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)

Here we report that photoactivated hypericin can induce either apoptosis or necrosis in HeLa cells. Under apoptotic conditions the cleavage of poly(ADP-ribose) polymerase (PARP) into the 85-kDa product is blocked by the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (z-DEVD-fmk). Both inhibitors protect cells from apoptosis but cannot prevent hypericin-induced necrosis. Conversely, HeLa cells overexpressing the viral cytokine response modifier A (CrmA), which inhibits caspase-1 and -8, still undergo hypericin-induced apoptosis and necrosis. Evidence is provided for the release of mitochondrial cytochrome c in the cytosol and for procaspase-3 activation in the hypericin-induced cell killing.
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PMID:Hypericin-induced photosensitization of HeLa cells leads to apoptosis or necrosis. Involvement of cytochrome c and procaspase-3 activation in the mechanism of apoptosis. 986 16

Sphingosine and other long-chain bases (including sphinganine, dimethylsphingosine and stearylamine), but not octylamine (a short-chain analogue of sphinganine), induced apoptosis in Hep3B hepatoma cells. Because both D- and L-erythrosphingosine and stearylamine exert potent apoptotic effects on Hep3B cells, it is possible that these long-chain bases may activate apoptosis by inhibiting protein kinase C (PKC) activity. However, pretreatment with the PKC activator PMA could not rescue cells from apoptosis triggered by long-chain bases. Therefore the involvement of PKC in this apoptotic process requires further characterization. We also investigated whether these long-chain bases might be metabolized into ceramide in order to elicit their apoptotic action. We found that long-chain bases acted independently of ceramide in the induction of apoptosis, since addition of fumonisin B1, a fungal agent which effectively inhibits ceramide synthesis from sphingosine, did not protect against apoptosis. Additionally, we found that sphingosine-induced apoptosis was accompanied by activation of caspases. The functional role of caspases in this apoptotic process was examined by using specific caspase inhibitors. The general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone, which exhibits a broad specificity for caspase-family proteases, effectively blocked sphingosine-induced apoptosis. Furthermore, our results indicate that caspase-3-like proteases, but not caspase-1, are activated during apoptosis triggered by sphingosine. Enhancement of caspase-3-like activity and cleavage of poly(ADP-ribose) polymerase, an in vivo substrate for caspase-3, was clearly demonstrated in sphingosine-treated Hep3B cells. Considered together, these results suggest that caspase-3-like proteases participate in apoptotic cell death induced by sphingosine.
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PMID:Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells. 993 12

6-[3-(1-Adamantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) is a novel retinoid which induces apoptosis in the retinoic acid-resistant HL-60R human leukemia cell line. CD437-mediated poly(ADP-ribose) polymerase (PARP) cleavage and apoptosis of HL-60R cells does not require gene transcription or protein synthesis since it occurs in the presence or absence of either actinomycin D or cycloheximide. Marked activation of both the p38 and the JNK/SAPK serine and threonine kinases occurs at 1 h of exposure to CD437 with subsequent PARP cleavage at 2 h and apoptosis noted at 4 to 6 h. CD437 concentrations as little as 10 nM result in p38 activation and apoptosis of HL-60R cells. However, inhibition of p38 activation utilizing the specific inhibitor SB203580 does not block CD437-mediated PARP cleavage or apoptosis. In addition, p38 activation is dependent upon the activation of the caspase system since p38 activation is blocked by the pan ICE inhibitor Z-VAD fmk, which also inhibits CD437-mediated apoptosis and PARP cleavage in these cells. CD437-mediated activation of JNK/SAPK is not inhibited by Z-VAD fmk, suggesting that it lies upstream of CD437 activation of caspase activity and subsequent apoptosis. The role of JNK/SAPK activation in CD437-mediated apoptosis remains to be defined.
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PMID:Activation of the p38 and JNK/SAPK mitogen-activated protein kinase pathways during apoptosis is mediated by a novel retinoid. 1004 65

