UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A single intraperitoneal injection of 75 mg/kg N-methyl-N-nitrosourea (MNU) was given to 50-day-old female Sprague-Dawley rats and examined sequentially 12 and 24 hours, and 3 and 7 days after MNU treatment. Photoreceptor cell death was evoked in all treated rats. After MNU treatment, 7-methyldeoxyguanosine DNA adduct was detected selectively in photoreceptor cell nuclei at 12 hours, followed by photoreceptor cell apoptosis as confirmed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling signals which peaked at 24 hours and continued until day 7 when several layers of photoreceptor cell nuclei were left. In apoptosis cascade, down-regulation of Bcl-2 was seen at 12 hours and up-regulation of Bax was seen at 24 hours, and caspase family (caspase 3/CPP32, caspase 6/Mch2, and caspase 8/FLICE protease) activities peaked 72 hours after MNU treatment. Therefore MNU-induced photoreceptor cell death was attributed to DNA adduct formation restricted to photoreceptor cell nuclei leading to photoreceptor cell apoptosis by up-regulation of Bax protein, down-modulation of Bcl-2 protein, and activation of caspases 3, 6, and 8.
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PMID:Mechanisms of photoreceptor cell apoptosis induced by N-methyl-N-nitrosourea in Sprague-Dawley rats. 1057 6

In general, apoptotic stimuli lead to activation of caspases. Once activated, a caspase can induce intracellular signaling pathways involving proteolytic activation of other caspase family members. We report the in vitro processing of eight murine procaspases by their enzymatically active counterparts. Caspase-8 processed all procaspases examined. Caspase-1 and -11 processed the effector caspases procaspase-3 and -7, and to a lesser extent procaspase-6. However, vice versa, none of the caspase-1-like procaspases was activated by the effector caspases. This suggests that the caspase-1 subfamily members either act upstream of the apoptosis effector caspases or else are part of a totally separate activation pathway. Procaspase-2 was maturated by caspase-8 and -3, and to a lesser extent by caspase-7, while the active caspase-2 did not process any of the procaspases examined, except its own precursor. Hence, caspase-2 might not be able to initiate a wide proteolytic signaling cascade. Additionally, cleavage data reveal not only proteolytic amplification between caspase-3 and -8, caspase-6 and -3, and caspase-6 and -7, but also positive feedback loops involving multiple activated caspases. Our results suggest the existence of a hierarchic proteolytic procaspase activation network, which would lead to a dramatic increase in multiple caspase activities once key caspases are activated. The proteolytic procaspase activation network might allow that different apoptotic stimuli result in specific cleavage of substrates responsible for typical processes at the cell membrane, the cytosol, the organelles, and the nucleus, which characterize a cell dying by apoptosis.
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PMID:The proteolytic procaspase activation network: an in vitro analysis. 1057 81

Caspase activation and dependence on caspases has been observed in different paradigms of apoptotic cell death in vivo and in vitro. The present study examines the role of caspases in ionizing radiation-induced apoptosis in the developing cerebellum of rats subjected to a single dose (2-Gy gamma rays) of whole-body irradiation at postnatal day 3. Radiation-induced apoptosis in the external granule cell layer, as defined by the presence of cells by extremely condensed, often fragmented nucleus, which were stained with the method of in situ end-labeling of nuclear DNA fragmentation, first appeared at 3 h and peaked at 6 h following irradiation. Increased expression of the precursors of caspase 1 (ICE), 2 (Nedd2), 3 (CPP32), 6 (Mch2), and 8 (Mch5 and FLICE), and increased expression of active caspase 3, as revealed by immunohistochemistry, were observed in the external granule cell layer of the cerebellum. Radiation-induced apoptosis was accompanied by an increase in the expression of the poly(ADP-ribose) polymerase (PARP) fragment of about 89 kD, as revealed by Western blots of cerebellar homogenates. This was not associated with modifications of protein kinase Cdelta and Lamin B. Concomitant injection in the culmen of the cerebellum in irradiated rats of high doses of Y-VAD-cmk, DEV-fmk, or IETD-fmk resulted in decreased expression of the PARP fragment in cerebellar homogenates. This was accompanied by a decrease in the expression of active caspase 3, as shown by immunohistochemistry. These observations suggest caspase activation following ionizing radiation. However, no differences in the number and morphological and biochemical characteristics of apoptotic cells, including strong nuclear and cytoplasmic c-Jun/AP-1 (N) expression, were observed between irradiated and both irradiated and caspase inhibitor-treated rats. Taken together, these observations suggest that the caspases examined are not essential for radiation-induced apoptosis in the developing cerebellum.
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PMID:Role of caspases in ionizing radiation-induced apoptosis in the developing cerebellum. 1059 Jan 78

