Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent experimental evidence suggests that apoptosis pathways such as the CD95 system are an important mediator of chemotherapy-induced apoptosis in various tumor cell lines. Therapeutic concentrations of cytotoxic drugs induce CD95 and CD95-L that mediates apoptosis via an autocrine/paracrine loop by crosslinking CD95. Interfering with CD95-L/receptor interaction by antagonistic antibodies to the receptor or by inhibition of CD95-L expression strongly reduces apoptosis. Drug-induced apoptosis critically depends on activation of caspases since apoptosis is almost completely abrogated by the caspase inhibitor zVAD-fmk. The receptor apical caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3) are cleaved resulting in processing of substrates such as the nuclear enzyme PARP. In addition, the response to cytotoxic drugs is modulated by pro- and antiapoptotic proteins of the Bcl-2 family and p53. Defects in apoptosis pathways, e.g. deficient upregulation of CD95-L, downregulation of CD95 expression or blockade of caspase activation may confer resistance to cytotoxic drug treatment. Thus, chemosensitivity of tumor cells depends on intact apoptosis pathways such as the CD95 system that are activated by chemotherapeutic drugs. These findings may have implications for drug sensitivity and resistance of tumor cells.
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PMID:Molecular determinants of apoptosis induced by cytotoxic drugs. 974 44

Chlorambucil and prednisolone, two commonly used drugs in the treatment of chronic lymphocytic leukemia (CLL), induce apoptosis in CLL cells. We have investigated the involvement in this apoptotic cell death of caspases, which cleave critical cellular substrates thereby acting as the executioners of the apoptotic process. Induction of spontaneous or chlorambucil/prednisolone-induced apoptosis of freshly isolated B-CLL cells in culture resulted in the activation of the 'effector' caspases, -3 and -7, but generally not of caspase-2. Activation of caspases-3 and -7 was accompanied by the proteolysis of the DNA repair enzyme, poly (ADP-ribose) polymerase. Induction of apoptosis was also accompanied by the processing of caspase-8, the extent of which varied between patients. Induction of apoptosis and processing of all the caspases was inhibited by the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.fmk). Our results demonstrate a key role for the activation and processing of caspases in the execution phase of apoptosis in CLL cells. Apoptosis of CLL cells resulted in the selective activation of some but not all caspases. Our results suggest that the dysregulation of apoptosis observed in CLL may be due to the signalling leading to the activation of caspases rather than a deletion of pro-caspases. High levels of caspase-8 in CLL cells in conjunction with low levels of CD95 receptor may offer new therapeutic opportunities for the treatment of CLL.
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PMID:Processing/activation of caspases, -3 and -7 and -8 but not caspase-2, in the induction of apoptosis in B-chronic lymphocytic leukemia cells. 976 99

Apoptosis mediated by anticancer drugs may involve activation of death-inducing ligand/receptor systems such as CD95 (APO-1/Fas), cleavage of caspases, and perturbance of mitochondrial functions. We investigated the sequence of these events in SHEP neuroblastoma cells transfected with Bcl-2 or Bcl-X(L) using two different drugs, namely, doxorubicin (Doxo), which activates the CD95/CD95 ligand (CD95-L) system, and betulinic acid (Bet A), which does not enhance the expression of CD95 or CD95-L and which, as shown here, directly targets mitochondria. Apoptosis induced by both drugs was inhibited by Bcl-2 or Bcl-X(L) overexpression or by bongkrekic acid, an agent that stabilizes mitochondrial membrane barrier function, suggesting a critical role for mitochondria. After Doxo treatment, enhanced CD95/CD95-L expression and caspase-8 activation were not blocked by Bcl-2 or Bcl-X(L) and were found in cells with a mitochondrial transmembrane potential (delta psi(m)) that was still normal (delta psi(m)high cells). In marked contrast, after Bet A treatment, caspase-8 activation occurred in a Bcl-2- or Bcl-X(L)-inhibitable fashion and was confined to cells that had lost their delta psi(m) (delta psi(m)low cells). Mitochondria from cells treated with either Doxo or Bet A induced cleavage of both caspase-8 and caspase-3 in cytosolic extracts. Thus, caspase-8 activation may occur upstream or downstream of mitochondria, depending on the apoptosis-initiating stimulus. In contrast to caspase-8, cleavage of caspase-3 or poly(ADP-ribose)polymerase was always restricted to delta psi(m)low cells, downstream of the Bcl-2- or Bcl-X(L)-controlled checkpoint of apoptosis. Cytochrome c, released from mitochondria undergoing permeability transition, activated caspase-3 but not caspase-8 in a cell-free system. However, both caspases were activated by apoptosis-inducing factor, indicating that the mechanism of caspase-8 activation differed from that of caspase-3 activation. Taken together, our findings demonstrate that perturbance of mitochondrial function constitutes a central coordinating event in drug-induced cell death.
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PMID:Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. 976 78

