Activation of caspase-12, an endoplasmic reticulum resident caspase, after permanent focal ischemia in rat

Mouw, Graham; Zechel, Jennifer; Gamboa, Jorge L.; Lust, W. David; Selman, Warren R.; Ratcheson, Robert A.

doi:10.1097/00001756-200302100-00004

Cited by 54 publications

(23 citation statements)

References 19 publications

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“…Since the signaling pathways and machinery of the ER stress response are similar among mammalian cell types (DeGracia et al, 2002;Harding and Ron, 2002), the link between acidosis and ER stress is also likely to hold true in other cell types. Of note in this regard, colabeling with cell type markers showed the upregulation of caspase-12 in neurons as well as in astrocytes in the periinfarct region, consistent with prior reports that focused on neuronal caspase-12 expression (Mouw et al, 2003;Shibata et al, 2003).…”

Section: Discussionsupporting

confidence: 90%

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

Aoyama

Burns

Suh

et al. 2005

J Cereb Blood Flow Metab

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Endoplasmic reticulum (ER) stress leads to activation of caspase-12, which in turn can lead to activation of caspase-3 and cell death. Here we report that transient acidosis induces ER stress and caspase-12-mediated cell death in mouse astrocytes. After a 3-hour incubation at pH 6.0, astrocytes exhibited delayed cell death associated with nuclear condensation and fragmentation. Cell death was reduced by the protein synthesis inhibitor cycloheximide, further suggesting an active cell death program. Acidosis increased the expression of the ER chaperone protein GRP-78, indicative of ER stress. Acidosis also increased caspase-12 mRNA expression, caspase-12 protein expression, cleavage of caspase-12 to its active form, and activation of caspase-3. Each of these effects was suppressed in astrocytes pretreated with caspase-12 antisense phosphorodiamidate morpholino oligodeoxynucleotides (PMOs). Caspase-12 antisense PMOs also reduced the cell death induced by acidosis. Immunoprecipitation studies showed dissociation of both caspase-12 and Ire1-a from GRP-78, thereby suggesting a mechanism by which acidosis can initiate the ER stress response. To evaluate caspase-12 activation in vivo, rats were subjected to middle cerebral artery ischemiareperfusion. Immunostaining of brain sections harvested 24 hours later showed increased caspase-12 expression and nuclear condensation in astrocytes of the periinfarct region exposed to acidosis during ischemia. These findings suggest that acidosis induces ER stress and caspase-12 activation, and that these changes may contribute to delayed cell death after ischemia.

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Section: Discussionsupporting

confidence: 90%

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

Aoyama

Burns

Suh

et al. 2005

J Cereb Blood Flow Metab

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“…1D) and, since reactive astrocytes express OASIS in the cryo-injured brain, BBF2H7 could possibly also be induced in reactive astrocytes. In view of this hypothesis, we decided to assess the expression of BBF2H7 in a mouse model of permanent focal brain ischemia, which induces accumulation of immature proteins in the ER and causes ER stress (4,12,21). Moreover, brain ischemia induces hypoxia, which also causes ER stress (16,31).…”

Section: Resultsmentioning

confidence: 99%

BBF2H7, a Novel Transmembrane bZIP Transcription Factor, Is a New Type of Endoplasmic Reticulum Stress Transducer

Kondo

Saito

Hino

et al. 2007

Molecular and Cellular Biology

147

167

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Endoplasmic reticulum (ER) stress transducers IRE1 (inositol requiring 1), PERK (PKR-like endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6) are well known to transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins accumulate in the ER. Recently, we identified OASIS (old astrocyte specifically induced substance) as a novel ER stress transducer expressed in astrocytes. We report here that BBF2H7 (BBF2 human homolog on chromosome 7), an ER-resident transmembrane protein with the bZIP domain in the cytoplasmic portion and structurally homologous to OASIS, is cleaved at the membrane in response to ER stress. The cleaved fragments of BBF2H7 translocate into the nucleus and can bind directly to cyclic AMP-responsive element sites to activate transcription of target genes. Interestingly, although BBF2H7 protein is not expressed under normal conditions, it is markedly induced at the translational level during ER stress, suggesting that BBF2H7 might contribute to only the late phase of unfolded protein response signaling. In a mouse model of focal brain ischemia, BBF2H7 protein is prominently induced in neurons in the peri-infarction region. Furthermore, in a neuroblastoma cell line, BBF2H7 overexpression suppresses ER stress-induced cell death, while small interfering RNA knockdown of BBF2H7 promotes ER stress-induced cell death. Taken together, our results suggest that BBF2H7 is a novel ER stress transducer and could play important roles in preventing accumulation of unfolded proteins in damaged neurons.

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“…61 A key role of caspase-12 in a number of clinical disorders and in neurodegeneration has recently been suggested providing a novel angle on apoptosis research which may offer a key to apoptosis-associated diseases. 11,12,61,[65][66][67][68][69][70] There are different mechanisms through which altered Ca 2+ signalling and/or ER stress may act on caspase-12. 1,2,[10][11][12][13]71 For instance, prolonged ER stress can result in the disruption of the Bip/GRP78/pro-caspase-12 complex, which prevents release of active caspase-12 from the ER.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic effects and apoptotic signalling mechanisms of the sesquiterpenoid euplotin C, a secondary metabolite of the marine ciliate Euplotes crassus, in tumour cells

Cervia¹,

Martini²,

Garcia‐Gil³

et al. 2006

Apoptosis

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Most antitumour agents with cytotoxic properties induce apoptosis. The lipophilic compound euplotin C, isolated from the ciliate Euplotes crassus, is toxic to a number of different opportunistic or pathogenic microorganisms, although its mechanism of action is currently unknown. We report here that euplotin C is a powerful cytotoxic and pro-apoptotic agent in mouse AtT-20 and rat PC12 tumour-derived cell lines. In addition, we provide evidence that euplotin C treatment results in rapid activation of ryanodine receptors, depletion of Ca2+ stores in the endoplasmic reticulum (ER), the release of cytochrome c from the mitochondria, activation of caspase-12, and activation of caspase-3, leading to apoptosis. Intracellular Ca2+ overload is an early event which induces apoptosis and is parallelled by ER stress and the release of cytochrome c, whereas caspase-12 may be activated by euplotin C at a later stage in the apoptosis pathway. These events, either independently or concomitantly, lead to the activation of the caspase-3 and its downstream effectors, triggering the cell to undergo apoptosis. These results demonstrate that euplotin C may be considered for the design of cytotoxic and pro-apoptotic new drugs.

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Activation of caspase-12, an endoplasmic reticulum resident caspase, after permanent focal ischemia in rat

Cited by 54 publications

References 19 publications

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

BBF2H7, a Novel Transmembrane bZIP Transcription Factor, Is a New Type of Endoplasmic Reticulum Stress Transducer

Cytotoxic effects and apoptotic signalling mechanisms of the sesquiterpenoid euplotin C, a secondary metabolite of the marine ciliate Euplotes crassus, in tumour cells

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