Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Trans retinoic acid (RA) has proven to be a potent therapeutic agent in the treatment of acute promyelocytic leukemia. Unfortunately, other subtypes of acute myelogenous leukemia are resistant to the antiproliferative and differentiating effects of RA. In this report, we describe a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN; CD437) that not only totally inhibits the proliferation of RA-resistant leukemic cell lines HL-60R and K562 but also induces apoptosis in these cells. Exposure of HL-60R to CD437 results in the rapid (within 30 minutes) increase of the cyclin-dependent kinase inhibitor p21(waf1/cip1) as well as GADD45 mRNA. Manifestations of CD437-mediated programmed cell death are noted within 2 hours, as indicated by both the cleavage and activation of the CPP32 protease and cleavage of poly (ADP-ribose) polymerase. This is followed by cleavage of bcl-2 and internucleosomal DNA degradation. HL-60R cells do not express the retinoid nuclear receptor RAR beta and RAR gamma and express a truncated RAR alpha. Thus, CD437 induction of p21(waf1/cip1) and GADD45 mRNAs and apoptosis occurs through a unique mechanism not involving the retinoid nuclear receptors. CD437 represents a unique retinoid with therapeutic potential in the treatment of myeloid leukemia.
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PMID:Retinoid induced apoptosis in leukemia cells through a retinoic acid nuclear receptor-independent pathway. 919 71

The tumor suppressor p53 has been implicated in apoptosis induction and is mutated in human T-ALL CCRF-CEM cells. To investigate possible consequences of wild-type p53 loss, we reconstituted CEM-C7H2, a subclone of CCRF-CEM, with a temperature-sensitive p53 allele (p53ts). Stably transfected lines expressed high levels of p53ts and shift to the permissive temperature (32 degrees C) caused rapid induction of p53-regulated genes, such as p21(CIP1/WAF1), mdm-2 and bax. This was followed by extensive apoptosis within 24 h to 36 h, supporting the notion that mutational p53 inactivation contributed to the malignant phenotype. p53-dependent apoptosis was preceded by digestion of poly(ADP-ribose) polymerase, a typical target of interleukin-1beta-converting enzyme (ICE)-like proteases/caspases, and was markedly resistant to the ICE/caspase-1 and FLICE/caspase-8 inhibitor acetyl-Tyr-Val-Ala-Asp.chloromethylketone (YVAD), but sensitive to the CPP32/caspase-3 inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp.fluoromethylketone (DEVD) and benzyloxycarbonyl-Val-Ala-Asp.fluoromethylketone (zVAD), a caspase inhibitor with broader specificity. This indicated an essential involvement of caspases, but argued against a significant role of ICE/caspase-1 or FLICE/caspase-8. Actinomycin D or cycloheximide prevented cell death, suggesting that, in this system, p53-induced apoptosis depends upon macromolecule biosynthesis. Introduction of functional p53 into CEM cells enhanced their sensitivity to the DNA-damaging agent doxorubicin, but not to the tubulin-active compound vincristine. Thus, mutational p53 inactivation in ALL might entail relative resistance to DNA-damaging, but not to tubulin-destabilizing, chemotherapy.
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PMID:p53-induced apoptosis in the human T-ALL cell line CCRF-CEM. 939 39