We have previously shown that nitric oxide (NO) induces apoptosis in different human neoplastic lymphoid cells through caspase activation. Here we studied the NO-mediated apoptosis in human breast cancer cell lines derived from primary tumor (BT-20) or from metastasis (MCF-7). NO donor glycerol trinitrate (GTN) induced apoptosis in both cell lines which was completely abrogated after pretreatment with the broad spectrum caspase inhibitor zVAD-fmk. NO triggered also a time-dependent activation of caspase-1, caspase-3, and caspase-6 in these cells. Moreover, NO caused a release of mitochondrial protein cytochrome c into the cytosol, an increase in the number of cells with low mitochondrial transmembrane potential and with high level of reactive oxygen species production. However, NO did not induce mRNA expression of CD95 (APO-1/Fas) ligand. FAS-associated phosphatase-1 (FAP-1) molecule was constitutively expressed at the mRNA level and did not show any changes upon NO treatment in both breast cancer cell lines. The expression of the pro-apoptotic protein Bax and of the anti-apoptotic protein Bcl-2 remained unchanged in MCF-7 and BT-20 cells upon GTN treatment. We suggest that the mechanism of NO-mediated activation of the caspase cascade and subsequent apoptosis in human breast cancer cells required mitochondrial damage (in particular, cytochrome c release, disruption of mitochondrial transmembrane potential and generation of reactive oxygen species) but not the activation of the CD95/CD95L pathway.
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PMID:Nitric oxide-mediated apoptosis in human breast cancer cells requires changes in mitochondrial functions and is independent of CD95 (APO-1/Fas). 1060 55

Binding of HIV type 1 (HIV-1) envelope glycoproteins to the surface of a CD4(+) T cell transduces intracellular signals through the primary envelope receptor, CD4, and a coreceptor, either CCR5 or CXCR4. Furthermore, envelope-CD4(+) cell interactions increase rates of apoptosis in peripheral blood mononuclear cells (PBMCs). We demonstrate that in primary T lymphocytes, recombinant HIV-1 envelope proteins induce the activation of caspase-3 and caspase-6, which belong to a family of cysteine proteases that, upon activation, promote programmed cell death. Envelope-mediated activation of caspase-3 and caspase-6 depended on envelope-CD4 receptor interactions; CCR5-utilizing as well as CXCR4-utilizing envelopes elicited this response. Focal adhesion kinase (FAK) is a substrate of both caspase-3 and caspase-6, and inactivation of FAK by these caspases promotes apoptosis. En-velope treatment of lymphocytes led to the cleavage of FAK in a manner consistent with caspase-mediated cleavage.
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PMID:HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells. 1065 4

