Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.36 (caspase-1)
6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Garcinol, a polyisoprenylated benzophenone, was purified from Garcinia indica fruit rind. The effects of garcinol and curcumin on cell viability in human leukemia HL-60 cells were investigated. Garcinol and curcumin displayed strong growth inhibitory effects against human leukemia HL-60 cells, with estimated IC(50) values of 9.42 and 19.5 microM, respectively. Garcinol was able to induce apoptosis in a concentration- and time-dependent manner; however, curcumin was less effective. Treatment with garcinol caused induction of caspase-3/CPP32 activity in a dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly(ADP-ribose) polymerase (PARP). Pretreatment with caspase-3 inhibitor inhibited garcinol-induced DNA fragmentation. Treatment with garcinol (20 microM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. The cleavage of D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, occurred simultaneously with the activation of caspase-3 but preceded DNA fragmentation and the morphological changes associated with apoptotic cell death. Of these, Bcl-2, Bad, and Bax were studied. The level of expression of Bcl-2 slightly decreased, while the levels of Bad and Bax were dramatically increased in cells treated with garcinol. These results indicate that garcinol allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. It is suggested that garcinol-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by garcinol may provide a pivotal mechanism for its cancer chemopreventive action.
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PMID:Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells. 1131 81

This study investigated the possible involvement of a specific caspase(s) (a family of aspartate-specific cysteine proteases) in programmed cell death of islet beta-cells due to sustained GTP depletion. Treatment (up to 48 h) with 3 microg/ml mycophenolic acid (MPA), which specifically depletes intracellular guanine nucleotides, reduced cell-cycle progression from G1 phase into S and G2/M phases (as assessed by flow cytometry) and, subsequently, induced apoptosis of HIT-15 cells (transformed pancreatic beta-cells). The latter was accompanied by a marked increase of caspase-2 activity (+343%) and moderate activation of caspase-9 (+150%) and caspase-3 (+145%). Importantly, only caspase-2 activation preceded induction of apoptosis. There was no change in activity of caspase-1, -4, -5, -6, and -8. Release of the mitochondrial protein cytochrome c into cytosol was also observed at a late stage. Cotreatment of cells with a permeable pan-caspase inhibitor (Z-VAD-FMK) blocked GTP depletion-induced cell death in a dose-dependent manner. A specific caspase-2 inhibitor (Z-VDVAD-FMK), but not a caspase-3 inhibitor (DEVD-CHO), was also capable of restoring cell viability. Interestingly, activation of caspase-2 leads to caspase-3 activation because the caspase-2 inhibitor abrogated caspase-3 activity. Our results indicate that, while activation of multiple caspases are involved in the execution phase of GTP depletion-induced apoptosis, caspase-2 appears to play the major role in the initiation of this program. This study revealed a novel, caspase-2 mediated form of apoptosis that may be consequent to impaired mitogenesis.
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PMID:Activation of caspase-2 mediates the apoptosis induced by GTP-depletion in insulin-secreting (HIT-T15) cells. 1195 51

Estrogen plays a critical role in the protection from apoptosis in several cell types because the withdrawal of estrogen leads to increased apoptosis in tissues such as the brain, endothelium, testes, and uterus. Our recent report demonstrated that the chick oviduct also regresses through apoptotic mechanisms during estrogen deficiency. Despite these observations, very little is known concerning the intracellular mechanisms by which estrogen opposes apoptosis. To better understand how estrogen exerts its antiapoptotic effects, several key apoptotic genes were examined for their regulation by estrogen. Our results show that mRNA expression levels of Bcl-2, hsp-70, c-myc, Bcl-X(l), caspase-3, and caspase-6 remain essentially constant when apoptosis is stimulated by estrogen withdrawal. However, the genes for caspase-1 and caspase-2 are rapidly stimulated, at least for the most part, at the transcriptional level after the withdrawal of estrogen. This increase in caspase-2 mRNA is followed by an increase in enzyme activity. Furthermore, although mRNA expression levels are unaffected, both caspase-3 and caspase-6 proenzymes are activated in the estrogen-withdrawn cells. Taken together, these results demonstrate that estrogen has the potential to oppose apoptosis by regulating caspase activity through both transcriptional and posttranscriptional mechanisms in reproductive tissues.
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PMID:Tissue-protective effects of estrogen involve regulation of caspase gene expression. 1204 18

