Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The appearance of phosphatidylserine (PS) on the outer surface of apoptotic cells is an important signal for their ingestion. In platelets, elevation of intracellular Ca2+ with thapsigargin can trigger large amounts of PS exposure within minutes. We detected PS exposure in U937 promonocytes and Jurkat T-cells after incubation with thapsigargin, but in only 10% of the cells, and it took up to 6 h to occur. Tumor necrosis factor and anti-Fas antibody rapidly trigger apoptosis in these cells, and chelation of extracellular Ca2+ with 5 mM EGTA inhibited PS exposure by 65% and 50%, respectively. Chelation of intracellular Ca2+ with BAPTA-AM had no effect. Other parameters of apoptosis, including cell blebbing, shrinkage, nuclear fragmentation, activation of the ICE-like proteases, and fodrin cleavage, were not inhibited by extracellular EGTA. We conclude that while an elevation of intracellular Ca2+ is an ineffective trigger of apoptosis in the cells investigated, extracellular Ca2+ is required for efficient PS exposure during apoptosis.
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PMID:Involvement of extracellular calcium in phosphatidylserine exposure during apoptosis. 898 62

Tumor necrosis factor (TNF)-induced apoptosis is mediated by caspases, which are cysteine proteases related to interleukin 1beta-converting enzyme. We report here that TNF-induced activation of caspases results in the cleavage and activation of cytosolic phospholipase A2 (cPLA2) and that activated cPLA2 contributes to apoptosis. Inhibition of caspases by expression of a cowpox virus-derived inhibitor, CrmA, or by a specific tetrapeptide inhibitor of CPP32/caspase-3, acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), inhibited TNF-induced activation of cPLA2 and apoptosis. TNF-induced activation of cPLA2 was accompanied by a cleavage of the 100-kDa cPLA2 to a 70-kDa proteolytic fragment. This cleavage was inhibited by Ac-DEVD-CHO in a similar manner as that of poly(ADP)ribose polymerase, a known substrate of CPP32/caspase-3. Interestingly, specific inhibition of cPLA2 enzyme activity by arachidonyl trifluoromethylketone (AACOCF3) partially inhibited TNF-induced apoptosis without inhibition of caspase activity. Thus, our results suggest a novel caspase-dependent activation pathway for cPLA2 during apoptosis and identify cPLA2 as a mediator of TNF-induced cell death acting downstream of caspases.
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PMID:Involvement of caspase-dependent activation of cytosolic phospholipase A2 in tumor necrosis factor-induced apoptosis. 914 92

Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of oligodendrocytes (OLGs) in multiple sclerosis (MS). We report here the involvement of the interleukin 1beta-converting enzyme (ICE)/Caenorhabditis elegans gene ced-3 (CED-3) family in TNF-mediated cell death of OLGs. The addition of TNF-alpha to primary cultures of OLGs that express ice and cpp32 significantly decreased the number of live OLGs in 72 h. DNA fragmentation was detected in TNF-treated OLGs at 36 h with the terminal deoxynucleotidyl transferase dUTP nick end-labeling assay. Benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene, an inhibitor of the ICE/CED-3 family that shows p35-like inhibitory specificity, protected against the TNF-induced cell death of OLGs. Furthermore, acetyl-YVAD-CHO (a specific inhibitor of ICE-like proteases) as well as acetyl-DEVD-CHO (a specific inhibitor of CPP32-like proteases) enhanced the survival of OLGs treated with TNF-alpha, indicating that ICE- and the CPP32-mediated cell death pathways are activated in TNF-induced OLG cell death. Our results suggest that the inhibition of ICE/CED-3 proteases may be a novel approach to treat neurodegenerative diseases such as MS.
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PMID:ICE/CED-3 family executes oligodendrocyte apoptosis by tumor necrosis factor. 920 89

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces apoptosis in various cell systems by binding to the TNF receptor (TNFR). To study TNF-alpha-induced apoptosis, we isolated and characterized a novel TNF-alpha-resistant variant, U937/TNF clone UA, from human monocytic leukemia U937 cells. The UA cells resist apoptosis induced by TNF-alpha and anti-Fas antibody but not by anticancer drugs, such as VP-16 and Ara-C. Somatic cell hybridization between U937 and UA showed that apoptosis resistance to TNF-alpha in UA was genetically recessive. The hybridization analysis also showed that UA and another recessive mutant clone, UC, belong to different complementation groups in TNF-alpha-induced apoptosis signaling. In UA cells, TNF-alpha-induced disruption of mitochondrial membrane potential and CPP32 activation were abrogated. Expression of TNFR, Fas, and Bcl-2 family proteins was not changed in UA cells. These results suggest that the apoptosis resistant UA cells could have a functional defect in apoptosis signaling from the TNFR to mitochondria and interleukin-1beta converting enzyme (ICE) family protease activation. UA cells could be used to study signaling linkage between cell death-inducing receptor and mitochondria.
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PMID:Genetically recessive mutant of human monocytic leukemia U937 resistant to tumor necrosis factor-alpha-induced apoptosis. 942 4