Merbarone (5-[N-phenyl carboxamido]-2-thiobarbituric acid) is an anticancer drug that inhibits the catalytic activity of DNA topoisomerase II (topo II) without damaging DNA or stabilizing DNA-topo II cleavable complexes. Although the cytotoxicity of the complex-stabilizing DNA-topo II inhibitors such as VP-16 (etoposide) has been partially elucidated, the cytotoxicity of merbarone is poorly understood. Here, we report that merbarone induces programmed cell death or apoptosis in human leukemic CEM cells, characterized by internucleosomal DNA cleavage and nuclear condensation. Treatment of CEM cells with apoptosis-inducing concentrations of merbarone caused activation of c-Jun NH2-terminal kinase/stress-activated protein kinase, c-jun gene induction, activation of caspase-3/CPP32-like protease but not caspase-1, and the proteolytic cleavage of poly(ADP-ribose) polymerase. Treatment of CEM cells with a potent inhibitor of caspases, Z-Asp-2. 6-dichlorobenzoyloxymethyl-ketone, inhibited merbarone-induced caspase-3/CPP32-like activity and apoptosis in a dose-dependent manner. These results indicate that the catalytic inhibition of topo II by merbarone leads to apoptotic cell death through a caspase-3-like protease-dependent mechanism. These results further suggest that c-Jun and c-Jun NH2-terminal kinase/stress-activated protein kinase signaling may be involved in the cytotoxicity of merbarone.
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PMID:Merbarone, a catalytic inhibitor of DNA topoisomerase II, induces apoptosis in CEM cells through activation of ICE/CED-3-like protease. 1005 40

In this study, we elucidate signaling pathways induced by photodynamic therapy (PDT) with hypericin. We show that PDT rapidly activates JNK1 while irreversibly inhibiting ERK2 in several cancer cell lines. In HeLa cells, sustained PDT-induced JNK1 and p38 mitogen-activated protein kinase (MAPK) activations overlap the activation of a DEVD-directed caspase activity, poly(ADP-ribose) polymerase (PARP) cleavage, and the onset of apoptosis. The caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (zDEVD-fmk) protect cells against apoptosis and inhibit DEVD-specific caspase activity and PARP cleavage without affecting JNK1 and p38 MAPK activations. Conversely, stable overexpression of CrmA, the serpin-like inhibitor of caspase-1 and caspase-8, has no effect on PDT-induced PARP cleavage, apoptosis, or JNK1/p38 activations. Cell transfection with the dominant negative inhibitors of the c-Jun N-terminal kinase (JNK) pathway, SEK-AL and TAM-67, or pretreatment with the p38 MAPK inhibitor PD169316 enhances PDT-induced apoptosis. A similar increase in PDT-induced apoptosis was observed by expression of the dual specificity phosphatase MKP-1. The simultaneous inhibition of both stress kinases by pretreating cells with PD169316 after transfection with either TAM-67 or SEK-AL produces a more pronounced sensitizing effect. Cell pretreatment with the p38 inhibitor PD169316 causes faster kinetics of DEVD-caspase activation and PARP cleavage and strongly oversensitizes the cells to apoptosis following PDT. These observations indicate that the JNK1 and p38 MAPK pathways play an important role in cellular resistance against PDT-induced apoptosis with hypericin.
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PMID:The activation of the c-Jun N-terminal kinase and p38 mitogen-activated protein kinase signaling pathways protects HeLa cells from apoptosis following photodynamic therapy with hypericin. 1008 20