We have investigated the hepatic response of female C57BL/6J wild-type and p53(+/-) hemizygous mice to genotoxic levels of diethylstilbestrol (DES) using cell cycle and apoptosis-focussed cDNA expression arrays. DES induced the expression of 12 genes (bad, bax, bcl-x, caspase-1, p53, cyclin D3, GADD45, p21, p15, p27, p57 and Skp1) and down-regulated the expression of eight genes (bcl-2, caspase-2, caspase-7, caspase-8, E124, iNOS, mdm2 and NFkappab1) at twofold or greater levels. Taken together, these changes were strongly reflective of the induction of apoptosis in the livers of DES-treated mice. Of those genes showing the greatest changes in response to DES, p53, p21 and p57 were expressed at 2.1, 1.7 and 1.6 times greater (respectively) in wild-type mice as compared with p53(+/-) hemizygous mice. Differences in p53, p21 and bax expression were confirmed by RT-PCR and we conclude that the compromised response of p53(+/-) mice is likely to play a central role in the earlier appearance of tumours in this model, following exposure to genotoxic carcinogens.
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PMID:A comparison of gene expression changes in response to diethylstilbestrol treatment in wild-type and p53+/- hemizygous knockout mice using focussed arrays. 1250 44

In order to assess the neuronal expression of caspase mRNA in primary cultures of rat superior cervical ganglion (SCG) neurones a method of differential cell purification and comparative RT-PCR was devised. SCG primary cultures generally contain variable percentages of non-neuronal contaminants, which influence RT-PCR results. We optimised a neuronal purification method, allowing the preparation of both highly purified neuronal cultures and mixed cultures, enriched in non-neuronal contaminants. These two sets of cells were cultured in parallel and subsequently analysed by RT-PCR. The use of cell type specific oligonucleotides allowed evaluation of the relative distribution of neuronal (neurofilament) and non-neuronal transcripts in the two cultures. In parallel, specific oligonucleotides were used to detect the mRNA levels of caspase family members. The partition of neurofilament transcript between pure and mixed cultures was found to be statistically different from the partition of the non-neuronal markers. Therefore statistical difference from the partition of non-neuronal markers was taken as evidence for expression in neurones. We show that caspase-2, -3, -6, -7 and -9 transcripts are expressed in SCG neurones whereas caspase-1 is probably absent. Furthermore, none of these transcripts are upregulated during neuronal death induced by nerve growth factor withdrawal. This method could be applied to the analysis of other transcripts in SCG and other primary neuronal cultures containing significant percentages of contaminant cell types.
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PMID:A method utilizing differential culture and comparative RT-PCR for determining RNA expression in superior cervical ganglion neurones. 1258 53

Lesions in the parkin gene cause early onset Parkinson's disease by a loss of dopaminergic neurons, thus demonstrating a vital role for parkin in the survival of these neurons. Parkin is inactivated by caspase cleavage, and the major cleavage site is after Asp126. Caspases responsible for parkin cleavage were identified by several experimental paradigms. Transient coexpression of caspases and wild type parkin in HEK-293 cells identified caspase-1, -3, and -8 as efficient inducers of parkin cleavage whereas caspase-2, -7, -9, and -11 did not induce cleavage. A D126A parkin mutation abrogates cleavage induced by caspase-1 and -8, but not by caspase-3. In anti-Fas-treated Jurkat T cells, parkin cleavage was inhibited by caspase inhibitors hFlip and CrmA (but not by X-linked inhibitor of apoptosis (XIAP)), indicating that caspase-8 (but not caspase-3) is responsible for the parkin cleavage in this model. Moreover, induction of apoptosis in caspase-3-deficient MCF7 cells, either by caspase-1 or -8 overexpression or by tumor necrosis factor-alpha treatment, led to parkin cleavage. These results demonstrate that caspase-1 and -8 can directly cleave parkin and suggest that death receptor activation and inflammatory stress can cause loss of the ubiquitin ligase activity of parkin, thus causing accumulation of toxic parkin substrates and triggering dopaminergic cell death.
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PMID:Caspase-1 and caspase-8 cleave and inactivate cellular parkin. 1269 30

We demonstrate here that selective activation of endogenous members of the caspase family and cleavage of substrates responsible for the maintenance of nuclear functional and structural integrity are major effectors of antigen receptor (AgR)- and ionomycin-triggered apoptosis in Ramos-Burkitt lymphoma (Ramos-BL) B cells. Ramos-BL B cells express significant proenzyme levels of caspase-2, -3, -7 and -8, low levels of caspase-6 and are caspase-1-negative. However, while anti-IgM and ionomycin trigger for significant activation of caspase-3, -7 and -8 at 12-16 h and at 4 h post-stimulation respectively, both anti-IgM and ionomycin fail to activate caspase-2 indicating that AgR- and ionomycin-triggered Ramos-BL B cell apoptosis is mediated by the selective activation of, at least, caspase-3, -7 and -8. Anti-IgM triggers for cleavage of the resident nuclear proteins poly(ADP-ribose) polymerase (PARP) at 8 h, lamins B1 and B2 from 12 to 16 h; likewise, ionomycin triggers for degradation of PARP at 2 h, lamins B1 and B2 at 4 h. Signal transduction through CD40 rescues Ramos-BL B cells from AgR- and ionomycin-triggered apoptosis at a very early stage of the apoptotic process by inhibiting both the early cleavage of PARP as well as the activation of caspase-3, -7 and -8 and cleavage of lamin B1; CD40-mediated rescue occurs upstream of CD40-induced expression of Bcl-2 and increased expression of Bcl-xL. In such cellular populations subject to regulation through apoptosis, dysregulation of the apoptotic mechanisms can have devastating consequences by contributing to the pathogenesis of malignancy as well as to lymphoproliferative and autoantibody disorders. An understanding of the role played by caspases in the execution of apoptosis may provide insight into the pathogenesis of these disease states and thereby provide targets for novel therapeutic strategy.
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PMID:Temporal ordering of caspase activation and substrate cleavage during antigen receptor-triggered apoptosis in Ramos-Burkitt lymphoma B cells. 1285 74

