Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Costimulation of T cells via CD28 promotes both proliferation and resistance to apoptosis. In this study, we show that the immunosuppressive drug cyclosporin A (CsA) fully reverses resistance to CD95-mediated cell death after TCR/CD28 costimulation or superagonistic anti-CD28 mAb stimulation of primary rat lymph node T cells. This effect correlated with a pronounced superinduction of caspase-3 on both mRNA and protein levels, whereas its main antagonist, X chromosome-linked inhibitor of apoptosis, was unaffected by inclusion of CsA. Apoptosis triggered by CD95 cross-linking was characterized by robust caspase-3 activation. Furthermore, CsA sensitization to CD95-mediated apoptosis of CD28-activated T cells did not alter mRNA stability of superinduced caspase-3 mRNA, suggesting a transcriptional regulation of the caspase-3 gene. Addition of Ca(2+) ionophores to TCR/CD28 or superagonistic CD28-stimulated cells reduced caspase-3 levels, further supporting a role for Ca(2+)-dependent signaling pathways in negatively regulating caspase-3. Taken together, these findings suggest that CsA promotes sensitivity to CD95-mediated apoptosis in CD28-stimulated T cells by superinduction of the caspase-3 gene via a mechanism involving suppression of the calcineurin pathway.
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PMID:Cyclosporin A abolishes CD28-mediated resistance to CD95-induced apoptosis via superinduction of caspase-3. 1711 39

Hypomagnesemia, which is frequently observed in patients treated with calcineurin inhibitors to prevent rejection after allogeneic transplantation, has been associated with a faster rate of decline in allograft function. The effect of hypomagnesemia on lung allograft has not been reported yet. In our model of isolated mouse lung, we have evaluated the early effects of allogeneic lung perfusion with blood from magnesium (Mg)-deficient mice for 3 h on lung activation and remodelling, compared to isogeneic perfusion. Hypomagnesemia (0.21+/-0.07 mmol Mg(2+)/l) was observed in blood from Mg-deficient mice, but no inflammatory pattern. The mRNA level of the intercellular adhesion molecule (ICAM)-1, but neither of the vascular cell adhesion molecule (VCAM)-1, nor of the cytokines tumor necrosis factor (TNF)alpha and interleukin (IL)-2, was enhanced (p<0.05). Although caspase-3 mRNA was transiently enhanced, no apoptotic cells were evidenced in lung tissues even after 3 h. Using cDNA array, we found that the genes encoding RANKL, RANK, TNFR2, NFATX, IL-1R2, IL-6R gp130, SOCS3, PDGFRB, P63, CSF3R, CXCL1, CXCL5, CX3CL1, CSF1, which are involved in inflammation and apoptosis regulation, were markedly up-regulated in allogeneic conditions. Our results support a limited allogeneic activation and an early stage of the inflammatory process in lung, at the time of inflammatory cell recruitment without lung tissue remodelling, as a result of hypomagnesemia. These findings suggest that cyclosporine-related hypomagnesemia, observed in most of the transplanted patients, does not constitute an additional risk for lung allograft outcome.
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PMID:Allogeneic activation is attenuated in a model of mouse lung perfused with magnesium-deficient blood. 1713 54

Calcineurin is selectively enriched within neurons of the central nervous system. The mechanism of calcineurin inhibitor-induced neurotoxicity remains poorly understood. The purpose of this study is to examine whether glycogen synthase-3 (GSK-3) is involved in calcineurin inhibitor-induced apoptosis. Calcineurin inhibitors such as cyclosporine A (CsA) and FK506 increased apoptotic cell death with morphological changes characterized by cell shrinkage, nuclear condensation of fragmentation, and internucleosomal DNA fragmentation. Alsteropaullone and 1-azakenpaullone, GSK-3 inhibitors, prevented calcineurin inhibitor-induced apoptosis. In addition, insulin growth factor-I (IGF-I) and cycloheximide completely blocked cell death. Moreover, caspase-3 activation was accompanied by calcineurin inhibitor-induced cell death. These results suggest that calcineurin inhibitors induce caspase-dependent apoptosis and activation of GSK-3 is involved in cell death in rat cortical neurons.
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PMID:Caspase-dependent apoptosis induced by calcineurin inhibitors was prevented by glycogen synthase kinase-3 inhibitors in cultured rat cortical cells. 1716 86

We have previously shown that procaspase-3 exists in a high molecular weight complex in neonatal rat brain. Here, we purify and identify the protein that interacts with procaspase-3 from rat neonatal cortex. We searched binding proteins to procaspase-3 from a cytosolic extract of neonatal rat brain using chromatogram, two-dimensional gel electrophoresis, and far Western immunoblot. Analysis by tandem mass spectrometry identified the protein as a regulatory subunit of calcineurin (calcineurin B). Overexpression of calcineurin B in HEK293 cells potentiated processing of caspase-3 and apoptosis triggered by tumor necrosis factor-alpha and cycloheximide treatment. In a cell-free system, overexpression of calcineurin B in HEK293 cells markedly increased processing of caspase-3 by cytochrome c. Immunodepletion of calcineurin B from cytosolic extracts from Jurkat cells decreased processing of caspase-3 by cytochrome c. Knockdown of calcineurin B by RNA interference resulted in reduced apoptosis in HEK293 cells but not in caspase-3-deficient MCF-7 cells. These results suggest that calcineurin B potentiates the activation of procaspase-3 by accelerating its proteolytic maturation.
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PMID:Calcineurin potentiates the activation of procaspase-3 by accelerating its proteolytic maturation. 1732 36