Upon treatment with NO-releasing compounds such as S-nitrosoglutathione or spermine NO, human myeloid leukemia U937 cells undergo apoptosis. Early NO-mediated signals comprise activation of a Z-A-DCB (benzoyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene)-sensit ive, caspase-3 like cysteine protease that cleaved poly (ADP-ribose) polymerase (PARP), U1 small nuclear ribonucleoprotein (U1 snRNP), and the fluorogenic substrate N-acetyl-Asp-Glu-Val-Asp-7-amido-4-methylcoumarin. In association with these early apoptotic alterations p21 (WAF1/Cip1) is upregulated, but NO affected cell proliferation and apoptosis at a similar dose. At later time points the classical antiapoptotic protein Bcl-2 is downregulated, indicating that decreased Bcl-2 expression is secondary and not a prerequisite for initiation of apoptosis. N-Acetylcysteine (1 mM) interfered with NO-mediated apoptotic signaling, blocking DNA fragmentation as well as PARP and U1 snRNP cleavage. In contrast Z-A-DCB suppressed DNA fragmentation and U1 snRNP cleavage, while PARP breakdown proceeded unaltered. Observing proteolytic PARP digestion without apoptotic alterations questions PARP cleavage as an apoptotic parameter. These results suggest that a Z-A-DCB-sensitive caspase that is distinct from the PARP-cleaving enzyme is activated during NO exposure. NO-mediated apoptotic signaling in U937 cells activates caspases, some of which are dispensable for propagating the death signal.
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PMID:U937 apoptotic cell death by nitric oxide: Bcl-2 downregulation and caspase activation. 945 54

Paclitaxel-induced cytotoxicity, cell cycle perturbation, and apoptosis were determined in a human ovarian cancer cell line expressing wt p53 (A2780) and in a subclone (A2780/E6) obtained upon transfection with the product of the E6 gene of the human papilloma virus HPV16. The inactivation of wt p53 in A2780/E6 was verified by measuring the inability of the clone to induce p53 and p21 expression after paclitaxel treatment. The p53-negative clone (A2780/E6) was approximately 50-fold more sensitive to paclitaxel than wt p53-expressing A2780 cells. This increased sensitivity was related to the ability of paclitaxel to induce a strong arrest of cells in the G2/M phase of the cell cycle in A2780/E6 but not in A2780 cells. This different cell cycle arrest was accompanied by increased frequency of paclitaxel-induced p53-independent apoptosis. Initial studies on proteases activation tend to exclude a direct role of ICE and CPP32 in the induction of apoptosis in these cells and show a paclitaxel-dependent increase in FLICE levels, whose biological relevance is however at present not defined.
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PMID:Inactivation of p53 in a human ovarian cancer cell line increases the sensitivity to paclitaxel by inducing G2/M arrest and apoptosis. 963 17

Activation of the p53-mediated DNA damage response induces either G1 cell cycle arrest or apoptosis. The G1 cell cycle arrest is in part caused by the p53-dependent transcriptional activation of the CDK inhibitor, p21(Cip1/Waf1). We report here that human p21 protein is rapidly induced but selectively cleaved during the apoptotic response to gamma-irradiation. Such an event occurred early, well before the morphological appearance of apoptosis. Ectopical expression of p53 in tumor cells alone could induce p21 expression, followed by p21 cleavage and apoptosis. The cleavage of p21 could be reproduced in extracts prepared from irradiated cells or by recombinant caspase-3, suggesting that a caspase-like activity is responsible for this cleavage. p21 binds independently to both CDK2 and proliferation cell nuclear antigen (PCNA). Our studies indicated that p21 cleavage by the caspase-like activity specifically abolished its interaction with PCNA, suggesting that p21 cleavage may interfere with normal PCNA-dependent repair. Our data suggest that p21 may serve as a critical checkpoint regulator for both cell cycle arrest and apoptosis during the p53-mediated DNA damage response. Manipulation of the checkpoint regulators involved in cell cycle arrest and apoptosis may thus provide a novel strategy to cancer therapy.
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PMID:Cleavage of CDK inhibitor p21(Cip1/Waf1) by caspases is an early event during DNA damage-induced apoptosis. 966 8

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

The death mediator caspase acts as the dominant regulator during cell death induction. The CPP32 subfamily, including caspase 3 (CPP32/Yama/Apopain), is essential for the cell death signaling. We recently reported that activation of caspase 3 is regulated by complex formation with p21 or ILP. In the present study, we investigated the binding domain with p21 and ILP to further characterize the caspase 3 inactivation machinery. Our results show that caspase 3 contains p21 binding domain in the N-terminus and ILP binding domain in the active site. Further, the caspase 3 binding domain in p21 was independent of the Cdk- or PCNA-binding domain. We also found caspase 3 protection by p21 from the p3-site cleavage serineproteinase contributes to the suppression machinery. Here, we propose the caspase 3 inactivation system by p21 and ILP as new essential system in the regulation of cell death.
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PMID:Caspase 3 inactivation to suppress Fas-mediated apoptosis: identification of binding domain with p21 and ILP and inactivation machinery by p21. 1002 30

