Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry and controlling ploidy (chromosome number), the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein, survivin, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of survivin's anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.
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PMID:Control of apoptosis and mitotic spindle checkpoint by survivin. 985 93

Caspase-3 (CPP32/Yama/apopain), one of the interleukin 1 -converting enzyme (ICE)-like proteases (caspases), is anticipated to mediate apoptotic cell death. We observed the expression of caspase-3 in various cancer cell lines and lack of normal expression of mRNA and protein in MCF-7, human breast carcinoma cell line. Sequence analysis of cDNA showed 125 nucleotides deletion in spite of no gross gene alteration of caspase-3 in MCF-7. The possible cause is altered splicing of the fragment followed by frame shift at translation level. MCF-7 cells are widely used in the research of apoptosis because of the high sensitivity to tumor necrosis factor induced cell death. However, our results suggest the existence of other apoptotic pathways independent on caspase-3 at least in MCF-7 cells.
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PMID:Alteration of caspase-3 (CPP32/Yama/apopain) in wild-type MCF-7, breast cancer cells. 986 97

We previously demonstrated that treatment with cycloheximide (CHX) converted the phenotype of Fas-resistant human prostatic carcinoma cell lines to Fas-sensitive and that resistance to Fas-mediated apoptosis was due to a dominant-negative protein(s). In this study, we investigated the sequential activation of caspase family members, to gain insight into the likely site of action of the suppressor protein(s). We did not find Tyr-Val-Ala-Aspase activity in any of the cell lines examined. Time-dependent Asp-Glu-Val-Aspase activity was detected during Fas-mediated apoptosis in Fas-sensitive cell lines PC3 and ALVA31. Asp-Glu-Val-Aspase activity in Fas-resistant cell lines DU145 and JCA1, was detected only under combined treatment with CHX and anti-Fas agonistic mAb. In experiments with caspase inhibitors we show that Fas-mediated apoptosis in PC3 is mainly executed by the caspase-3 subfamily, but another member(s) of the caspase family may be involved in Fas-mediated apoptosis in ALVA31, DU145, and JCA1. Western blot analysis revealed that Fas-ligation activated caspase-7, but not caspase-3. The activated form of caspase-8 was detected in DU145 only after 4 h of simultaneous treatment with CHX and anti-Fas mAb, whereas in PC3 caspase-8 was found to be activated after 1 h of Fas-ligation. We have also found that treatment with staurosporin did not activate caspase-8, whereas staurosporin induced apoptosis at the same levels in both Fas-resistant and Fas-sensitive cell lines. These results suggest that an inhibitory protein(s), which suppresses apoptosis in Fas-resistant cell lines, presumably acts at the apex of apoptotic cascade by preventing the activation of caspase-8.
Cancer Res 1998 Dec 15
PMID:Fas-mediated apoptosis in human prostatic carcinoma cell lines occurs via activation of caspase-8 and caspase-7. 986 48

In this study, we first demonstrated that the widely used oral antifungal drug, ketoconazole (KT), can induce apoptosis in various type of human cancer cells and in a primary culture of rat liver cells. We further investigated the molecular mechanisms of KT-induced apoptosis. It was found that KT induced nuclear accumulation of p53 protein in a dose- and time-dependent manner. The level of p53 protein was elevated approximately three times as much in treated cells 24 h after KT (5 microM) exposure as in cells receiving mock treatment. We found that cells containing wild-type p53 (COLO 205 and Hep G2) were more sensitive to KT exposure. The bax protein was induced and the bcl-2 protein was inhibited by KT in cells containing wild-type p53 (Hep G2, COLO 205) but not in cells without p53 (Hep 3B). The caspase-3 was activated 24 h after KT treatment. The Poly-(ADP ribose) polymerase (PARP) and the lamin A degradation was induced by KT, which promoted nuclear membrane disassembly and eventually caused apoptosis. Our results also indicated that none of the PKC gene family was involved in KT-induced apoptosis.
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PMID:Ketoconazole-induced apoptosis through P53-dependent pathway in human colorectal and hepatocellular carcinoma cell lines. 987 98