Previous studies suggest the protective potentiality of Ginkgo biloba (EGb 761) against apoptotic cell death induced by hydroxyl radicals, staurosporine, serum deprivation and beta-amyloid (betaA) peptide. We have extended these observations to cultured cortical neurons and studied the effect of EGb 761 on neuronal survival (evaluated as MTT reduction), the presence of condensed nuclei (monitored as Hoechst staining), the time-course of caspase-1, caspase-3 and caspase-9 activation (measured by cleavage of specific fluorescent substrates) and superoxide anion production (evaluated by hydroethidine staining) after the exposure to staurosporine. Results show that 200 microg/ml of EGb 761 increased cell survival and reduced the number of condensed nuclei after the exposure to 200 nM staurosporine. Vitamin E and the spin trapper alpha-phenyl-N-tert-butylnitrone (PBN) also significantly increased cell survival. In contrast, the broad-spectrum caspase inhibitors ZVAD and ZBIOT showed no protection. Similarly, selective inhibitors of caspase-1 (YVAD-CHO), caspase-2 (VDVAD-CHO), caspase-3 (DEVD-CHO) and caspase-8 (IETD-CHO) did not protect against cell damage induced by staurosporine. The protective effect of EGb 761 was not enhanced when coincubated with vitamin E or DEVD-CHO. Caspase-3 activity was maximally induced 5-8 h after staurosporine exposure. Both EGb 761 and vitamin E showed a tendency to decrease caspase-3 activity. In contrast, activation of caspase-1 and caspase-9 was not observed at any of the times studied after STS exposure. Exposure to staurosporine resulted in increased superoxide production that was maximal at 5 h. EGb 761 significantly inhibited superoxide production at short times after staurosporine exposure. Vitamin E and PBN also significantly reduced superoxide production. Results suggest that EGb 761 neuroprotective effect might be mediated by its well-known antioxidant activity, which might also influence caspase-3 activation. Inhibition of capase-3 induced by EGb 761 and vitamin E does not seem to contribute to their observed protective action.
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PMID:Effect of Ginkgo biloba (EGb 761) on staurosporine-induced neuronal death and caspase activity in cortical cultured neurons. 1498 36

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. 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). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.
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PMID:Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. 1512 68

Lyssaviruses, which are members of the Rhabdoviridae family, induce apoptosis, which plays an important role in the neuropathogenesis of rabies. However, the mechanisms by which these viruses mediate neuronal apoptosis have not been elucidated. Here we demonstrate that the early induction of apoptosis in a model of lyssavirus-infected neuroblastoma cells involves a TRAIL-dependent pathway requiring the activation of caspase-8 but not of caspase-9 or caspase-10. The activation of caspase-8 results in the activation of caspase-3 and caspase-6, as shown by an increase in the cleavage of the specific caspase substrate in lyssavirus-infected cells. However, neither caspase-1 nor caspase-2 activity was detected during the early phase of infection. Lyssavirus-mediated cell death involves an interaction between TRAIL receptors and TRAIL, as demonstrated by experiments using neutralizing antibodies and soluble decoy TRAIL-R1/R2 receptors. We also demonstrated that the decapsidation and replication of lyssavirus are essential for inducing apoptosis, as supported by UV inactivation, cycloheximide treatment, and the use of bafilomycin A1 to inhibit endosomal acidification. Transfection of cells with the matrix protein induced apoptosis using pathways similar to those described in the context of viral infection. Furthermore, our data suggest that the matrix protein of lyssaviruses plays a major role in the early induction of TRAIL-mediated apoptosis by the release of a soluble, active form of TRAIL. In our model, Fas ligand (CD95L) appears to play a limited role in lyssavirus-mediated neuroblastoma cell death. Similarly, tumor necrosis factor alpha does not appear to play an important role.
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PMID:Lyssavirus matrix protein induces apoptosis by a TRAIL-dependent mechanism involving caspase-8 activation. 1516 47


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