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

Apoptosis is a highly regulated biochemical process that results in the selective death of cells. Members of the caspase family of cysteine proteases play a pivotal role in the effector phase of apoptosis. We show that, in HL-60 cells, the addition of either anisomycin, a protein synthesis inhibitor, or geranylgeraniol, an intermediate in the cholesterol biosynthetic pathway, results in a rapid and en masse induction of apoptosis. The levels of actin, p42 and p44 MAPK, JNK1, JNK2, p38, and PCNA were not substantially altered during this process. Although these treatments appear to function by diverse pathways, they both result in the processing and activation of caspase-3 (CPP32beta/Yama/Apopain). In contrast, no activation of caspase-1 (interleukin-1beta converting enzyme (ICE)) was observed. Furthermore, we obtained ambiguous results regarding the activation of caspase-2 (Ich-1) depending on the antibody used. Pretreatment of the cells with benzyloxycarbonyl-Val-Ala-Asp-(OMe)-fluoromethylketone (zVAD.fmk), a tetrapeptide inhibitor of caspases, prevented the induction of apoptosis for 24 h. Even after 72 h of treatment, some cells were still alive and progressing through the cell cycle, suggesting that blockage of caspase activity is able to protect cells. These results suggest that selective activation of some caspases is necessary to induce apoptosis in HL-60 cells.
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PMID:Selective activation of caspases during apoptotic induction in HL-60 cells. Effects Of a tetrapeptide inhibitor. 905 91

Members of the CED-3/interleukin-1beta-converting enzyme (ICE) protease (caspase) family are synthesized as proforms, which are proteolytically cleaved and activated during apoptosis. We report here that caspase-2 (ICH-1/NEDD-2), a member of the ICE family, is activated during apoptosis by another ICE member, a caspase-3 (CPP32)-like protease(s). When cells are induced to undergo apoptosis, endogenous caspase-2 is first cleaved into three fragments of 32-33 kDa and 14 kDa, which are then further processed into 18- and 12-kDa active subunits. Up to 50 microM N-acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), a caspase-3-preferred peptide inhibitor, inhibits caspase-2 activation and DNA fragmentation in vivo, but does not prevent loss of mitochondrial function, while higher concentrations of DEVD-CHO (>50 microM) inhibit both. In comparison, although the activity of caspase-3 is very sensitive to the inhibition of DEVD-CHO (<50 nM), inhibition of caspase-3 activation as marked by processing of the proform requires more than 100 microM DEVD-CHO. Our results suggest that the first cleavage of caspase-2 is accomplished by a caspase-3-like activity, and other ICE-like proteases less sensitive to DEVD-CHO may be responsible for activation of caspase-3 and loss of mitochondrial function.
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PMID:Activation of caspase-2 in apoptosis. 926 Nov 2

Apoptosis is a major form of cell death, characterized initially by a series of stereotypic morphological changes. In the nematode Caenorhabditis elegans, the gene ced-3 encodes a protein required for developmental cell death. Since the recognition that CED-3 has sequence identity with the mammalian cysteine protease interleukin-1 beta-converting enzyme (ICE), a family of at least 10 related cysteine proteases has been identified. These proteins are characterized by almost absolute specificity for aspartic acid in the P1 position. All the caspases (ICE-like proteases) contain a conserved QACXG (where X is R, Q or G) pentapeptide active-site motif. Capases are synthesized as inactive proenzymes comprising an N-terminal peptide (prodomain) together with one large and one small subunit. The crystal structures of both caspase-1 and caspase-3 show that the active enzyme is a heterotetramer, containing two small and two large subunits. Activation of caspases during apoptosis results in the cleavage of critical cellular substrates, including poly(ADP-ribose) polymerase and lamins, so precipitating the dramatic morphological changes of apoptosis. Apoptosis induced by CD95 (Fas/APO-1) and tumour necrosis factor activates caspase-8 (MACH/FLICE/Mch5), which contains an N-terminus with FADD (Fas-associating protein with death domain)-like death effector domains, so providing a direct link between cell death receptors and the caspases. The importance of caspase prodomains in the regulation of apoptosis is further highlighted by the recognition of adapter molecules, such as RAIDD [receptor-interacting protein (RIP)-associated ICH-1/CED-3-homologous protein with a death domain]/CRADD (caspase and RIP adapter with death domain), which binds to the prodomain of caspase-2 and recruits it to the signalling complex. Cells undergoing apoptosis following triggering of death receptors execute the death programme by activating a hierarchy of caspases, with caspase-8 and possibly caspase-10 being at or near the apex of this apoptotic cascade.
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PMID:Caspases: the executioners of apoptosis. 933 44

