UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Fas (APO-1/CD95) is a cell-surface protein that can mediate apoptosis upon specific ligand or antibody binding. The Bcl-2 protein may function as a modulator of Fas-induced apoptosis by blocking a downstream activation step, and Bcl-2 expression in acute lymphoblastic leukemia (ALL) cells appears to depend partly on expression of a wild-type (wt) p53 tumor suppressor gene (Findley et al, Blood 1997; 89: 2986). We therefore investigated the relationship between sensitivity to Fas-mediated apoptosis and (1) Fas expression, (2) p53 status, and (3) Bcl-2 protein levels in pediatric ALL cell lines and primary leukemic cells. Cell lines included 21 B cell precursor (BCP)-ALL and four T-ALL lines; in five cases, cryopreserved primary leukemic cells from which these lines were established were also examined. Additionally, we evaluated the effect of anti-Fas monoclonal antibody on the activation of protease CPP32 and induction of apoptosis in these lines. By SSCP analysis and DNA sequencing, we detected p53 mutations (mt) in eight out of 25 ALL cell lines (exon-7, codon 248 n=6; exon-8, codon 273, n=2). The expression of Fas and Bcl-2 was examined by immunofluorescence staining and quantified as the number of molecules of equivalent soluble fluorochrome (MESF). Elevated levels of Fas were expressed in all six lines with a mutation of p53 in codon 248 (1500 to 10800 MESF). Although Fas was detectable in seven of the 17 lines with wt-p53, expression was lower (150-900 MESF) compared with mt-p53+ lines. Bcl-2 was expressed in 10 of the 25 lines. Most (9/10) wt-p53+ lines expressed Bcl-2, whereas only one of eight mt-p53+ lines and no p53-null lines expressed this protein. Treatment of Fas-positive lines with anti-Fas monoclonal antibody (200 ng/ml) for 6 h induced activation of CPP32 and apoptosis in eight of 13 Fas+ lines. Sensitivity to Fas-mediated apoptosis was associated with a mt-p53 phenotype and absence of Bcl-2 expression. Six of eight Fas+/Fas-sensitive (S) lines were mt-53+/Bcl-2-, whereas only two Fas+/Fas-S lines were wt-p53+/Bcl-2+; both of these latter lines expressed low levels of Bcl-2 compared to Fas-resistant lines. In contrast, four of five Fas+/Fas-resistant (R) lines were wt-p53+/Bcl-2+; the exception was p53-null/Bcl-2- but expressed a low level of Fas (150 MESF). Activation of the cysteine protease CPP32 and cleavage of its substrate poly(ADP-ribose)polymerase (PARP) was also detected in Fas-S but not Fas-R lines. We obtained similar results from both the primary leukemic cells and the corresponding cell lines in five cases: overexpression of Fas and Fas-sensitivity were present in mt-p53+/Bcl-2- but not wt-p53+/Bcl-2+ cells. These results suggest that some pediatric ALL cells expressing mt-p53+ may be sensitive to Fas-mediated apoptosis due to high levels of Fas expression and lack of Bcl-2, and further suggest that molecular methods of activating Fas may be useful for therapy of refractory ALL with the Fas+/mt-p53+ phenotype.
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PMID:Sensitivity to Fas-mediated apoptosis in pediatric acute lymphoblastic leukemia is associated with a mutant p53 phenotype and absence of Bcl-2 expression. 982 51

Several malignant cell lines are resistant to CD95-(Apo1/Fas)-mediated apoptosis, even when the CD95 receptor is highly expressed. Sensitivity to CD95-induced apoptosis can be restored using different molecules. In this study, we showed that quercetin, a naturally occurring flavonoid, in association with the agonistic anti-CD95 monoclonal antibody, increases DNA fragmentation and caspase-3 activity in HPB-ALL cells. These cells have been selected for their known resistance to CD95-induced apoptosis. At molecular level, quercetin lowers the level of intracellular reactive oxygen species, reduces mitochondrial transmembrane potential, thereby leaving the expression of CD95 receptor unchanged.
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PMID:Quercetin and anti-CD95(Fas/Apo1) enhance apoptosis in HPB-ALL cell line. 1062 19