beta-Hydroxyisovalerylshikonin (beta-HIVS), which was isolated from the plant, Lithospermium radix, inhibited the growth of various lines of cancer cells derived from human solid tumors at low concentrations between 10(-8) and 10(-6) M. When HL-60 cells were treated with 10(-6) M beta-HIVS for 3 h, characteristic features of apoptosis, such as DNA fragmentation, nuclear fragmentation, and activation of caspase-3-like activity, were observed. The most characteristic features of the effect of beta-HIVS were the remarkable morphological changes induced upon treatment of HL-60 cells with beta-HIVS, as visualized on the staining of actin filaments with phalloidin labeled with tetramethylrhodamine B isothiocyanate. Moreover, activation of MAP kinases, such as ERK2, JNK and p38, was detected after treatment with 10(-6) M beta-HIVS preceding the appearance of the characteristics of apoptosis, and the features of the activation of these MAP kinases were quite different from those of Fas and anticancer drug-induced apoptosis. The activation of JNK by beta-HIVS was not inhibited by inhibitors of caspases, suggesting that JNK is located either upstream or independent of the caspase signaling pathway. beta-HIVS did not inhibit the activity of topoisomerase II. These results indicate that beta-HIVS induces apoptosis in HL-60 cells through a mechanism unlike those reported for anti-Fas antibodies and etoposide.
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PMID:beta-hydroxyisovalerylshikonin inhibits the cell growth of various cancer cell lines and induces apoptosis in leukemia HL-60 cells through a mechanism different from those of Fas and etoposide. 988 Jul 90

Solid tumors usually have regions of hypoxia and glucose deprivation. Human colon carcinoma HT-29 cells show an apoptosis-resistant phenotype in response to microenvironmental stresses. In this study, we isolated a novel mutant of HT-29, designated as HA511, that showed a high apoptotic response to hypoxia, glucose deprivation and treatment with the chemical stressors tunicamycin and glucosamine. The mutant HA511 cells exhibited nuclear condensation and fragmentation and activation of CPP32 (caspase-3) protease under the stress conditions, while the parental HT-29 cells did not. We found that apoptosis occurred in HA511 cells after prolonged cell cycle arrest at the G1 phase, while in the parental cells a progression to S phase occurred after the G1 arrest. Upon exposure to an anti-Fas antibody, HA511 cells underwent apoptosis, whereas the parental cells proliferated without substantial cell death. Furthermore, HA511 cells were preferentially hypersensitive to cisplatin. We found no alteration in expression of GRP78, anti-apoptotic protein Bcl-XL, or p53, of which the gene was mutated in HT-29 cells. The mutant HA511 cells could provide useful information on the mechanism of apoptosis of solid tumors.
Jpn J Cancer Res 1998 Nov
PMID:A novel mutant from apoptosis-resistant colon cancer HT-29 cells showing hyper-apoptotic response to hypoxia, low glucose and cisplatin. 991 86

We studied the molecular mechanisms of apoptosis in the prostate cancer cell line LNCaP and whether overexpression of caspase activity could force this cell line to undergo apoptosis. The inhibitor of phosphomevalonate decarboxylase, sodium phenylacetate, and the protein kinase inhibitor staurosporine induced (a) release of cytochrome c from the mitochondria to the cytosol; (b) reduction in mitochondrial transmembrane potential; (c) proteolytic processing of caspase-3 and -7 but not -2; (d) cleavage of the DEVD substrate and the death substrates poly(ADP-ribose) polymerase and DNA fragmentation factor; and (e) apoptosis. The panspecific inhibitor of caspase activation N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-FMK) prevented all of these events except release of mitochondrial cytochrome c into the cytosol. None of these apoptotic signaling events were elicited by staurosporine or sodium phenylacetate treatment of LNCaP-Bcl-2 cells that overexpress the oncoprotein Bcl-2. Because caspase-7 is activated in every model of apoptosis that we have characterized thus far, we wished to learn whether overexpression of this protease could directly cause apoptosis of LNCaP cells. By using a replication-defective adenovirus, overexpression of caspase-7 protein in both LNCaP and LNCaP-Bcl-2 cells was accompanied by induction of cleavage of the DEVD substrate and TUNEL. These studies have demonstrated that caspase-7 and -3 are critical mediators of apoptosis in LNCaP cells. Caspase-7 was proteolytically activated in every model of apoptosis that we have developed, and the overexpression of it induced apoptosis of LNCaP and LNCaP-Bcl-2 cells. Thus, adenoviral-mediated transfer of caspase-7 may offer a new effective approach for the treatment of prostate cancer.
Cancer Res 1999 Jan 15
PMID:Signaling pathway activated during apoptosis of the prostate cancer cell line LNCaP: overexpression of caspase-7 as a new gene therapy strategy for prostate cancer. 992 51