Our previously performed experiments clearly showed a significant VDR-mediated growth inhibitory effect of 1,25-dihydroxyvitamin D3 and its synthetic analogs in a variety of human cancer cells including human colon and breast cancer, soft tissue sarcoma, and malignant melanoma cell lines. The mechanisms by which 1, 25-dihydroxyvitamin D3 and its synthetic analogs growth inhibit human cancer cells is poorly elucidated. The exposure of human colon cancer cells HT-29 to 1,25-dihydroxyvitamin D3 or its analog, 1alpha, 25-dihydroxy-16-ene-23yne-26,27-hexafluoro-19-nor-choleca lci ferol (Ro 25-6760), at the 10(-6) M concentration resulted in significant growth inhibition with induction of the apoptotic process after three days of treatment detected by TUNEL assay and agarose gel electrophoresis of DNA. As a logical link with DNA fragmentation analyses and TUNEL assay, cleavage of the 116 kDa PARP protein was accompanied by the appearance of a characteristic 85 kDa fragment of PARP in a population of floating cells after both treatments. The results of cell cycle analysis showed a G0/G1 phase block after three days of administration of either compound when compared with untreated cells. On day 4, G0/G1 cell cycle arrest remained on the same level in comparison with control. Paralleling the G0/G1 phase block, was a notable decrease in the number of cells in the S phase which also became significant after three days of treatment. The results of these experiments show that the newly developed 19-nor synthetic vitamin D3 analog, Ro 25-6760, as well as 1, 25-dihydroxyvitamin D3, induced the expression of p21waf1, resulted in a significant G1/G0 cell cycle arrest leading to impressive growth inhibition and induction of apoptosis associated with proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) showing a possible involvement of apoptosis-specific activation of the ICE/CED-3 proteolitic pathway.
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PMID:Novel 19-nor-hexafluoride vitamin D3 analog (Ro 25-6760) inhibits human colon cancer in vitro via apoptosis. 1020 Mar 51

1. Activation of macrophages with lipopolysaccharide (LPS) and low doses of interferon-gamma (IFN-gamma) induced apoptotic death through a nitric oxide-dependent pathway. 2. Treatment of cells with the immunosuppressors cyclosporin A (CsA) or FK506 inhibited the activation-dependent apoptosis. 3. These drugs decreased the up-regulation of p53 and Bax characteristic of activated macrophages. Moreover, incubation of activated macrophages with CsA and FK506 contributed to maintain higher levels of Bcl-2 than in LPS/IFN-gamma treated cells. 4. The inhibition of apoptosis exerted by CsA and FK506 in macrophages was also observed when cell death was induced by treatment with chemical nitric oxide donors. 5. Incubation of macrophages with LPS/IFN-gamma barely affected caspase-1 but promoted an important activation of caspase-3. Both CsA and FK506 inhibited pathways leading to caspase-3 activation. Moreover, the cleavage of poly(ADP-ribose) polymerase, a well established caspase substrate, was reduced by these immunosuppressive drugs. 6. CsA and FK506 reduced the release of cytochrome c to the cytosol and the activation of caspase-3 in cells treated with nitric oxide donors. 7. These results indicate that CsA and FK506 protect macrophages from nitric oxide-dependent apoptosis and suggest a contribution of the macrophage to innate immunity under conditions of immunosuppression of the host.
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PMID:Protective effect of cyclosporin A and FK506 from nitric oxide-dependent apoptosis in activated macrophages. 1020 1

NF-kappa B is involved in the transcriptional control of various genes that act as extrinsic and intrinsic survival factors for T cells. Our findings show that suppression of NF-kappa B activity with cell-permeable SN50 peptide, which masks the nuclear localization sequence of NF-kappa B1 dimers and prevents their nuclear localization, induces apoptosis in resting normal human PBL. Inhibition of NF-kappa B resulted in the externalization of phosphatidylserine, induction of DNA breaks, and morphological changes consistent with apoptosis. DNA fragmentation was efficiently blocked by the caspase inhibitor Z-VAD-fmk and partially blocked by Ac-DEVD-fmk, suggesting that SN50-mediated apoptosis is caspase-dependent. Interestingly, apoptosis induced by NF-kappa B suppression, in contrast to that induced by TPEN (N,N,N',N'-tetrakis [2-pyridylmethyl]ethylenediamine) or soluble Fas ligand (CD95), was observed in the absence of active death effector proteases caspase-1-like (IL-1 converting enzyme), caspase-3-like (CPP32/Yama/apopain), and caspase-6-like and without cleavage of caspase-3 substrates poly(ADP-ribose) polymerase and DNA fragmentation factor-45. These findings suggest either low level of activation is required or that different caspases are involved. Preactivation of T cells resulting in NF-kappa B nuclear translocation protected cells from SN50-induced apoptosis. Our findings demonstrate an essential role of NF-kappa B in survival of naive PBL.
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PMID:Inhibition of NF-kappa B activity in human T lymphocytes induces caspase-dependent apoptosis without detectable activation of caspase-1 and -3. 1039 45

