Disease relevance of CASP12

• Similar results were observed in humans affected with sporadic and variant Creutzfeldt-Jakob disease, implicating for the first time the caspase-12 dependent pathway in a neurodegenerative disease in vivo, and thus offering novel potential targets for the treatment of prion disorders [1].
• RNA interference to knock down caspase-12 levels or salubrinal (an ER stress inhibitor) partially protected against cell death and further reduced A53T toxicity after treatment with z-VAD [2].
• Recent findings from population studies and animal models of infectious diseases and sepsis have uncovered a role for full-length caspase-12 in blocking the inflammatory response initiated by caspase-1, thus predisposing the organism to severe sepsis and sepsis-related lethality [3].
• Ischemic acidosis causes apoptosis in coronary endothelial cells through activation of caspase-12 [4].
• The sustained increase in [Ca(2+)](i) in breast cancer cells was associated with activation of the Ca(2+)-dependent apoptotic proteases, mu-calpain and caspase-12, as evaluated with antibodies to active (cleaved) forms of the enzymes and the fluorogenic peptide substrates [5].

Psychiatry related information on CASP12

• Based on our data we conclude that functional caspase 12 is lost in humans and that it can therefore not play a role in Alzheimer's disease [6].

High impact information on CASP12

• Of 1176 toxicology-related genes, glucose-regulated proteins (GRP-78 and -94), growth arrest/DNA damage-inducible protein 153 (CHOP/GADD153), and caspase-12 indicative of an ER stress response were among the alcohol-responsive genes [7].
• Although caspase-12 has been implicated in ER stress-induced apoptosis and amyloid-beta (Abeta)-induced apoptosis in rodents, it is controversial whether similar mechanisms operate in humans [8].
• We found that both AIF and caspase-12 translocate to the nucleus of dying photoreceptors in vivo and in an in vitro cellular model [9].
• Furthermore, induction of A53T alpha-synuclein increased endoplasmic reticulum (ER) stress and elevated caspase-12 activity [2].
• Expanded polyglutamine 72 repeat (polyQ72) aggregates induce endoplasmic reticulum (ER) stress-mediated cell death with caspase-12 activation and vesicular formation (autophagy) [10].

Chemical compound and disease context of CASP12

• Genistein induces Ca2+ -mediated, calpain/caspase-12-dependent apoptosis in breast cancer cells [11].
• Taken together, our findings indicate that the clofibrate-induced myopathy is triggered by Ca2+ influx, then activated cytosolic caspase-12 through calpain-independent cascade, and consequently caused apoptotic DNA fragmentation [12].

Biological context of CASP12

• Other differences arise from single nucleotide changes in protease genes, such as NAPSB and CASP12, resulting in the presence of functional genes in chimpanzee and pseudogenes in human [13].
• Caspase 12 has been cloned from rodent cells, in which it mediated apoptosis in response to endoplasmic reticulum stress [6].
• By alignment of the murine caspase 12 cDNA with the human genome sequence we localized the human caspase 12 gene at a single locus within the caspase 1/ICE gene cluster on chromosome 11q22 [6].
• Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L) [14].
• Rapamycin, a stimulator of autophagy, inhibited the polyQ72-induced cell death with caspase-12 activation [10].

Anatomical context of CASP12

• In conclusion, we propose that mitochondria play a secondary role in ER-mediated apoptosis and that TUDCA prevents apoptosis by blocking a calcium-mediated apoptotic pathway as well as caspase-12 activation [15].
• Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress [16].
• Endoplasmic reticulum stress-associated caspase 12 mediates cisplatin-induced LLC-PK1 cell apoptosis [17].
• We found that 3 ng/ml of BMP-4 is sufficient to induce the expression of proapoptotic proteins, puma and bax, in a p53-dependent mechanism, and facilitate Ca(2+) release from the ER to the cytosol, resulting in the activation of caspase-12 and ER dysfunction [18].
• However, it is not known whether the depletion of ER Ca(2+) is linked to caspase-12 signalling in endothelial cells [19].

Associations of CASP12 with chemical compounds

• Caspase-12 processing and fragment translocation into nuclei of tunicamycin-treated cells [20].
• Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation [15].
• Consistent with this hypothesis, cisplatin induced calpain-dependent activation of the ER-specific caspase-12 in cytoplasts as well as in intact cells [21].
• Treatment of cells with ER stress inducers such as brefeldin-A or thapsigargin induces the expression of caspase-12 protein and also leads to translocation of cytosolic caspase-7 to the ER surface [22].
• Induction of apoptosis with APG and GST showed activation of caspase-12 as well [23].

Regulatory relationships of CASP12

• Nuclear factor-kappaB translocation mediates double-stranded ribonucleic acid-induced NIT-1 beta-cell apoptosis and up-regulates caspase-12 and tumor necrosis factor receptor-associated ligand (TRAIL) [24].

Other interactions of CASP12

• Thus, we provide a missing link in the ER stress-induced apoptosis-signaling pathway, one which connects the stress sensor molecule IRE1 and the activation of caspase-12 [16].
• Our studies showed that overexpressed RTN3 induced EOR, eliciting ER-specific apoptosis with activation of caspase-12 and mitochondrial dysfunction through ER Ca(2+) depletion and the sustained elevation of cytosolic Ca(2+) [25].
• In addition, caspase-12 was cleaved, and phosphorylation of eukaryotic initiation factor 2alpha occurred, suggesting that an endoplasmic reticulum stress pathway was involved in addition to NF-kappaB induction of an extrinsic pathway, possibly mediated by TNF-related apoptosis-inducing ligand [24].
• The expression and localisation of caspase-12, an enzyme that has been involved in the apoptosis triggered by a stress on the endoplasmic reticulum, was not different in TRPC2(+) and TRPC2(-) cells [26].
• TNF-alpha-mediated cardiomyocyte apoptosis involves caspase-12 and calpain [27].

Analytical, diagnostic and therapeutic context of CASP12

• Caspase-12 activity was detected by Western blotting [28].

References