It has been previously shown that Walker 256 tumor cells express a high content of the anti-apoptotic protein Bcl-2 which protects mitochondria against the damaging effects of Ca(2+). In the present study, we analyze H(2)O(2)-induced apoptotic death in two different types of tumor cells: Walker 256 and SCC-25. Treatment with H(2)O(2) (4mM) increased reactive oxygen species generation and the concentration of cytosolic free Ca(2+). These alterations preceded apoptosis in both cell lines. In Walker cells, which show a high Bcl-2/Bax ratio, apoptosis was dependent on calcineurin activation and independent of changes in mitochondrial membrane potential (DeltaPsi(m)), as well as cytochrome c release. In contrast, in SCC-25 cells, which show a lower Bcl-2/Bax ratio, apoptosis was preceded by a decrease in DeltaPsi(m), mitochondrial permeability transition, and cytochrome c release. Caspase-3 activation occurred in both cell lines. The data suggest that although the high Bcl-2/Bax ratio protected the mitochondria of Walker cells from oxidative stress, it was not sufficient to prevent apoptosis through calcineurin pathways.
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PMID:High Bcl-2/Bax ratio in Walker tumor cells protects mitochondria but does not prevent H2O2-induced apoptosis via calcineurin pathways. 1743 54

alpha-4 is an essential gene and is a dominant antiapoptotic factor in various tissues that is a regulatory subunit for type 2A protein phosphatases. A multiplexed phosphorylation site screen revealed that knockdown of alpha-4 by small interfering RNA (siRNA) increased p38 mitogen-activated protein kinase (MAPK) and c-Jun phosphorylation without changes in JNK or ERK. FLAG-alpha-4 coprecipitated hemagglutinin-MEK3 plus endogenous protein phosphatase 2A (PP2A) and selectively enhanced dephosphorylation of Thr193, but not Ser189, in the activation loop of MEK3. Overexpression of alpha-4 suppressed p38 MAPK activation in response to tumor necrosis factor alpha (TNF-alpha). The alpha-4 dominant-negative domain (DND) (residues 220 to 340) associated with MEK3, but not PP2A, and its overexpression sensitized cells to activation of p38 MAPK by TNF-alpha and interleukin-1beta, but not by ansiomycin or sorbitol. The response was diminished by nocodazole or by siRNA knockdown of the Opitz syndrome protein Mid1 that binds alpha-4 to microtubules. Interference by alpha-4 DND or alpha-4 siRNA increased caspase 3/7 activation in response to TNF-alpha. Growth of transformed cells in soft agar was enhanced by alpha-4 and suppressed by alpha-4 DND. The results show that alpha-4 targets PP2A activity to MEK3 to suppress p38 MAPK activation by cytokines, thereby inhibiting apoptosis and anoikis.
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PMID:Cytokine activation of p38 mitogen-activated protein kinase and apoptosis is opposed by alpha-4 targeting of protein phosphatase 2A for site-specific dephosphorylation of MEK3. 1743 31

Testicular germ cell tumours (TGCT) represent the most common malignancy in young males. We reported previously that two prototype members of the mitogen-activated protein kinase (MAPK) family, the MAPK ERK kinase (MEK) and extracellular signal-regulated kinase (ERK), are inactive in malignant testicular germ cells and become active after drug stimulation, leading to apoptosis of tumour cells. In this study, we asked whether the protein phosphatase PP2A, a known inhibitor of the MEK-ERK pathway, participates in the proliferation and/or apoptosis of primary TGCT (n = 48) as well as two TGCT cell lines (NTERA and NCCIT). Quantitative RT-PCR, immunohistochemistry, western blot analyses and phosphatase assay indicate that primary TGCT as well as TGCT cell lines express PP2A and that PP2A is active in TGCT cell lines. The inhibition of PP2A by application of two PP2A inhibitors, cantharidic acid (CA) and okadaic acid (OA), results in a significant increase in caspase-3-mediated apoptosis of TGCT cell lines. Thereby, PP2A inhibition was accompanied by phosphorylation and activation of MEK and ERK. Functional assays using the MEK inhibitor PD98059 demonstrated that the phosphorylation of MEK and ERK was required for the induction of caspase-3-mediated apoptosis of malignant germ cells. Thus, our data suggest that inhibition of PP2A mediates its apoptosis-inducing effect on TGCT through activation of the MEK-ERK signalling pathway that leads to caspase-3-mediated apoptosis of tumour cells. In addition our results support previous observations that PP2A exerts an anti-apoptotic effect on malignant tumour cells.
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PMID:Expression and function of protein phosphatase PP2A in malignant testicular germ cell tumours. 1759 Aug 61