Although nitric oxide (NO) induces neuronal cell death under some conditions, it also can prevent apoptosis resulting from growth factor withdrawal. We investigated the molecular mechanism by which NO protects undifferentiated and differentiated PC12 cells from trophic factor deprivation-induced apoptosis. PC12 cells underwent apoptotic death in association with increased caspase-3-like activity, DNA fragmentation, poly(ADP-ribose) polymerase (PARP) cleavage, and cytochrome c release after 24 hr of serum withdrawal. The apoptosis of PC12 cells was inhibited by the addition of NO-generating donor S-nitroso-N-acetylpenicillamine (SNAP) (5-100 microM) and the specific caspase-3-like protease inhibitor Ac-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-cho) but not the YVADase (or caspase-1-like protease) inhibitor N-acetyl-Tyr-Val-Ala-Asp-aldehyde (Ac-YVAD-cho). SNAP and Ac-DEVD-cho prevented the increase in DEVDase (caspase-3-like protease) activity. The SNAP-mediated suppression of DEVDase activity was only minimally reversed by the incubation of cell lysate with dithiothreitol, indicating that NO did not S-nitrosylate caspase-3-like proteases in PC12 cells. Western blot analysis showed that NO inhibited the proteolytic activation of caspase-3. The cGMP analog 8-bromo-cGMP (8-Br-cGMP) blocked apoptotic cell death, caspase-3 activity and activation, and cytochrome c release. The soluble guanylyl cyclase inhibitor 1-H-oxodiazol-[1,2,4]-[4,3-a] quinoxaline-1-one (CODQ) significantly attenuated NO-mediated, but not 8-Br-cGMP-dependent, inhibition of apoptotic cell death, PARP cleavage, cytochrome c release, and DEVDase activity. Furthermore, the protein kinase G inhibitor KT5823 reversed both SNAP- and 8-Br-cGMP-mediated anti-apoptotic events. All these apoptotic phenomena were also suppressed by NO production through neuronal NO synthase gene transfer into PC12 cells. Furthermore, similar findings were observed in differentiated PC12 cells stimulated to undergo apoptosis by NO donors and NGF deprivation. These findings indicate that NO protects against PC12 cell death by inhibiting the activation of caspase proteases through cGMP production and activation of protein kinase G.
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PMID:Nitric oxide protects PC12 cells from serum deprivation-induced apoptosis by cGMP-dependent inhibition of caspase signaling. 1043 31

Bcl-2 family proteins and interleukin-1-beta converting enzyme/Caenorhabditis elegans cell death gene-3 (ICE/CED-3) family proteases (caspases) represent the basic regulators of apoptosis. However, the precise mechanism by which they interact is unclear. In this study, we found that gamma-radiation-induced apoptosis of leukemia cells was associated with activation of multiple caspases and bax up-regulation. Membrane changes and caspase activities were suppressed by specific caspase inhibitors. Similarly, the serine protease inhibitors z-Ala-Ala-Asp-cmk (AAD) and tosyl-lysine chloromethyl ketone (TLCK) also prevented caspase activation and poly(ADP-ribose) polymerase cleavage in vivo but had no effect on caspase activity in vitro. TLCK also prevented bax up-regulation as a result of its inhibitory effect on p53 function. Inhibitors of caspases and serine proteases partially prevented cell death, suggesting a caspase involvement in Bax-mediated cell death. We propose an ordering of signaling events in Bax-mediated cell death, including steps upstream and downstream of p53 and bax up-regulation.
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PMID:Ionizing radiation-induced, Bax-mediated cell death is dependent on activation of cysteine and serine proteases. 1043 17


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