The CD95 signaling pathway comprises proteins that contain one or two death effector domains (DED), such as FADD/Mort1 or caspase-8. Here we describe a novel 37 kDa protein, DEDD, that contains an N-terminal DED. DEDD is highly conserved between human and mouse (98. 7% identity) and is ubiquitously expressed. Overexpression of DEDD in 293T cells induced weak apoptosis, mainly through its DED by which it interacts with FADD and caspase-8. Endogenous DEDD was found in the cytoplasm and translocated into the nucleus upon stimulation of CD95. Immunocytological studies revealed that overexpressed DEDD directly translocated into the nucleus, where it co-localizes in the nucleolus with UBF, a basal factor required for RNA polymerase I transcription. Consistent with its nuclear localization, DEDD contains two nuclear localization signals and the C-terminal part shares sequence homology with histones. Recombinant DEDD binds to both DNA and reconstituted mononucleosomes and inhibits transcription in a reconstituted in vitro system. The results suggest that DEDD is a final target of a chain of events by which the CD95-induced apoptotic signal is transferred into the nucleolus to shut off cellular biosynthetic activities.
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PMID:DEDD, a novel death effector domain-containing protein, targeted to the nucleolus. 977 41

This review covers recent advances of CD95 signaling. It focuses on CD95-interacting molecules, formation of the death inducing signaling complex and the role of caspases, particularly caspase-8, and their death substrates. We also discuss the relevance of mitochondria in the CD95-mediated apoptotic process and how viral proteins interfere with crucial steps of this signaling pathway.
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PMID:Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis. 979 32

Sendai virus (SV) infection and replication lead to a strong cytopathic effect with subsequent death of host cells. We now show that SV infection triggers an apoptotic program in target cells. Incubation of infected cells with the peptide inhibitor z-VAD-fmk abrogated SV-induced apoptosis, indicating that proteases of the caspase family were involved. Moreover, proteolytic activation of two distinct caspases, CPP32/caspase-3 and, as shown for the first time in virus-infected cells, FLICE/caspase-8, could be detected. So far, activation of FLICE/caspase-8 has been described in apoptosis triggered by death receptors, including CD95 and tumor necrosis factor (TNF)-R1. In contrast, we could show that SV-induced apoptosis did not require TNF or CD95 ligand. We further found that apoptosis of infected cells did not influence the maturation and budding of SV progeny. In conclusion, SV-induced cell injury is mediated by CD95- and TNF-R1-independent activation of caspases, leading to the death of host cells without impairment of the viral life cycle.
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PMID:Sendai virus infection induces apoptosis through activation of caspase-8 (FLICE) and caspase-3 (CPP32). 984 76

Expression of the proto-oncogene c-myc stimulates cell proliferation in the presence of the appropriate survival factors and triggers apoptosis in their absence; this dual capacity ensures that cell growth is restricted to the correct paracrine environment and is thereby strictly controlled. Recently our laboratory demonstrated that c-Myc-induced apoptosis requires the CD95 death receptor pathway and that insulin-like growth factor (IGF-1) signalling suppresses this killing. To investigate further the links between c-Myc and IGF-1 pathways in CD95-induced apoptosis, we examined the effects of c-Myc and a downstream IGF-1 survival kinase, Akt, on killing mediated by CD95 and its recruited effector proteins (FADD and caspase-8). Here, we show that c-Myc activation does not exacerbate killing induced by FADD or pro-caspase-8, which narrows the point at which c-Myc exerts its action downstream of the interaction of CD95 with its ligand and upstream of FADD. We show further that activated Akt suppresses CD95-induced apoptosis and that Akt exerts its activity at a point downstream of FADD but upstream of caspase-8. These results restrict the possible mechanisms by which CD95-induced apoptosis is modulated by death signals and survival factors.
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PMID:The opposing roles of the Akt and c-Myc signalling pathways in survival from CD95-mediated apoptosis. 987 87

