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

c-Fos is a transcription factor that promotes cell growth, differentiation, and transformation. We found that c-Fos was degraded when WEHI7.2 mouse lymphoma cells were induced to undergo apoptosis with the calcium ATPase inhibitor, thapsigargin, or the glucocorticoid hormone, dexamethasone. The degradation of c-Fos preceded caspase-3 activation and apoptotic nuclear chromatin condensation and was inhibited by the proteasome inhibitors MG132, N-acetyl-leucyl-leucyl-norleucinal, and lactacystin. Stable transfection of WEHI7.2 cells with a mutant form of c-Fos that was not degraded by the proteasome inhibited apoptosis. Also, overexpression of Bcl-2 in WEHI7.2 cells blocked c-Fos degradation and inhibited apoptosis. The results indicate that proteasome-mediated degradation of c-Fos is an early, Bcl-2-regulated step in apoptosis induction by thapsigargin and dexamethasone. These findings suggest that c-Fos may have a protective action that is eliminated by proteasome-mediated degradation and preserved by Bcl-2.
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PMID:c-Fos degradation by the proteasome. An early, Bcl-2-regulated step in apoptosis. 973 57

Interleukin-1beta-converting enzyme (ICE) is believed to be one of the key proteases involved in apoptosis. Since the precursor form of interleukin-1beta (pre-IL-1beta) is one of the well known substrates for ICE, and a potassium/proton ionophore, nigericin, enhances IL-1beta processing, the authors hypothesized that nigericin induces apoptosis through the activation of ICE. In a lipopolysaccharide (LPS)-stimulated and nigericin-treated human monocytic cell line, THP-1, apoptosis was induced, as assessed as to a decrease in cell size, chromatin condensation, exposure of phosphatidylserine and DNA fragmentation. Under exactly the same conditions, nigericin also induced IL-1beta processing in these cells, which was significantly inhibited by an ICE inhibitor, acetyl-Tyr-Val-Ala-Asp-CHO. On the contrary, treatment with this inhibitor at the same concentration did not inhibit nigericin-induced apoptosis, assessed as to the decrease in cell size, chromatin condensation and DNA fragmentation. Although apoptosis induced by nigericin was also observed for LPS-stimulated human peripheral blood mononuclear cells and a mouse T lymphoma cell line, EL-4, the ICE inhibitor did not inhibit the apoptosis in the cells. These results suggest that activated ICE is not involved in the apoptosis induced by nigericin. Since apopain activity was not augmented under the same conditions, neither ICE nor apopain may play any role in the nigericin-induced apoptosis.
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PMID:Activation of interleukin-1beta-converting enzyme by nigericin is independent of apoptosis. 977 Mar 25

The adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cell lines. When cells were incubated in the presence of both dCF and 2'-deoxyadenosine (dAd), the concentration of dCF required to induce apoptosis of monocytoid leukemia cells was much lower than that required for myeloid, erythroid, or lymphoma cell lines. Among the cell lines tested, U937 cells were the most sensitive to this treatment. The concentration of dCF that effectively inhibited the proliferation of U937 cells was 1/1,000 of that required for lymphoma cell lines, on a molar basis. However, the uptake of dCF or dAd in U937 cells was comparable with that in other leukemia and lymphoma cell lines. The intracellular accumulation of dATP in U937 cells was only slightly higher than that in other leukemia cells in dCF-treated culture. Treatment with dCF plus dAd induced apoptosis in U937 cells at low concentrations, and this apoptosis was reduced by treatment with caspase inhibitors. Induction of caspase-3 (CPP32) activity accompanied the apoptosis induced by dCF plus dAd. No activation of CPP32 was observed in cytosol prepared from exponentially growing leukemia and lymphoma cells. However, dATP effectively induced CPP32 activation in cytosol from monocytoid cells, but not in that from nonmonocytoid cells, suggesting that dATP-dependent CPP32 activation is at least partly involved in the preferential induction of apoptosis in monocytoid leukemia cells. The combination of dCF and dAd may be useful for the clinical treatment of acute monocytic leukemia.
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PMID:Human monocytoid leukemia cells are highly sensitive to apoptosis induced by 2'-deoxycoformycin and 2'-deoxyadenosine: association with dATP-dependent activation of caspase-3. 978 75

The molecular events involved in apoptosis induced by ionizing radiation remain unresolved. In this paper we show that the cleavage of fodrin to a 150 kDa fragment is an early proteolytic event in radiation-induced apoptosis in the Burkitts' Lymphoma cell line BL30A and requires 100 microM zVAD-fmk for inhibition. Caspases-1, -3, -6 and -7 were shown to cleave fodrin to the 150 kDa fragment in vitro and all were inhibited by 10 microM zVAD-fmk. We also show that the in vitro cleavage of fodrin by calpain is inhibited by 100 microM zVAD-fmk as was the calpain-mediated hydrolysis of casein. We demonstrate that calpain is activated within 15 min after radiation exposure, concomitant with the cleavage of fodrin to the 150 kDa fragment whereas caspase-3 is activated at 2 h correlating with the cleavage of fodrin to the 120 kDa fragment. These results support a role for calpain in the early phases of the radiation-induced apoptosis pathway, upstream of the caspases.
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PMID:Calpain activation is upstream of caspases in radiation-induced apoptosis. 989 12

