calpain inhibitors did not preserve cell viability. Ca2+ was the death-mediating factor, because restoration of extracelMar Ca2+ protected against cell death induced by EGTA and blockade of Ca2+ channels by Ni'+ protected against that induced by high Ca2+. We conclude that the EGTA treatment lowered intracellular Ca2+ and elicited caspase-3-like protease activity, which led to apoptosis. Conversely, excess extracellular Ca2+ entered Ca2+ channels and increased intracellular Ca2+ leading to calpain activation and necrosis. The mode of cell death and protease activation in response to changing Ca2+ were selective and mutually exclusive, demonstrating that these are useful models to individually investigate apoptosis and necrosis. Key Words: Apoptosis-Necrosis-Calpain-Caspase-3-Ca2+ homeostasis-Neuronal death.

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Section: Cu2+ -Mediated Cell Death and Protease Activationmentioning

confidence: 97%

Section: K M Mcginnis Et Almentioning

confidence: 99%

Section: Cu2+ -Mediated Cell Death and Protease Activationmentioning

confidence: 99%

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Alterations of Extracellular Calcium Elicit Selective Modes of Cell Death and Protease Activation in SH‐SY5Y Human Neuroblastoma Cells

McGinnis¹,

Wang²,

Gnegy³

1999

Journal of Neurochemistry

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“…18 The catalytic activity of calpain is specifically inhibited by an endogenous inhibitor calpastatin. 19 The following observations suggested the proapoptotic role of calpain: (1) calpain inhibitors such as acetyl-Leu-Leu-norleucinal (ALLN, calpain inhibitor I), acetyl-Leu-Leu-methioninal (ALLM, calpain inhibitor II) and benzyloxycarbonyl-Leu-Leu-Tyr diazomethylketone suppressed dexamethasone-induced apoptotic cell death in thymocyte, 20,21 serum deprivationinduced apoptosis in muscle satellite cells, 22 apoptosis in rat cerebellar granule neurons exposed to low potassiumcontaining medium, 23 TGF-b-induced apoptosis in primary cultures of hepatocytes, 24 NGF-deprivation-induced neuronal cell death, 25 calphostin-induced apoptosis in U937 human promonocytic leukemia, 26 and reovirus-induced apoptosis in murine L929 fibroblast. 27 Calpain inhibitors also suppressed activation of caspase-7 during B cell receptor crosslinking on immature B cells.…”

Section: Introductionmentioning

confidence: 99%

Increase in ultraviolet sensitivity by overexpression of calpastatin in ultraviolet-resistant UVr-1 cells derived from ultraviolet-sensitive human RSa cells

et al. 2000

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Human RSa cells are highly sensitive to apoptotic-like cell death by ultraviolet irradiation (UV) while UV r -1 cells are their variant with an increased resistance to UV. Three days after UV at 10 J/m 2 , the viability of RSa cells was approximately 17% while that of UV r -1 cells was 65%. This different survival might reflect apoptotic cell death since apoptosis-specific DNA ladder was more clearly observed in RSa cells than in UV r -1 cells after UV. Addition of ALLN/calpain inhibitor I to the culture medium after UV resulted in similar survival (14 ± 18%) between RSa and UV r -1 cells. Immunoblot analysis showed down-regulation of protein kinase Cy, Src, Bax and m-calpain after UV was more prominent in UV r -1 than in RSa cells. Activated m-calpain appeared within 1 h post-UV only in UV r -1 cells. The expression of calpastatin, a specific endogenous inhibitor of calpain, was higher in RSa than in UV r -1 cells. To further examine the role of calpain in UV-induced cell death, cDNA of human calpastatin was transfected into UV r -1 cells. The results showed that overexpression of calpastatin suppressed down-regulation of Src, m-calpain and Bax. Concomitantly, colony survival after UV was reduced in calpastatin-transfected cells as compared to vector control cells. Our results suggest that activation of calpain might account for, at least in part, the lower susceptibility to UVinduced cell death in UV r -1 cells. Cell Death and Differentiation (2000) 7, 531 ± 537.

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“…Inhibition of caspase-3 activity attenuates apoptosis in osteosarcoma cells (7) and Jurkat T-cells (8,9). Our laboratory has demonstrated that caspase-3 inhibition protects against apoptosis in neuroblastoma cells (10,11) and neurons in primary culture (12). Caspase-3 knockout mice show reduced neuronal death during brain development (13).…”

mentioning

confidence: 99%

Calcium/Calmodulin-dependent Protein Kinase IV Is Cleaved by Caspase-3 and Calpain in SH-SY5Y Human Neuroblastoma Cells Undergoing Apoptosis

McGinnis¹,

Whitton²,

Gnegy³

et al. 1998

Journal of Biological Chemistry

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We have previously demonstrated cleavage of ␣-spectrin by caspase-3 and calpain during apoptosis in SH-SY5Y neuroblastoma cells (Nath, R., Raser, K. J., Stafford, D., Hajimohammadreza, I., Posner, A., Allen, H., Talanian, R. V., Yuen, P., Gilbertsen, R. B., and Wang, K. K. (1996) Biochem. J. 319, 683-690). We demonstrate here that calcium/calmodulin-dependent protein kinase IV (CaMK IV) is cleaved during apoptosis by caspase-3 and calpain. We challenged SH-SY5Y cells with the proapoptotic agent thapsigargin. Western blot analysis revealed major CaMK IV breakdown products of 40, 38, and 33 kDa. Digestion of control SH-SY5Y lysate with purified caspase-3 produced a 38-kDa CaMK IV fragment; digestion with purified calpain produced a major fragment of 40 kDa. Pretreatment with carbobenzoxyAsp-CH 2 OC(O)-2,6-dichlorobenzene or Z-Val-Ala-Aspfluoromethylketone was able to block the caspase-3-mediated production of the 38-kDa fragment both in situ and in vitro. Calpain inhibitor II similarly blocked formation of the calpain-mediated 40-kDa fragment both in situ and in vitro. Digestion of recombinant CaMK IV by other caspase family members revealed that only caspase-3 produces a fragmentation pattern consistent to that seen in situ. The major caspase-3 and calpain cleavage sites are respectively identified as PAPD 176 *A and CG 201 *A, both within the CaMK IV catalytic domain. Furthermore, calmodulin-stimulated protein kinase activity decreases within 6 h in thapsigargin-treated SH-SY5Y. The loss of activity precedes cell death.

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Effects of ICE-like protease and calpain inhibitors on neuronal apoptosis

Cited by 117 publications

References 9 publications

Alterations of Extracellular Calcium Elicit Selective Modes of Cell Death and Protease Activation in SH‐SY5Y Human Neuroblastoma Cells

Alterations of Extracellular Calcium Elicit Selective Modes of Cell Death and Protease Activation in SH‐SY5Y Human Neuroblastoma Cells

Increase in ultraviolet sensitivity by overexpression of calpastatin in ultraviolet-resistant UVr-1 cells derived from ultraviolet-sensitive human RSa cells

Calcium/Calmodulin-dependent Protein Kinase IV Is Cleaved by Caspase-3 and Calpain in SH-SY5Y Human Neuroblastoma Cells Undergoing Apoptosis

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