We have cloned and sequenced cDNAs corresponding to the complete coding regions of the chicken homologues to mammalian caspase-3 and caspase-6. Both caspases are included among members of the cysteine protease (caspase) family that are most closely identified with mediating apoptosis. The deduced amino acid sequences for chicken caspase-3 and -6 show 65% and 68% identity with the respective human sequences, with complete conservation found within the QACRG active peptide region. Both caspase-3 and -6 are widely expressed within various tissues from the hen. Within the ovary, levels of caspase-3 and caspase-6 mRNA and protein do not change significantly in theca tissue during follicle development. On the other hand, procaspase-3 and -6 protein levels are elevated by 2- to 5-fold in preovulatory, compared to prehierarchal (6- to 8-mm diameter), follicle granulosa cells. Nevertheless, the function of this family of cell death-inducing proteins requires activation of the proenzyme caspase, which occurs after cleavage at predictable sites within the N-terminal domain. Accordingly, it was determined that okadaic acid, a pharmacologic inducer of apoptotic cell death in cultured apoptosis-resistant, preovulatory follicle granulosa cells, induced both caspase-3- and caspase-6-like activity within 8-16 h of treatment. By comparison, spontaneous apoptotic cell death that occurs in apoptosis-sensitive, prehierarchal follicle granulosa cells after short-term suspension culture is accompanied by a more rapid increase (within 2 h) in both caspase-3- and -6-like activity. Treatment with 8-bromo-cAMP, which has previously been shown to attenuate, or at least slow, the onset of apoptosis in prehierarchal follicle granulosa cells, mitigates this suspension culture-induced increase in caspase activity. While the present results provide further support for the relationship between caspase activation and apoptotic cell death in hen granulosa cells, the molecular ordering of enzymatic events and the caspase-specific substrates remain to be elucidated.
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PMID:Caspase-3 and -6 expression and enzyme activity in hen granulosa cells. 1068 99

In rat hepatocytes and isolated liver mitochondrial fractions, Cyclosporine A (CsA) is often used as a specific inhibitor of mitochondrial Ca(2+) release and as a specific blocker of mitochondrial membrane potential and permeability transition (MPT), which are all processes involved in the inhibition of apoptosis. However, neither inhibition nor induction of apoptosis by CsA has yet been described in the rat hepatocyte primary culture during incubation for 4 and 20 h. It was the purpose of the present study to examine by means of morphological and biochemical criteria the effects of CsA on apoptosis and to characterize the underlying mechanisms. Rat hepatocytes were cultured for 4 or 20 h with CsA at concentrations of 0, 10, 25, and 50 microM. Chromatin condensation and fragmentation, DNA fragmentation (TUNEL), membrane phosphatidylserine distribution (Annexin V), caspase-1, -3, and -6 activity, mitochondrial membrane potential (Rhodamine 123), and cytochrome c release into the cytosol were investigated. Four hours after CsA treatment, chromatin condensation and fragmentation and the number of TUNEL- and Annexin V-positive cells increased dose-dependently without any observable enzyme leakage, which indicated the integrity of the outer cell membrane. After 20 h of CsA incubation apoptosis parameters were further increased and were accompanied by the increased activity of the cysteine protease, caspase-3 (CPP 32), and slightly increased caspase-6 (Mch 2), but not caspase-1 (ICE). The caspase-3 inhibitor, Ac-DEVD-CHO, inhibited caspase-3 activation and attenuated CsA-induced apoptosis and LDH leakage. The caspase-6 inhibitor, Ac-VEID-CHO, only marginally inhibited CsA-induced apoptosis. Decreased mitochondrial membrane potential and cytochrome c release went in parallel with ultrastructural mitochondrial changes and might be regarded as early events that trigger the apoptosis cascade. Transmission electron microscopy confirmed an increase in the number of necrotic cells after 20 h, but not after 4 h, compared with controls.
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PMID:Mechanisms of cyclosporine A-induced apoptosis in rat hepatocyte primary cultures. 1070 60