Most solid tumor cells are less sensitive to apoptosis induced by anticancer drugs than hematopoietic cancer cells. However, the mechanisms of the different responses to apoptosis in these cell types remain unknown. To explore this question, we used B16 melanoma and EL-4 lymphoma cells as solid tumor- and hematopoietic cancer-derived cell lines, and examined the effects of two apoptosis inducers, cytostatin and bactobolin, on both cell lines. Apoptosis in B16 cells was induced strongly by bactobolin, but weakly by cytostatin. In contrast, apoptosis in EL-4 cells was induced strongly by cytostatin, but weakly by bactobolin. While caspase-3 was activated upon induction of apoptosis in both cell lines, Ac-DEVD-CHO, a specific inhibitor of caspase-3, suppressed only the apoptosis in B16 cells. In B16 cells, cyclins E, A, and B1 were decreased by strongly apoptosis-inducing bactobolin prior to apoptosis commitment, but cyclin E was not decreased by weakly apoptosis-inducing cytostatin. On the other hand, in EL-4 cells cyclins D1, E, A, and B1 were decreased by strongly apoptosis-inducing cytostatin prior to apoptosis commitment, but neither cyclin A nor B1 was decreased by weakly apoptosis-inducing bactobolin. These results indicate that the dependency of apoptosis induction on caspase activity is different between the two cell lines. Furthermore, there may be an inverse correlation between specific cyclins and apoptosis induction in the two cell lines.
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PMID:Differential induction of apoptosis in B16 melanoma and EL-4 lymphoma cells by cytostatin and bactobolin. 1018 93

A murine erythroleukemic cell line (1-2-3) which expresses only the temperature-sensitive mutant p53 gene (Ala-to-Val substitution at codon 135) was established. These cells showed typical characteristics of apoptosis, when they were cultured at 32 degrees C. In this process, p53 recovered the wild-type p53 function and the expression of the p21 (waf1/cip1/sdi1), cyclin G1 and gadd45 genes was increased. However, no significant changes were detected in the expression of the mdm2, bcl-2, bax, fas and fasl genes, suggesting the existence of other genes associated with apoptosis. Genes up-regulated by p53 were screened by the mRNA differential display method. One of the up-regulated genes was identified as the elongation factor 1 alpha (EF-1 alpha) gene. EF-1 alpha is also a microtubule-severing protein. Upon the temperature-shift, the cells developed the morphology and the localization of alpha-tubulin similar to those of the cells treated with vincristine, a drug that affects microtubules. The microtubule-severing associated with up-regulation of EF-1 alpha by p53 may be a cause of the cell death. On the other hand, the function of cyclin G1 is not so clear despite the fact that 1-2-3 cells showed a significant increase of the cyclin G1 gene during the early stage of apoptosis. The yeast two-hybrid system was used to identify cyclin G1-associated proteins. One is a cytochrome c (Cyt c) oxidase subunit II (COXII). Cyclin G1 and COXII were co-immunoprecipitated from an extract of human osteosarcoma cell line that expressed high levels of cyclin G1. COX activity was also increased by temperature-shift in this cell line. The pattern of changes in COX activity was closely reflected by the expression of the cyclin G1 gene. Cyclin G1 and COXII associate physically with each other in vivo and that activation of COXII by binding to cyclin G1 upregulated by p53 may be associated with apoptosis. These two new pathways, p53-EF-1 alpha-microtubule-severing (-distortion of cytoskeleton) and p53-cyclin G1-COXII (-CytC, ATP-caspase-3 activation), may cooperate to induce apoptosis in this cell line.
Leuk Lymphoma 1999 Mar
PMID:The mechanisms of death of an erythroleukemic cell line by p53: involvement of the microtubule and mitochondria. 1019 36