Beta-lapachone (beta-Lap) has been found to inhibit DNA topoisomerases (Topos) by a mechanism distinct from that of other commonly known Topo inhibitors. Here, we demonstrated a pronounced elevation of H2O2 and O2- in human leukemia HL-60 cells treated with beta-Lap. Treatment with other Topo poisons, such as camptothecin (CPT), Vbeta-16, and GL331, did not have the same effect. On the other hand, antioxidant vitamin C (Vit C) treatment effectively antagonized beta-Lap-induced apoptosis. This suggested that a reactive oxygen species (ROS)-related pathway was involved in beta-Lap-induced apoptosis program. We also found that c-Jun NH2-terminal kinase (JNK) but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 was persistently activated in apoptosis induced by beta-Lap. Overexpression of a dominant-negative mutant mitogen-activated protein kinase kinase kinase 1 (MEKK1-DN) or treatment with JNK-specific antisense oligonucleotide or Vit C all prevented beta-Lap-induced JNK activation and the subsequent apoptosis. Only the expression of MEKK1-DN, not Vit C treatment, blocked the JNK activity induced by CPT, Vbeta-16, or GL331. These results confirm again that ROS acts as a mediator for JNK activation during beta-Lap-induced apoptosis. Furthermore, we found that beta-Lap can stimulate CPP32/Yama activity, which was, however, markedly inhibited by the MEKK1-DN expression or Vit C treatment. Again, CPT-induced CPP32/Yama activation can be abolished by MEKK1-DN but not by Vit C treatment. Taken together, these results indicate that beta-Lap but not other Topo inhibitors triggers apoptosis signaling, i.e., JNK and subsequent CPP32/Yama activation are mediated by the generation of ROS.
Cancer Res 1999 Jan 15
PMID:Activation of c-Jun NH2-terminal kinase and subsequent CPP32/Yama during topoisomerase inhibitor beta-lapachone-induced apoptosis through an oxidation-dependent pathway. 992 52

Expression and function of the TRAIL apoptotic pathway was investigated in normal and malignant breast epithelial cells. Glutathione-S-transferase (GST)-TRAIL extracellular domain fusion proteins were produced to analyze TRAIL-induced apoptosis. Only GST-TRAIL constructs containing regions homologous to the Fas self-association and ligand binding domains could induce apoptosis. GST-TRAIL induced significant (>90%) apoptosis in just one of eight normal and one of eight malignant breast cell lines. All other lines were relatively resistant to TRAIL-induced apoptosis. Activating TRAIL receptors DR4 and DR5 were expressed in all normal and malignant breast cell lines. The inhibitory receptor TRID was highly expressed in one of four normal and two of seven malignant breast cell lines. DR4, DR5, or TRID expression did not correlate with sensitivity to TRAIL-induced apoptosis. Incubation of cell lines with doxorubicin or 5-fluorouracil significantly augmented TRAIL-induced apoptosis in most breast cell lines. By fractional inhibition analysis, the toxicity of the combination of TRAIL and doxorubicin or 5-fluorouracil was synergistic compared with either agent alone. In contrast, melphalan and paclitaxel augmented TRAIL-induced apoptosis in few cell lines, and methotrexate did not augment it in any cell line. Augmentation of TRAIL-induced apoptosis by doxorubicin or 5-fluorouracil was mediated through caspase activation. This was evidenced by the fact that chemotherapy agents that synergized with TRAIL (e.g., doxorubicin) themselves caused cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and their toxicity was blocked by the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2 (ZVAD-fmk). The combination of TRAIL and doxorubicin caused significantly greater caspase-3 and PARP cleavage, and the combined toxicity also was inhibited by ZVAD-fmk. In contrast, chemotherapy agents that did not augment TRAIL-induced apoptosis (e.g., methotrexate) caused minimal caspase-3 and PARP cleavage by themselves, and their toxicity was not inhibited by ZVAD-fmk. These drugs also did not increase caspase-3 or PARP cleavage when combined with TRAIL. In summary, few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines. Treatment with chemotherapy provides an approach to sensitize breast cancer cells to TRAIL-induced apoptosis.
Cancer Res 1999 Feb 01
PMID:Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. 997 25

The cyclin-dependent kinase inhibitor p21waf1/Cip1 is a downstream effector of the p53-dependent cell growth arrest. We report herein that p21 was cleaved by caspase-3/CPP32 at the site of DHVD112L during the DNA damage-induced apoptosis of cancer cells. The cleaved p21 fragment could no more arrest the cells in G1 phase nor suppress the cells undergoing apoptosis because it failed to bind to the proliferating cell nuclear antigen (PCNA) and lost its capability to localize in the nucleus. Thus, caspase-3-mediated cleavage and inactivation of p21 protein may convert cancer cells from growth arrest to undergoing apoptosis, leading to the acceleration of chemotherapy-induced apoptotic process in cancer cells.
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PMID:Caspase-mediated cleavage of p21Waf1/Cip1 converts cancer cells from growth arrest to undergoing apoptosis. 1002 18


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