Glioblastoma is the deadliest and most prevalent brain tumor, which is not yet amenable to any treatments. Therefore, new and innovative therapeutic strategies need to be developed for treating this deadly disease. We found that all-trans retinoic acid (ATRA) or 13-cis retinoic acid (13-CRA) induced astrocytic differentiation with down regulation of telomerase activity in rat glioblastoma C6 cells and enhanced sensitivity of the cells to interferon-gamma (IFN-gamma) or taxol (TXL) for apoptosis. Sensitivity of differentiated cells to IFN-gamma or TXL was greatly increased for apoptosis with increases in calcineurin expression, Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and expression and activity of calpain and caspases. Treatment with IFN-gamma activated caspase-8 indicating induction of apoptosis via the receptor-mediated pathway. Notably, IFN-gamma activated the signal transducer and activator of transcription-1 (STAT-1) for signaling via binding to gamma activator sequence (GAS), whereas TXL activated Raf-1 kinase for inactivation of Bcl-2 by its phosphorylation. We confirmed involvement of different proteolytic mechanisms in cell death by pretreating the cells with caspase-8 inhibitor II, calpeptin (calpain inhibitor), and caspase-9 inhibitor I, and caspase-3 inhibitor IV. Results demonstrated that retinoids induced astrocytic differentiation with down regulation of telomerase activity and worked synergistically to enhance sensitivity of cells to the cytotoxic agent IFN-gamma and the cytostatic agent TXL for apoptosis. This combination therapy for differentiation and apoptosis could be highly effective for controlling the malignant growth of glioblastoma.
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PMID:Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosis. 1769 33

A better understanding of dysregulated signaling pathways in cancer cells may suggest novel strategies to prevent tumor development and/or progression. Here we show that Jurkat and CCRF-CEM human T-leukemia cell lines were more sensitive than normal human T cells to the cytotoxic effect of inhibiting protein phosphatase 2A (PP2A). Inhibition of PP2A by okadaic acid (OA) caused T-leukemia cells to die by apoptosis, as indicated by DNA fragmentation, caspase-3 activation, loss of mitochondrial membrane potential (DeltaPsi(m)), and changes in nuclear morphology that were consistent with apoptosis. PP2A might therefore be a useful intracellular target for the treatment of T cell-derived leukemias. We also observed that reactive oxygen species (ROS) were generated in response to PP2A inhibition in T-leukemia cells. However, loss of DeltaPsi(m) that resulted from PP2A inhibition was not prevented by exogenous antioxidants (glutathione and N-acetyl-cysteine), indicating that OA-induced changes in mitochondrial membrane permeability were not a consequence of ROS production. Moreover, exogenous antioxidants protected CCRF-CEM T-leukemia cells from apoptosis caused by PP2A inhibition but failed to prevent OA-induced apoptosis in Jurkat T-leukemia cells, indicating a differential role for ROS in apoptosis caused by PP2A inhibition in two different human T-leukemia cell lines.
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PMID:Differential involvement of reactive oxygen species in apoptosis caused by the inhibition of protein phosphatase 2A in Jurkat and CCRF-CEM human T-leukemia cells. 1793 51

Post-transplant diabetes is an untoward effect often observed under immunosuppressive therapy with cyclosporin A. Besides the development of peripheral insulin resistance and a decrease in insulin gene transcription, a beta-cell toxic effect has been described. However, its molecular mechanism remains unknown. In the present study, the effect of cyclosporin A and the dual leucine-zipper-bearing kinase (DLK) on beta-cell survival was investigated. Cyclosporin A decreased the viability of the insulin-producing pancreatic islet cell line HIT in a time- and concentration-dependent manner. Upon exposure to the immunosuppressant fragmentation of DNA, the activation of the effector caspase-3 and a decrease of full-length caspase-3 and Bcl(XL) were observed in HIT cells and in primary mature murine islets, respectively. Cyclosporin A and tacrolimus, both potent inhibitors of the calcium/calmodulin-dependent phosphatase calcineurin, stimulated the enzymatic activity of cellular DLK in an in vitro kinase assay. Immunocytochemistry revealed that the overexpression of DLK but not its kinase-dead mutant induced apoptosis and enhanced cyclosporin A-induced apoptosis to a higher extent than the drug alone. Moreover, in the presence of DLK, the effective concentration for cyclosporin A-caused apoptosis was similar to its known IC(50) value for the inhibition of calcineurin activity in beta cells. These data suggest that cyclosporin A through inhibition of calcineurin activates DLK, thereby leading to beta-cell apoptosis. This action may thus be a novel mechanism through which cyclosporin A precipitates post-transplant diabetes.
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PMID:Activation of the dual-leucine-zipper-bearing kinase and induction of beta-cell apoptosis by the immunosuppressive drug cyclosporin A. 1804 35


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