The expression of Bcl-2 family proteins (Bcl-2, Bcl-X, Bcl-XL, Bcl-Xs, BAX, BAD, MCL-1) and of Interleukin-1 converting enzyme (ICE)-related proteins (ICE, CPP32, ICH- 1) was analyzed in acute leukemia cells by flow cytometry. Most proteins studied were detectable in cell lines such as KG1a, HL60, K562 (myeloblastic), REH, RAJI and MOLT4 (lymphoblastic) and VAL (B-cell lymphoma). However, BCL-Xs and BAK were weakly expressed in K562, as were Bcl-X, BAD and BAK in the VAL line. In acute myeloid leukemia (66 cases studied), the proteins were expressed in most cases in a high percentage of cells, especially BAX and CPP32, without correlation with hematological characteristics. However, Bcl-2 was expressed in a higher percentage of cells in FAB M1 and M5 cases, and in CD34-positive cases, whereas Bcl-Xs was more frequently expressed in M3 cases. No differences were observed regarding fluorescence intensity. Higher percentages of Bcl-2-positive cells were associated with low remission rate, while expression of Bcl-Xs was predictive of high remission rate. In acute lymphoblastic leukemia (36 cases), all proteins studied were expressed in a majority of cases. Bcl-Xs was more frequently detected in T-cell type, and was also associated with a higher remission rate. These results suggest that apoptosis-controlling proteins may have a role in the pathogenesis and response to therapy of acute leukemia.
Leuk Lymphoma 1999 May
PMID:Expression of apoptosis-controlling proteins in acute leukemia cells. 1034 77

In this study, we investigated the involvement of caspases in TGFbeta-induced apoptosis in human B cells. Our results show that TGFbeta-mediated nuclear fragmentation, observed in the Epstein-Barr virus-negative Burkitt's Lymphoma cell line BL41, was abolished in the presence of the tripeptide caspase inhibitor zVAD-fmk or the specific caspase-3 inhibitor DEVD-fmk. Other apoptotic manifestations such as cell shrinkage, surface phosphatidylserine expression and chromatin condensation were strongly inhibited by zVAD-fmk but only partially by DEVD-fmk. This suggests that other caspases in addition to caspase-3 control these apoptotis-associated features. Specific activation of caspase-3 during TGFbeta-induced apoptosis was demonstrated by the DEVD-fmk-sensitive expression of the active p17 subunit of caspase-3 and by in vivo cleavage of PARP. In addition, TGFbeta treatment of BL41 promoted the expression of both dephosphorylated and truncated forms of the retinoblastoma protein. Inhibition of caspase-3 activity abolished both nuclear fragmentation and expression of the truncated retinoblastoma protein, without modifying the G1 cell cycle arrest induced by TGFbeta. Our data thus demonstrate that TGFbeta-induced apoptosis of lymphoma B lymphocytes is dependent on caspase activation and involves caspase-dependent cleavage of the retinoblastoma protein.
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PMID:Role of caspases and possible involvement of retinoblastoma protein during TGFbeta-mediated apoptosis of human B lymphocytes. 1037 29

The effect of 3-nitrosobenzamide (NOBA) on the etoposide, staurosporine and dexamethason induced rapid (4-6 hr), caspase-dependent apoptosis was investigated in thymocytes and lymphoma cells by flow cytometric assay of DNA fragmentation. When NOBA (ED(50) = 4 microM) was added to these cell systems, the rapid onset of apoptosis was prevented. Such apparent protection by NOBA was related to the inactivation of caspase-3, by s-nitrosylation of 1.3 mol -SH per enzyme molecule out of 7 -SH groups. Since NOBA by itself induces DNA fragmentation within 18 hr in lymphoma cells, our results indicate that at least two active cell death pathways exist with apparent dissimilar kinetics and molecular mechanisms.
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PMID:Interaction of cytocidal drugs and the inhibition of caspase-3 by 3-nitrosobenzamide. 1044 56

Although B-cell diffuse large-cell lymphoma (DLCL) can respond to chemotherapy and radiotherapy, a large number of patients are still resistant to treatment. Caspase-3 is an enzyme crucial to the apoptotic process and may be important in the clinical outcome of these patients. The pattern of caspase-3 expression was studied in 54 cases of DLCL using immunohistochemistry and quantitative reverse-transcription PCR. Tumor cells displayed both a diffuse cytosolic and a punctate cytosolic staining for caspase-3. Kaplan-Meier survival curves indicated that tumor cells with a diffuse cytosolic expression of caspase-3 correlated with a poor prognosis (P > 0.0004). In addition, a punctate cellular localization was associated with complete response to treatment (P = 0.011). Cases with a small percentage of lymphoma cells expressing caspase-3 also tended to show poor survival (P > 0.09). Levels of caspase-3 mRNA were not significant (P > 0.17), although a weak trend was observed similar to the immunohistochemical analysis. The pattern of expression of caspase-3 was also assessed with respect to terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) positivity in both reactive lymph nodes and B-cell DLCL cases. Our results suggest that TUNEL-positive cells are not caspase-3-positive and that there is no correlation between DLCL cases with a high degree of DNA fragmentation and caspase-3 immunostaining. Furthermore, a survival curve indicated that a high TUNEL positivity was associated with a poor survival probability (P < 0.02) and a poor response to treatment (P = 0.04). These results confirm the dynamic nature of caspase-3 expression in DLCL and suggests that the pattern of expression of the enzyme has prognostic significance.
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PMID:Immunohistochemical localization of caspase-3 correlates with clinical outcome in B-cell diffuse large-cell lymphoma. 1053 24


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