We analyzed changes of growth and apoptotic cell death in human hair follicles. In anagen hair follicles, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate-biotin nick labeling-positive cells were observed in the keratogenous zone of the upper bulb matrix, the inner root sheath, and the companion layer of the outer root sheath. DNA ladder formation was also detected in anagen hair follicles. In catagen hair follicles, the lower bulb matrix cells around the dermal papilla and the outer layer cells of the outer root sheath became strongly positive, showing that apoptosis in catagen hair is distinct from that in anagen hair. We also confirmed the mRNA expression of four caspases (caspase-1, caspase-3, caspase-4, and caspase-7) in anagen hair follicles by reverse transcriptase-polymerase chain reaction and in situ hybridization. When human anagen hair follicles were cultured in the presence of transforming growth factor-beta or tumor necrosis factor-alpha in the serum-free medium, transforming growth factor-beta but not tumor necrosis factor-alpha induced catagen-like morphologic changes, which were indistinguishable from normal catagen hair follicles. Tumor necrosis factor-alpha, however, strongly inhibited the elongation of the hair shaft in a dose-dependent manner, accompanied by abnormal morphology and increased cell death in the bulb matrix cells. Our results suggest that apoptosis in hair follicles involves two different types. One is related to the terminal differentiation of follicular epithelial cells in anagen hair. The other occurs as a major driving force to eliminate the distinct portion of epithelial components in catagen hair. Furthermore, this study strongly indicates that the transforming growth factor-beta pathway is involved in the induction of catagen phase in human hair cycle.
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PMID:Analysis of apoptotic cell death in human hair follicles in vivo and in vitro. 985 1

Oligodendrocytes are myelin forming cells in mammalian central nervous system. About 50% of oligodendrocytes (OLGs) undergo cell death in normal development. In addition, massive OLG cell deaths have been observed in multiple sclerosis (MS). Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of oligodendrocytes (OLGs). The addition of TNF-a to primary cultures of OLGs significantly decreased the number of live OLGs in 72 h. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1-like proteases) enhanced the survival of OLGs treated with TNF-a, indicating that caspase-1-mediated cell-death pathway are activated in TNF-induced OLG cell death, caspase-11 is involved in activation of caspase-1. Oligodendrocytes from CASP-11-deficient mice are partially resistant to TNF-induced cell death. These results suggest that the activation of caspases is crucial in TNF-induced OLG cell death and inhibition of caspase family may be a novel approach to treat neurodegenerative diseases such as MS.
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PMID:[Oligodendrocyte cell death by caspase family proteases]. 1019 Jan 26

Tumor necrosis factor (TNF)alpha is considered to play a key pathogenetic role in inflammatory bowel diseases. In this study we analyzed the mechanisms by which TNFalpha induces intestinal epithelial cell apoptosis. TNFalpha alone, and more potently in combination with IFNgamma, induced a high degree of IEC-6 cell apoptosis. This effect was more than 100-fold stronger if both of the TNF-R were stimulated, compared to stimulation of the p55-TNF-R alone, indicating an important apoptosis enhancing effect of the p75-TNF-R. TNFalpha-induced apoptosis required activation of ICE caspases and was completely abolished by its inhibitor, zVAD-fmk. Specific inhibition of caspase-3 with zDEVD-fmk did not alter the effect of TNFalpha. Western blot analyses confirmed that caspase-3 was not activated in response to TNFalpha. In the presence of complete inhibition of the caspase cascade with zVAD-fmk (>/=50 microM), TNFalpha induced cell necrosis rather than apoptosis. Our data reveal that TNFalpha can trigger enterocyte cell death via apoptosis or necrosis, depending upon the activation or blockade of specific caspases.
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PMID:TNFalpha-induced IEC-6 cell apoptosis requires activation of ICE caspases whereas complete inhibition of the caspase cascade leads to necrotic cell death. 1038 60