IkappaB proteins function as direct regulators of Rel/NF-kappaB transcription complexes. We show that the cell-death protease CPP32 (caspase-3) in vitro specifically cleaved chicken and human IkappaB-alpha at a conserved Asp-Ser sequence. This cleavage site appears to be identical to the site at which chicken IkappaB-alpha is cleaved in vivo in temperature-sensitive v-Rel-transformed chicken spleen cells undergoing apoptosis. Other caspases, namely interleukin-1beta-converting enzyme (caspase-1) and Ich-1 (caspase-2), did not cleave IkappaB-alpha. CPP32 also cleaved mammalian IkappaB-beta in vitro at the analogous Asp-Ser sequence. Cleavage of IkappaB-alpha by CPP32 was blocked by serine phosphorylation of IkappaB-alpha. Cleavage of IkappaB-alpha by a CPP32- like protease could generate a constitutive inhibitor of Rel transcription complexes. This report provides evidence for a direct biochemical interaction between the NF-kappaB signaling pathway and a cell-death protease signaling pathway.
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PMID:Phosphorylation of IkappaB-alpha inhibits its cleavage by caspase CPP32 in vitro. 936 96

It has been well documented that caspase-1 (interleukin-1beta-converting enzyme, ICE) and its related cysteine proteinases such as caspase-3 (CPP32, apopain) and caspase-2 (ICH-1L) play important roles in apoptosis. In the present study, these genes were inserted into an inducible eukaryotic expression vector, pMSG, and transfected into NIH 3T3 mouse fibroblasts. The expression of caspases-1 and -3 was effectively induced by treatment with dexamethasone (Dex). The expression of caspase-2 was elevated in the transfected cells without treatment with Dex but was not further stimulated by Dex. High expression of these proteases alone induced neither apoptosis-like cell death nor any morphological change. However, the expression of caspase-1 but not of caspase-2 or -3 enhanced chemosensitivity toward cytotoxic anticancer drugs such as aclarubicin, epirubicin, adriamycin, nimustine and ifosfamide. It is thus concluded that caspase-1 mediates cytotoxic effects of these drugs.
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PMID:Enhancement of chemosensitivity toward anticancer drugs by high expression of caspase-1 in NIH 3T3 cells. 949 96

The authors recently cloned a cDNA for an ICE/CED3-related cysteine protease from rat brain, which is closely related to human CPP32 (now designated caspase-3). In situ hybridization histochemistry revealed a profound developmental regulation of the caspase-3 transcript in rat brain, with relatively high levels of caspase-3 mRNA observed in neurons of the fetal and neonatal brain and low levels of mRNA in neurons of the adult brain. The authors report that transient forebrain ischemia, which results in a delayed apoptotic death of CA1 pyramidal neurons, results in prolonged expression of caspase-3 mRNA in these same pyramidal neurons. Up-regulation of caspase-3 mRNA in CA1 pyramidal neurons is prominent 24 hours after transient global ischemia, and expression is maintained at higher levels for at least 72 hours after ischemia. However, by 96 hours after ischemia, a marked decrease in caspase-3 mRNA expression is observed in CA1 pyramidal neurons, showing severe degenerative changes (e.g., nuclear condensation). By contrast, there is no change in the expression of a closely related member of caspase family, caspase-2, in CA1 pyramidal neurons after global ischemia. Instead, caspase-2 mRNA is induced in lamina layers of cerebral cortex 24 hours after the ischemia. A selective and prolonged induction of the caspase-3 gene in committed CA1 pyramidal neurons suggests that transcriptional activation of this caspase-3 gene may be involved in the apoptotic cell death cascade of CA1 neurons after transient global ischemia.
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PMID:Transient global forebrain ischemia induces a prolonged expression of the caspase-3 mRNA in rat hippocampal CA1 pyramidal neurons. 949 41

In the present study, we demonstrate that rat kidney contains caspase activity that was markedly inhibited by specific peptide inhibitors of caspases but not by inhibitors of Ser, Cys, Asp, or metalloproteinases. Using primers based on the nucleotide sequence of known members of Ced-3/interleukin-1 beta-converting enzyme (ICE) family from human origin, we have identified by reverse-transcription (RT) polymerase chain reaction (PCR) analyses that rat kidney transcribes the genes for caspase-1 (ICE), caspase-2 (Nedd2), caspase-3 (CPP32), and caspase-6 (Mch2). RT-PCR products, when subcloned and sequenced, provided full-length cDNAs for ICE (1,209 bp) and CPP32 (786 bp) and partial cDNA products for Mch2 (561 bp) and Nedd2 (811 bp). The sequence analysis of the caspase cDNAs showed conserved catalytic site QACRG as well as Asp cleavage site. Rat kidneys subjected to ischemia-reperfusion injury revealed differential expression of caspases with marked increase in CPP32 and ICE mRNA and proteins during reperfusion, transient increase in Nedd2 mRNA and proteins during ischemia and the early period of reperfusion, and little change in Mch2 expression during the ischemia or reperfusion period. The altered expression suggests that caspases may act in concert in a cascade and may play an important role in ischemic acute renal failure.
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PMID:Identification of gene family of caspases in rat kidney and altered expression in ischemia-reperfusion injury. 953 Feb 76

