Disease relevance of Casp12

• The results indicate that oxidative and ER induced stress causing caspase-12 activation are involved in neuronal death and disease progression in ALS [1].
• Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice [2].
• The resulting survival advantage was conferred by the ability of the caspase-12-deficient mice to clear bacterial infection more efficiently than wild-type littermates [2].
• We show that in mice, gene-targeted deletion of caspase-12 renders animals resistant to peritonitis and septic shock [2].
• Caspase-12 seems to be involved in neuronal death induced by ischemia/reperfusion [3].

High impact information on Casp12

• Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta [4].
• Here we show that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals [4].
• Here we demonstrate that activation of an unfolded protein response (UPR) associated with the upregulation of BiP and CHOP and the activation of JNK2 and caspase-12 leads to neuronal apoptosis in the mouse model of GM1-gangliosidosis [5].
• In a culture model, we demonstrate activation of caspase-12, the initiator of the endoplasmic reticulum (ER) stress-specific caspase cascade, during apoptosis associated with myoblast differentiation [6].
• However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage [7].

Biological context of Casp12

• Mice that are deficient in caspase-12 are resistant to ER stress-induced apoptosis, but their cells undergo apoptosis in response to other death stimuli [4].
• In this study, we show that UPR gene expression is induced in cells treated with ER stress agents in the presence or absence of murine caspase-12 or human caspase-4 expression and in cells that overexpress Bcl-x(L) or a dominant negative caspase-9 [8].
• Caspase-12 and the ER pathway for cell death may constitute potential novel targets for the treatment of ALS [1].
• Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS [1].
• Caspase-9 and caspase-8 deficiency inhibited and delayed the onset of DNA fragmentation but did not inhibit caspase-12 processing induced by ER stress [9].

Anatomical context of Casp12

• Moreover, although caspase-12 is highly expressed in mature megakaryocytes, it is undetectable in platelets [10].
• Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis [8].
• Constitutive expression of the caspase-12 protein was restricted to certain cell types, such as epithelial cells, primary fibroblasts, and L929 fibrosarcoma cells [11].
• In contrast to caspase-1 and -11, no caspase-12 protein was detected in macrophages in any of these treatments [11].
• Activated caspase-12 is detectable as non-complexed free enzyme in the cytosol [12].

Associations of Casp12 with chemical compounds

• Caspase-12: a developmental link between G-protein-coupled receptors and integrin alphaIIbbeta3 activation [10].
• Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation [13].
• Nevertheless, Mn(II), in part, exerts its effect via its ability to replace Ca(II) in the activation of m-calpain, which in turn activates caspase-12 and degrades Bcl-xL [14].
• Interestingly, after treatment of murine tubular cells with paracetamol and calpain inhibitors, the caspase-12 cleavage product was still detectable, and calpain inhibitors were unable to protect tubular cells from paracetamol-induced apoptosis [15].
• We have shown that ER stress and caspase-12 activation occur in ALS transgenic mice carrying the mutant copper/zinc superoxide dismutase (SOD1) gene [16].

Physical interactions of Casp12

• Formation of noncanonical high molecular weight caspase-3 and -6 complexes and activation of caspase-12 during serum starvation induced apoptosis in AKR-2B mouse fibroblasts [12].

Regulatory relationships of Casp12

• Caspase-12 is the most down-regulated gene we identified in NF-E2(-/-) megakaryocytes [10].
• Despite wild-type levels of alphaIIbbeta3, caspase-12(-/-) platelets exhibit reduced fibrinogen binding to alphaIIbbeta3 following stimulation by adenosine diphosphate (ADP) or protease-activated receptor 4 (PAR4) receptor-activating peptide [10].
• Furthermore, we show that caspase-12-deficient cortical neurons are defective in apoptosis induced by amyloid-beta protein but not by staurosporine or trophic factor deprivation [4].
• Accumulation of unfolded and malfolded proteins causes endoplasmic reticulum (ER) stress, stimulating unfolded protein response (UPR) and c-Jun N-terminal kinase (JNK) activation and activating caspase-12 located on the ER [13].
• In fibroblasts and B16/B16 melanoma cells, caspase-12 expression is stimulated by IFN-gamma but not by IFN-alpha or -beta [11].

Other interactions of Casp12

• Mechanistically, caspase-12 associated with caspase-1 and inhibited its activity [2].
• The IFN-gamma pathway was crucial in mediating survival of septic caspase-12-deficient mice, because administration of neutralizing antibodies to IFN-gamma receptors ablated the survival advantage that otherwise occurred in these animals [2].
• This notion is confirmed by the observations that pretreatment of NIH3T3 cells with either caspase-12 antisense RNA or dsRNA corresponding to the full-length caspase-12 led to a dramatic decrease in caspase-3-like activity induced by Mn(II) [14].
• These data suggest that procaspase-9 is a substrate of caspase-12 and that ER stress triggers a specific cascade involving caspase-12, -9, and -3 in a cytochrome c-independent manner [17].
• We did not detect the presence of caspase-7 in the ER fraction at the period of caspase-12 cleavage [3].

Analytical, diagnostic and therapeutic context of Casp12

• Molecular cloning and characterization of murine caspase-12 gene promoter [18].
• To investigate how caspase-12 is transcriptionally and translationally regulated, we isolated and sequenced the 5'-flanking region of mouse caspase-12 gene by a PCR-mediated chromosome-walking technique, using mouse genomic DNA as a template [18].
• Our results imply that cerebral ischemia/reperfusion induces ER stress and that caspase-12 activation concurred with ER stress [3].
• We found the co-localization of caspase-12 immunoreactivity and DNA fragmentation detectable by the TUNEL method [3].
• Western blot analysis revealed that caspase-12 activation occurred at 5-23 h of reperfusion, and immunoreactivity for caspase-12 was enhanced mainly in striatal neurons on the ischemic side at the same time points [3].

References