Children with acute lymphoblastic leukemia (ALL) who are treated with chemotherapy have remissions in more than 95% of the cases. However, 25% of the patients relapse and show resistance to chemotherapy. In this investigation we compared 25 newly diagnosed and 25 relapsed cases of ALL with respect to proliferation and apoptosis. Using immunocytochemistry and Western blotting, we determined the expression of cyclin A protein as a measure of the proliferative activity and the pro-apoptotic and anti-apoptotic factors, Fas, Fas ligand, caspase-3 and Bcl-2. Cyclin A expression was observed in 32% of the newly diagnosed cases and in 52% of the relapsed cases. Expression of Fas was found in 58% of the newly diagnosed and in only 27% of the relapsed samples. Of the newly diagnosed ALL, 88% expressed the Fas ligand while such expression was observed in 54% of the relapsed ALL. Sixty-four percent of the newly diagnosed cases expressed caspase-3 while only 48% of the relapsed samples did so. The anti-apoptotic factor, Bcl-2, was more frequently expressed in relapsed than in newly diagnosed cases. These data indicate that relapsed ALL more frequently exhibits high proliferative activity and reduced apoptosis than does newly diagnosed ALL.
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PMID:Proliferation and apoptosis in newly diagnosed and relapsed childhood acute lymphoblastic leukemia. 1062 95

Dysregulation of apoptosis is an important mechanism in leukemogenesis. Caspases are cysteine proteases that play a major role in the activation of apoptotic pathways and chemotherapy-induced cell death. High levels of inactive, uncleaved caspase 2 and caspase 3 have recently been associated with poor survival in patients with acute myelogenous leukemia. We hypothesized a similarly significant role for caspase 2 and caspase 3 in patients with acute lymphoblastic leukemia. We determined levels of uncleaved caspase 2 and caspase 3 by quantitative Western blot analysis in peripheral blood samples of 45 adults with newly diagnosed ALL. We evaluated patient prognostic variables and caspase levels using multivariate logistic and Cox regression models to determine their impact on complete remission rate and overall survival probability. Levels of caspase 2 and, to a lesser degree, caspase 3 were highly associated with cytogenetic abnormalities, with lower levels in the diploid group (P = 0.016 and P = 0.10, respectively). No association between either caspase level and the percentage of bone marrow blasts was found. A high level of caspase 3 (>0.37 as determined graphically) was significantly associated with achieving complete remission (CR; P = 0.006). A multivariate logistic regression analysis including age, WBC count, percentage of peripheral and marrow blasts, hemoglobin, albumin, lactate dehydrogenase, bilirubin, and creatinine determined that a high level of caspase 3 was the most significant predictor of CR (P = 0.025, adjusted), with albumin the only other significant variable (P = 0.031). Caspase 2 levels were not associated with probability of CR. In a multivariate Cox model for survival, however, levels of caspase 2 above 0.37 were associated with a lower survival probability than were levels below that threshold (P = 0.064). High levels of caspase 3 may have a significant effect on achieving CR. Because of the limited power (n = 45) of our study, the significance of caspase 2 and caspase 3 on overall survival remains to be validated by further investigations.
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PMID:Caspase 2 and caspase 3 as predictors of complete remission and survival in adults with acute lymphoblastic leukemia. 1063 37

Dysfunction of the p53/Bax/caspase-3 apoptosis signaling pathway has been shown to play a role in tumorigenesis and tumor progression, ie the development of acquired drug resistance. Low expression of the apoptosis inducer Bax correlates with poor response to therapy and shorter overall survival in solid tumors. In the present study, we analyzed the p53/Bax/caspase-3 pathway in a paired and an unpaired sample series of children with acute lymphoblastic leukemia (ALL) at initial diagnosis and relapse. The data demonstrate that both Bax expression levels and the Bax/Bcl-2 ratio are significantly lower in samples at relapse as compared with samples at initial diagnosis (P=0.013, Wilcoxon signed rank test (paired samples); P=0.0039, Mann-Whitney U test (unpaired samples)). The loss of Bax protein expression was not a consequence of Bax frameshift mutations of the G8 tract and could not be attributed to mutations of the p53 coding sequence (exons 5 to 8) which were detected to a similar extent in de novo ALL samples and at relapse. Analysis of the downstream effector caspase-3 showed loss of spontaneous caspase-3 processing at relapse. Whereas nine out of 14 (64%, paired samples) or 37 out of 77 (48%, unpaired samples) ALL patients at initial diagnosis displayed spontaneous in vivo processing of caspase-3, this was completely absent in patients at relapse (paired samples) or detected in only one out of 34 patients at relapse (2.9%, unpaired samples). We therefore conclude that in ALL relapse a severe disturbance of apoptotic pathways occurs, both at the level of Bax expression and caspase-3 activation.
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PMID:Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo. 1099 7