Apoptosis is induced in cells via distinct pathways, which may differ according to various stimuli and different cell types. One apoptotic stimulus is the activation of receptors such as the p55 tumor necrosis factor (TNF) receptor. These receptors transduce their apoptotic signals via a cytoplasmic region termed the death domain. Here we investigated the apoptotic pathway induced by overexpression of the intracellular domain of p55 TNF receptor (p55-IC) in a neuronal model system consisting of PC12 cells. Using the tetracycline-regulated transactivator system, which allows controlled gene expression, we show that overexpression of p55-IC induces apoptosis in both naive and neuronal PC12 cells. The apoptosis-inducing effect of p55-IC is blocked by the expression of bcl-2, suggesting that p55-IC induces apoptosis in PC12 cells via a pathway controlled by bcl-2. The need for caspases in the p55-IC-induced cell death effect in naive and neuronal PC12 cells was studied by examining the effects of broad-spectrum and specific inhibitors of caspases as well as expression of antisense caspase-2 RNA. The broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone blocked p55-IC-induced cell death in both naive and neuronal cells, suggesting that caspases are needed for this process in both cell types. Caspase-1-like proteases are most probably not involved in the process since neither expression of crmA nor treatment with the caspase-1-specific peptide inhibitor Ac-Try-Val-Ala-Asp-aldehyde had any protective effect. Interestingly, expression of antisense caspase-2 RNA blocked the p55-IC-induced cell death in naive but not in neuronal PC12 cells, whereas the caspase-3-like specific inhibitor Ac-Asp-Glu-Val-Asp-aldehyde partially inhibited this death in neuronal but not in naive cells. These results suggest that the apoptosis-inducing effect of p55-IC requires different caspases in naive and neuronal PC12 cells.
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PMID:The intracellular domain of p55 tumor necrosis factor receptor induces apoptosis which requires different caspases in naive and neuronal PC12 cells. 958 83

The neurotoxin 6-hydroxydopamine (6-OHDA) induces apoptosis in the rat phaeochromocytoma cell line PC12. 6-OHDA-induced apoptosis is morphologically indistinguishable from serum deprivation-induced apoptosis. Exposure of PC12 cells to a low concentration of 6-OHDA (25 microM) results in apoptosis, whereas an increased concentration (50 microM) results in a mixture of apoptosis and necrosis. We investigated the involvement of caspases in the apoptotic death of PC12 cells induced by 6-OHDA, using a general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk), and compared this with serum deprivation-induced apoptosis, which is known to involve caspases. We show that zVAD-fmk (100 microM) completely prevented the apoptotic morphology of chromatin condensation induced by exposure to either 6-OHDA (25 and 50 microM) or serum deprivation. Furthermore, cell lysates from 6-OHDA-treated cultures showed cleavage of a fluorogenic substrate for caspase-3-like proteases (caspase-2, 3, and 7), acetyl-Asp-Glu-Val-Asp-aminomethylcoumarin, and this was inhibited by zVAD-fmk. However, although zVAD-fmk restored total cell viability to serum-deprived cells or cells exposed to 25 microM 6-OHDA, the inhibitor did not restore viability to cells exposed to 50 microM 6-OHDA. These data show the involvement of a caspase-3-like protease in 6-OHDA-induced apoptosis and that caspase inhibition is sufficient to rescue PC12 cells from the apoptotic but not the necrotic component of 6-OHDA neurotoxicity.
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PMID:Caspases mediate 6-hydroxydopamine-induced apoptosis but not necrosis in PC12 cells. 960 31

Exposure of mammalian cells to ultraviolet (UV) light elicits a cellular response and can also lead to apoptotic cell death. In this report, we show that a 36-kDa myelin basic protein (MBP) kinase detected by an in-gel kinase assay can be dramatically activated during the early stages of UV irradiation-triggered apoptosis of A431 cells. Immunoblot analysis revealed that this 36-kDa MBP kinase could be recognized by an antibody against the C-terminal regions of a family of p21Cdc42/Rac-activated kinases (PAKs). By using this antibody and a PAK2-specific antibody against the N-terminal region of PAK2 as studying tools, we further demonstrated that UV irradiation caused cleavage of PAK2 to generate a 36-kDa C-terminal catalytic fragment and a 30-kDa N-terminal fragment in A431 cells. The appearance of the 36-kDa C-terminal catalytic fragment of PAK2 matched exactly with the activation of the 36-kDa MBP kinase in A431 cells upon UV irradiation. In addition, UV irradiation also led to activation of CPP32/caspase-3, but not ICH-1L/caspase-2 and ICE/caspase-1, in A431 cells and the kinetics of activation of CPP32/caspase-3 appeared to correlate well with that of DNA fragmentation and of cleavage/activation of PAK2, respectively. Moreover, blockage of activation of CPP32/caspase-3 by pretreating the cells with two specific tetrapeptidic inhibitors for caspases (Ac-DEVD-cho and Ac-YVAD-cmk) could significantly attenuate the extent of cleavage/activation of PAK2 induced by UV irradiation. Collectively, the results demonstrate that cleavage and activation of PAK2 can be induced during the early stages of UV irradiation-triggered apoptosis and indicate the involvement of CPP32/caspase-3 in this process.
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PMID:Proteolytic cleavage and activation of PAK2 during UV irradiation-induced apoptosis in A431 cells. 971 43


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