Upon stimulation, CD95 (APO-1/Fas) recruits the adapter molecule Fas-associated death domain protein (FADD)/MORT1 and caspase-8 (FADD-like interleukin-1beta-converting enzyme (FLICE)/MACH/MCH5) into the death-inducing signaling complex (DISC). Recently, a molecule with sequence homology to caspase-8 was identified, termed cellular FLICE-inhibitory protein (c-FLIP). c-FLIP has been controversially reported to possess apoptosis-promoting and -inhibiting functions. Using c-FLIP-specific monoclonal antibodies, we now show that c-FLIP is expressed in two isoforms, both of which, like FADD and caspase-8, are recruited to the CD95 DISC in a stimulation-dependent fashion. In stably transfected BJAB cells, c-FLIP blocks caspase-8 activation at the DISC and thereby inhibits CD95-mediated apoptosis. During this process, both caspase-8 and c-FLIP undergo cleavage between the p18 and p10 subunits, generating two stable intermediates of 43 kDa that stay bound to the DISC. c-FLIP has been suggested to play a role in protecting activated peripheral T cells from CD95-mediated apoptosis (Irmler, M., Thome, M., Hahne, M., Schneider, P., Hofmann, K., Steiner, V., Bodmer, J. L. , Schroter, M., Burns, K., Mattmann, C., Rimoldi, D., French, L. E., and Tschopp, J. (1997) Nature 388, 190-195). In contrast to this hypothesis, neither caspase-8 nor c-FLIP were cleaved in these cells, ruling out c-FLIP as the main factor regulating DISC activity. Moreover, recruitment of FADD, caspase-8, and c-FLIP to the DISC was strongly reduced in the apoptosis-resistant but readily detectable in the apoptosis-sensitive T cells.
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PMID:The role of c-FLIP in modulation of CD95-induced apoptosis. 988 May 31

Stimulation of the CD95/Fas/Apo-1 receptor leads to apoptosis through activation of the caspase family of cysteine proteases and disruption of the mitochondrial transmembrane potential (Deltapsim). We show that, in Jurkat human T cells and peripheral blood lymphocytes, Fas-induced apoptosis is preceded by 1) an increase in reactive oxygen intermediates (ROI) and 2) an elevation of Deltapsim. These events are followed by externalization of phosphatidylserine (PS), disruption of Deltapsim, and cell death. The caspase inhibitor peptides, DEVD-CHO, Z-VAD.fmk, and Boc-Asp.fmk, blocked Fas-induced PS externalization, disruption of Deltapsim, and cell death, suggesting that these events are sequelae of caspase activation. By contrast, in the presence of caspase inhibitors, ROI levels and Deltapsim of Fas-stimulated cells remained elevated. Because ROI levels and Deltapsim are regulated by the supply of reducing equivalents from the pentose phosphate pathway (PPP), we studied the impact of transaldolase (TAL), a key enzyme of the PPP, on Fas signaling. Overexpression of TAL accelerated Fas-induced mitochondrial ROI production, Deltapsim elevation, activation of caspase-8 and caspase-3, proteolysis of poly(A)DP-ribose polymerase, and PS externalization. Additionally, suppression of TAL diminished these activities. Therefore, by controlling the balance between mitochondrial ROI production and metabolic supply of reducing equivalents through the PPP, TAL regulates susceptibility to Fas-induced apoptosis. Early increases in ROI levels and Deltapsim as well as the dominant effect of TAL expression on activation of caspase-8/Fas-associated death domain-like IL-1beta-converting enzyme, the most upstream member of the caspase cascade, suggest a pivotal role for redox signaling at the initiation of Fas-mediated apoptosis.
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PMID:Elevation of mitochondrial transmembrane potential and reactive oxygen intermediate levels are early events and occur independently from activation of caspases in Fas signaling. 997 3

Release of cytochrome c is important in many forms of apoptosis. Recent studies of CD95 (Fas/APO-1)-induced apoptosis have implicated caspase-8 cleavage of Bid, a BH3 domain-containing proapoptotic member of the Bcl-2 family, in this release. We now demonstrate that both receptor-induced (CD95 and tumor necrosis factor) and chemical-induced apoptosis result in a similar time-dependent activation of caspases-3, -7, -8, and -9 in Jurkat T cells and human leukemic U937 cells. In receptor-mediated apoptosis, the caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD. FMK), inhibits apoptosis prior to commitment to cell death by inhibiting the upstream activator caspase-8, cleavage of Bid, release of mitochondrial cytochrome c, processing of effector caspases, loss of mitochondrial membrane potential, and externalization of phosphatidylserine. However, Z-VAD.FMK inhibits chemical-induced apoptosis at a stage after commitment to cell death by inhibiting the initiator caspase-9 and the resultant postmitochondrial activation of effector caspases. Cleavage of Bid but not release of cytochrome c is blocked by Z-VAD.FMK demonstrating that in chemical-induced apoptosis cytochrome c release is caspase-independent and is not mediated by activation of Bid. We propose that caspases form an integral part of the cell death-inducing mechanism in receptor-mediated apoptosis, whereas in chemical-induced apoptosis they act solely as executioners of apoptosis.
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PMID:Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. 998 52


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