Disruptions of pathways of programmed cell death, or apoptosis, are increasingly found in malignant cells of both solid and hematologic neoplasms. Caspases belong to a family of cysteine proteases and have emerged as central regulators of the apoptotic cascade. Despite many and diverse signals that can trigger apoptosis, the execution of apoptosis appears to be uniformly mediated through activation of caspase enzymes. Inapproriate expression of caspases or malfunctions in their regulation through other pathways may also be an important step in the pathogenesis of acute leukemias. Recent studies have shown that overexpression of the inactive forms of caspases CPP32 (caspase 3) and ICH-1 (caspase 2) is frequently observed in the blasts of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Many other enzymes involved in apoptosis are expressed at high levels in patients with acute leukemia. Whether this signals the capacity of leukemic cells to rapid induction of apoptosis with fast reduction of the burden of disease and favorable clinical outcome, or accumulation of inactive substrates that cannot be activated by lack of cellular mechanisms to do so, requires further investigation. With the identification of many other regulators of apoptotic activity in the leukemic cells, new targets for future therapy may be identified and many new insights can be gained in understanding the biological behavior of response and resistance to therapy as well as control and relapse from minimal residual disease.
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PMID:The clinical significance of caspase regulation in acute leukemia. 1142 20

We recently reported that butyrate, an inhibitor of histone deacetylases, is capable of inducing Fas-independent apoptosis in the acute lymphoblastic leukemia cell line CCRF-CEM. Here we demonstrate that butyrate enhances Fas-induced apoptosis in this cell line. The application of different histone deacetylase inhibitors revealed that tetra-acetylated histone H4 is associated with the amplifying effect of butyrate on Fas-induced cell death. FasL, Fas, FADD, RIP, caspase-8, caspase-3, Bid, FLIP(S+L), FLASH and FAP-1, proteins known to act within the Fas-apoptosis cascade, showed no changes in their expression levels in cells treated with butyrate compared with untreated cells. Analyses of Fas-oligomerization and Western blotting as well as enzyme activity assays of caspase-2, caspase-3 and caspase-8 suggest that butyrate enhances Fas-induced apoptosis downstream of Fas but upstream of caspase-8 activation. In immunoprecipitation experiments a 37 kD butyrate-regulated protein was detected which specifically interacts with caspase-8.
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PMID:Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts. 1159 99

The stilbene phytochemicals resveratrol and piceatannol have been reported to possess substantial antitumorigenic and antileukemic activities, respectively. Although recent experimental data revealed the proapoptotic potency of resveratrol, the molecular mechanisms underlying the antileukemic activity have not yet been studied in detail. In the present study, we show that resveratrol, as well as the hydroxylated analog piceatannol, are potent inducers of apoptotic cell death in BJAB Burkitt-like lymphoma cells with an ED50 concentration of 25 microM. Further experiments revealed that treatment of BJAB cells with both substances led to a concentration-dependent activation of caspase-3 and mitochondrial permeability transition. Using BJAB cells overexpressing a dominant-negative mutant of the Fas-associated death domain (FADD) adaptor protein to block death receptor-mediated apoptosis, we demonstrate that resveratrol- and piceatannol-induced cell death in these cells is independent of the CD95/Fas signaling pathway. To explore the antileukemic properties of both compounds in more detail, we extended our study to primary, leukemic lymphoblasts. Interestingly, piceatannol but not resveratrol is a very efficient inducer of apoptosis in this ex vivo assay with leukemic lymphoblasts of 21 patients suffering from childhood lymphoblastic leukemia (ALL).
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PMID:Piceatannol, a hydroxylated analog of the chemopreventive agent resveratrol, is a potent inducer of apoptosis in the lymphoma cell line BJAB and in primary, leukemic lymphoblasts. 1168 15

The concept that cells subjected to chromatin cleavage during apoptosis are destined to die is being challenged. The execution phase of apoptosis is characterized by the activation of effector caspases, such as caspase-3, that cleave key regulatory or structural proteins and in particular activate apoptotic nucleases such as the caspase activated deoxyribonuclease (CAD). It is apparent that caspases of this type may become active both through non-apoptotic processing and potentially within cells that exhibit apoptotic morphology but are subsequently able to survive. In such systems caspase suppressor molecules, the inhibitors of apoptotic proteins or IAP's, may rescue cells from apoptotic nuclease(s) attack initiated by transient caspase activation. The MLL gene is involved in leukemogenic translocations in ALL and AML and is a target of nuclease cleavage during apoptosis. Translocations initiated at the site of apoptotic nuclease attack within MLL have been identified and may offer a model, with clinical relevance, for DNA damage mediated by the apoptosis system in cells destined to survive. The specificity of apoptotic cleavage combined with the potential for recovery from the execution phase of apoptosis suggests a novel and pathogenic role for apoptosis in creating translocations with leukemogenic potential.
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PMID:Surviving apoptosis. 1186 2

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