The addition of lipopolysaccharide (LPS) together with cycloheximide (CHX) induced apoptosis in a subline of a J774.1 macrophage-like cell line, JA-4, as judged by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL)-staining and poly(adenosine 5'-diphosphate (ADP)-ribose) polymerase (PARP)-cleavage. Caspase activities were examined in these macrophages in vitro using fluorogenic substrates such as acetyl-DEVD-aminomethyl coumarine (Ac-DEVD-AMC, caspase-3-like), acetyl-YVAD-aminomethyl coumarine (Ac-YVAD-AMC, caspase-1-like), acetyl-VEID-aminomethyl coumarine (Ac-VEID-AMC, caspase-6-like), and carbobenzoxy-IETD-aminofluoro coumarine (Z-IETD-AFC; caspase-8-like). Kinetic studies revealed these caspase activities with different Km and Vmax values in extracts of apoptotic macrophages. In the course of apoptosis, caspase-3-like activity increased first at 75 min, simultaneously with the appearance of TUNEL staining and prior to PARP cleavage, and then caspase-6 and 8-like activities increased at 90 and 105 min, respectively. However, caspase-1-like activity did not change throughout the experiment. Furthermore, removal of LPS and CHX by extensive washing of the cells for 60 min completely abolished the apoptosis and the subsequent release of lactate dehydrogenase (LDH) during additional incubation until 4 h after LPS addition. However, washing of the cells after 75 min or later resulted in the progress of apoptosis and LDH release, which was coordinated with the elevation of caspase-3-like activity at 60 min and that of caspase-6 or 8-like activity at 90 min, but not with that of caspase-1-like activity. These results suggest that caspase-3-like activity represents the most apical caspase among these caspases in terms of the intiation of apoptosis in macrophages treated with LPS and CHX. In the present study, we also provide evidence on the relatively low specificities of a series of caspase inhibitors other than acetyl-DEVD-aldehyde (Ac-DEVD-CHO) which specifically inhibited the caspase-3-like activity.
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PMID:Changes of caspase activities involved in apoptosis of a macrophage-like cell line J774.1/JA-4 treated with lipopolysaccharide (LPS) and cycloheximide. 1070 74

The transmissible gastroenteritis coronavirus (TGEV), like many other viruses, exerts much of its cytopathic effect through the induction of apoptosis of its host cell. Apoptosis is coordinated by a family of cysteine proteases, called caspases, that are activated during apoptosis and participate in dismantling the cell by cleaving key structural and regulatory proteins. We have explored the caspase activation events that are initiated upon infection of the human rectal tumor cell line HRT18 with TGEV. We show that TGEV infection results in the activation of caspase-3, -6, -7, -8, and -9 and cleavage of the caspase substrates eIF4GI, gelsolin, and alpha-fodrin. Surprisingly, the TGEV nucleoprotein (N) underwent proteolysis in parallel with the activation of caspases within the host cell. Cleavage of the N protein was inhibited by cell-permeative caspase inhibitors, suggesting that this viral structural protein is a target for host cell caspases. We show that the TGEV nucleoprotein is a substrate for both caspase-6 and -7, and using site-directed mutagenesis, we have mapped the cleavage site to VVPD(359) downward arrow. These data demonstrate that viral proteins can be targeted for destruction by the host cell death machinery.
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PMID:The viral nucleocapsid protein of transmissible gastroenteritis coronavirus (TGEV) is cleaved by caspase-6 and -7 during TGEV-induced apoptosis. 1075 9

Both caspase-3 and -6-like activities increased in the cytosolic extract from ricin-treated U937 cells that were inhibited by glutathione disulfide (GSSG) in a dose-dependent manner, but reduced glutathione (GSH) had no effect. Interestingly, caspase-6 like activity was more sensitive to GSSG than caspase-3 like activity. The IC50 of GSSG against caspase-3 and caspase-6 like activities were estimated to be 2.8 mM and 0.8 mM, respectively. Cystine but not cysteine also showed similar inhibitory effect on caspase-3-like activity. The inhibitory effect of GSSG on these caspase-like activities was prevented by the addition of DTT to the assay mixture. These results suggest that an intact disulfide portion of GSSG is required for the effective inhibition of caspase activity.
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PMID:Effects of glutathione-related compounds on increased caspase-3 and caspase-6-like activities in ricin-treated U937 cells. 1076 9

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