Disease relevance of Cast

• Therefore, for determination of the role of calpain in the pathophysiology of acute glomerulonephritis, transgenic mice that constitutively express high levels of calpastatin, a calpain-specific inhibitor protein, were generated [1].
• Activation of calpains, calpastatin and spectrin cleavage in the brain during the pathology of fatal murine cerebral malaria [2].
• IVIg reduced PV IgG-mediated acantholysis and cell death and up-regulated the caspase inhibitor FLIP and the calpain inhibitor calpastatin [3].
• The novel calpain inhibitor SJA6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury [4].
• This effect appears attributable, at least in part, to reduced calpain-mediated myofibrillar breakdown (P < 0.05) due to decreased calpain autolysis or increased calpastatin levels [5].

High impact information on Cast

• Transplanted long-term cultured pre-BI cells expressing calpastatin are resistant to B cell receptor-induced apoptosis [6].
• Furthermore, calpain activation is associated with decreased expression levels of calpastatin, which is upregulated by CD40 ligation [7].
• Whereas wild-type cells extend lamellae within 30 min after plating, all of the calpastatin-overexpressing cell lines fail to spread and assemble actin-rich processes [8].
• The calpain inhibitor calpeptin increased WASP levels in activated T and B cells from the WASP patients, but not in primary T cells from the patients or from WIP(-/-) mice [9].
• N-acetyl-Leu-Leu-norleucinal, or overexpression of calpastatin, inhibits reporter gene expression mediated by the C/EBPalpha gene promoter by preventing C/EBPbeta, a transcriptional activator of the C/EBPalpha gene, from binding to the promoter [10].

Chemical compound and disease context of Cast

• In this report, we show a novel suppressive effect of calpeptin, a calpain inhibitor, on TNFalpha-induced cell death and accumulation of p53 in L929 mouse fibrosarcoma [11].

Biological context of Cast

• CS overexpression on a C57/BL 10 background produced no phenotype [12].
• Overexpression of a calpastatin transgene in mdx muscle reduces dystrophic pathology [12].
• Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: evidence from calpastatin mutant mice [13].
• We also established a semi-quantitative fluorescence resonance energy transfer assay using the calpastatin sequence specifically to measure p94 activity [14].
• The calpain-calpastatin system and cellular proliferation and differentiation in rodent osteoblastic cells [15].

Anatomical context of Cast

• Regulation of calpain activity by calpastatin thus provides a mechanism for regulating the anchoring of basal bodies to the apical cytoskeleton in ciliated cells [16].
• RNase protection confirmed the decrease in calpastatin expression and decreased calpastatin was detected in the proximal pulmonary epithelium of foxj1(-/-) mice by immunohistochemistry [16].
• Many studies have demonstrated that the calcium-dependent proteolytic system (calpains and calpastatin) is involved in myoblast differentiation [17].
• In the present experiments, using a mouse muscle cell line (C2C12) we have analyzed both the sequences of appearance and the expression profiles of calpains 1, 2, 3 and calpastatin during the course of myoblast differentiation [17].
• Exposure of preadipocytes to the calpain inhibitor N-acetyl-Leu-Leu-norleucinal or overexpression of calpastatin, a specific endogenous inhibitor of calpain, blocks expression of adipocyte-specific genes, notably the CCAAT/enhancer-binding protein (C/EBP)alpha gene, and acquisition of the adipocyte phenotype [10].

Associations of Cast with chemical compounds

• In addition, progressive neuronal loss between the acute and subacute phases of KA-induced injury was largely halted only in human calpastatin Tg mice [18].
• No significant effect on cycloheximide-triggered apoptosis was found by using inhibitors of the proteasome or of other papain-like cysteine proteases, providing further evidence that the active site calpain inhibitor prevents apoptosis via its action on calpain [19].
• Leupeptin, but not calpain inhibitor XI and Z-VAD.fmk, also inhibited nucleosomal DNA fragmentation [20].
• Serum depletion, treatment with the endoplasmic reticulum (ER) calcium ATPase inhibitor thapsigargin, and treatment with calcium ionophore A23187 produced apoptosis in CHO cells, which was increased in calpain overexpressing cells and decreased by induced expression of calpastatin [21].
• Immunohistochemistry revealed overexpression of calpastatin in the newly dividing/divided cells, explaining inhibition of hydrolytic enzyme calpain in perinecrotic areas and lower progression of APAP-initiated injury in the DB mice [22].

Physical interactions of Cast

• In addition, I-benzyl-CH=C(SH)COOH (PD150606), a calpain inhibitor directed toward the calcium binding sites of calpain, also prevents apoptosis [23].

Regulatory relationships of Cast

• In in vitro studies using protease inhibitors, IkappaBalpha proteolysis in ts1-infected astrocytes was significantly blocked by a specific calpain inhibitor calpeptin but not by MG-132, a specific proteasome inhibitor, whereas rapid IkappaBbeta proteolysis was blocked by MG-132 [24].
• Endogenous Lp82 in lens soluble proteins was activated by addition of calcium and caused limited proteolysis of crystallins even in the presence of large amounts of recombinant domain I from the natural calpain inhibitor calpastatin [25].
• Calpastatin (specific calpain inhibitor protein) also inhibited the insulin-induced down-regulation of IRS-1 in transiently permeabilized cells [26].
• Parathyroid hormone-induced retraction of MC3T3-E1 osteoblastic cells is attenuated by the calpain inhibitor N-Ac-Leu-Leu-norleucinal [27].

Other interactions of Cast

• Two calpain inhibitors, leupeptin and calpain inhibitor XI, inhibited apoptosis in the motor neurons while the caspase inhibitor Z-VAD.fmk had no effect [20].
• Calpastatin-overexpressing myoblasts unable to migrate were characterized by rounded morphology, the loss of membrane extensions, the disorganization of stress fibers and exhibited a major defect in new adhesion formation [28].
• Nevertheless, apoptosis signalled via the Fas antigen proceeds regardless of the presence of calpain inhibitor [19].
• In contrast, no inhibition of LPS-induced I kappa B alpha degradation and NF-kappa B activation was observed by the overexpression of calpastatin [29].
• For assessment of the role of vinculin and talin stability, cells treated with l-NAME showed a significant decrease in E(app), whereas addition of a calpain inhibitor abolished the effect [30].

Analytical, diagnostic and therapeutic context of Cast

• The occurrence and distribution of calpain-calpastatin system proteins were determined by immunofluorescent microscopy, measurement of calcium-dependent proteolytic activity, and Western blotting [15].
• In situ hybridization studies show that the Mnd mice have a significantly higher level of calpain I, calpain II and calpastatin than the congenic controls in the following brain regions and cell types: hippocampal CA3 region, pyramidal cells, cerebellar Purkinje cells and spinal cord motor neurons [31].
• Mouse calpastatin cDNAs were cloned by the method of RT-PCR using RNA isolated from myoblast C2C12 cells [32].
• Partial mouse and rat calpastatin cDNAs containing functionally unknown amino-terminal regions were cloned by the polymerase chain reaction (PCR) method [33].
• Expression of distinct calpain isoforms and calpastatin was investigated using immunofluorescence and immunoblotting [34].

References