Tumor necrosis factor-alpha (TNF-alpha) has been causally implicated in several demyelinating disorders, including multiple sclerosis. Because insulin-like growth factor I (IGF-I) is a potent stimulator of myelination, we investigated whether it can protect oligodendrocytes and myelination from TNF-alpha-induced damage using mouse glial cultures as a model. Compared with controls, TNF-alpha decreased oligodendrocyte number by approximately 40% and doubled the number of apoptotic oligodendrocytes and their precursors. Addition of Boc-aspartyl(Ome)-fluoromethyl ketone (BAF), an inhibitor of interleukin-1beta converting enzyme (ICE)/caspase proteases, blocked TNF-alpha-induced reductions in oligodendrocytes, indicating that the TNF-alpha-induced reduction in oligodendrocytes is, at least in part, due to apoptosis, and that ICE/caspases are one of TNF-alpha action mediators. Simultaneous addition of IGF-I to TNF-alpha-treated cultures negated these TNF-alpha effects nearly completely. Furthermore, IGF-I promoted oligodendrocyte precursor proliferation and/or differentiation in TNF-alpha-treated cultures. To analyze TNF-alpha and IGF-I actions on oligodendrocyte function, we measured the abundance of messenger RNAs (mRNAs) for two major myelin-specific proteins, myelin basic protein (MBP) and proteolipid protein (PLP). While TNF-alpha decreased MBP and PLP mRNA abundance by 5- to 6-fold, IGF-I abrogated TNF-alpha-induced reductions in a dose- and time-dependent manner. The changes in MBP and PLP mRNA abundance could not be completely explained by the changes in oligodendrocyte number, indicating that myelin protein gene expression is regulated by both TNF-alpha and IGF-I. These data support the hypothesis that TNF-alpha can mediate oligodendrocyte and myelin damage, and indicate that IGF-I protects oligodendrocytes from TNF-alpha insults by blocking TNF-alpha-induced apoptosis, and by promoting oligodendrocyte and precursor proliferation/differentiation and myelin protein gene expression.
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PMID:Insulin-like growth factor I protects oligodendrocytes from tumor necrosis factor-alpha-induced injury. 1038 98

The inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R), an IP(3)-gated Ca(2+) channel located on intracellular Ca(2+) stores, modulates intracellular Ca(2+) signaling. During apoptosis of the human T-cell line, Jurkat cells, as induced by staurosporine or Fas ligation, IP(3)R type 1 (IP(3)R1) was found to be cleaved. IP(3)R1 degradation during apoptosis was inhibited by pretreatment of Jurkat cells with the caspase-3 (-like protease) inhibitor, Ac-DEVD-CHO, and the caspases inhibitor, z-VAD-CH(2)DCB but not by the caspase-1 (-like protease) inhibitor, Ac-YVAD-CHO, suggesting that IP(3)R1 was cleaved by a caspase-3 (-like) protease. The recombinant caspase-3 cleaved IP(3)R1 in vitro to produce a fragmentation pattern consistent with that seen in Jurkat cells undergoing apoptosis. N-terminal amino acid sequencing revealed that the major cleavage site is (1888)DEVD*(1892)R (mouse IP(3)R1), which involves consensus sequence for caspase-3 cleavage (DEVD). To determine whether IP(3)R1 is cleaved by caspase-3 or is proteolyzed in its absence by other caspases, we examined the cleavage of IP(3)R1 during apoptosis in the MCF-7 breast carcinoma cell line, which has genetically lost caspase-3. Tumor necrosis factor-alpha- or staurosporine-induced apoptosis in caspase-3-deficient MCF-7 cells failed to demonstrate cleavage of IP(3)R1. In contrast, MCF-7/Casp-3 cells stably expressing caspase-3 showed IP(3)R1 degradation upon apoptotic stimuli. Therefore IP(3)R1 is a newly identified caspase-3 substrate, and caspase-3 is essential for the cleavage of IP(3)R1 during apoptosis. This cleavage resulted in a decrease in the channel activity as IP(3)R1 was digested, indicating that caspase-3 inactivates IP(3)R1 channel functions.
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PMID:Inositol 1,4,5-trisphosphate receptor type 1 is a substrate for caspase-3 and is cleaved during apoptosis in a caspase-3-dependent manner. 1056 23

Tumor necrosis factor (TNF) is known to be a growth factor for several myeloma cell lines. However, in the presence of the agonistic Fas antibody CH 11, TNF enhanced the level of apoptosis in cultures of the human myeloma cell line OH-2. This pro-apoptotic effect of TNF was explained at least in part by a TNF-mediated enhancement of Fas expression. TNF induces proliferation of OH-2 by activating nuclear transcription factor kappa-B (NF-kappaB). The proliferative effect of TNF on OH-2 cells was abrogated by CH11, but this was not caused by an inhibition of the translocation of NF-kappaB. On the contrary, CH11 could by itself activate NF-kappaB in OH-2 cells, and in the presence of an inhibitor of caspase-1 induce proliferation of the cells. The relationship between stimulation of TNF receptors and Fas and the level of NF-kappaB activation was also examined in three other myeloma cell lines. RPMI-8226 cells showed NF-kappaB activation by TNF, but contrary to OH-2, not by CH11. Unstimulated U-266 and JJN-3 cells had high levels of activated NF-kappaB. This shows that NFkappa-B is either constitutively activated or inducible in myeloma cells. Modulation of Fas expression and inhibition of NF-kappaB activation can potentially be of therapeutic importance in multiple myeloma.
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PMID:Apoptosis, proliferation and NF-kappaB activation induced by agonistic Fas antibodies in the human myeloma cell line OH-2: amplification of Fas-mediated apoptosis by tumor necrosis factor. 1058 May 67


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