The effects of dysregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 on the apoptotic response of U937 monocytic leukemia cells to 1-beta-D-arabinofuranosylcytosine (ara-C) were examined. After a 6-h exposure to 1 microM ara-C, cells stably transfected with a p21WAF1/CIP1 antisense construct were significantly more sensitive to the induction of classic apoptotic morphology, DNA fragmentation, caspase-3 activation, poly(ADP-ribose) polymerase degradation, and underphosphorylation of the retinoblastoma protein (pRb) than their empty-vector counterparts. Enhanced susceptibility of antisense-expressing cells to ara-C was accompanied by a corresponding reduction in clonogenic and suspension culture growth. The increased sensitivity of these cells to ara-C-mediated lethality could not be attributed to cytokinetic perturbations, nor did ara-CTP formation or (ara-C)DNA incorporation differ significantly between the cell lines. Moreover, synchronization of p21 antisense-expressing cells in S-phase by aphidicolin block resulted in a further increase in ara-C-mediated apoptosis, suggesting enhanced drug sensitivity of the S-phase cell fraction. After exposure to ara-C, p21 antisense-expressing cells displayed a greater decline in mitochondrial membrane potential (deltapsi(m)) and generation of reactive oxygen species than their empty-vector counterparts, as well as early potentiation (e.g., within 2-4 h) of cytochrome c release into the cytosolic S-100 fraction. Lastly, ara-C-mediated increases in mitogen-activated protein kinase activity over basal levels were attenuated in p21 antisense-expressing cells. Collectively, these findings indicate that dysregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 increases the susceptibility of U937 human leukemia cells to ara-C-related lethality, and this phenomenon occurs as a relatively early event that is independent of cell cycle or pharmacodynamic factors and is associated with mitochondrial perturbations implicated in activation of the apoptotic protease cascade.
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PMID:Dysregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1/MDA6 increases the susceptibility of human leukemia cells (U937) to 1-beta-D-arabinofuranosylcytosine-mediated mitochondrial dysfunction and apoptosis. 1009 57

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.
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PMID:The mechanisms of death of an erythroleukemic cell line by p53: involvement of the microtubule and mitochondria. 1019 36

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been shown to induce apoptosis in various tumor cell lines including human non-small cell lung carcinoma (NSCLC) cells, which are resistant to the natural all-trans retinoic acid and to many synthetic receptor-selective retinoids. Although the mechanism of this effect was not elucidated, it was found to be independent of nuclear retinoid receptors. In the present study, we analysed the mechanisms by which CD437 induces apoptosis in two human NSCLC cell lines: H460 with wild-type p53 and H1792 with mutant p53. Both cell lines underwent apoptosis after exposure to CD437, although the cell line with wild-type p53 (H460) was more sensitive to the induction of apoptosis. CD437 increased the activity of caspase in both cell lines, however, the effect was much more pronounced in the H460 cells. The caspase inhibitors (Z-DEVD-FMK and Z-VAD-FMK) suppressed CD437-induced CPP32-like caspase activation and apoptosis in both cell lines. CD437 induced the expression of the p53 gene and its target genes, p21, Bax, and Killer/DR5, only in the H460 cells. These results suggest that CD437-induced apoptosis is more extensive in NSCLC cells that express wild-type p53, possibly due to the involvement of the p53 regulated genes Killer/DR5, and Bax although CD437 can also induce apoptosis by means of a p53-independent mechanism. Both pathways of CD437-induced apoptosis appear to involve activation of CPP32-like caspase.
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PMID:Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells. 1032 56


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