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:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a binary co-transfection strategy of Ad/GT Bax and Ad/PGK-GV16, we have succeeded in inducing overexpression of Bax protein in three prostate cell lines (androgen-insensitive DU145 and PC3, and androgen-sensitive LNCaP). The expression of Bax protein by this system was sufficient to induce all three prostate lines to undergo apoptosis. The fact that DU145 cells which have a p53 mutation and are deficient in Bax, responded to this treatment, suggests that this effect is independent of these pathways. Initiation of the cleavage of Caspase-3 (CPP32/Yama/apopain) and PARP (poly (ADP-ribose) polymerase) by the introduction of Bax were confirmed by western blot analysis. Bcl-2 expression is relevant in the progression of prostate cancer and contributes to an androgen, apoptotic-resistant phenotype in the advanced stages. We examined stable Bcl-2 overexpressing DU145, PC3 and LNCaP cell lines as models of advanced prostate cancer. The adenoviral co-transfection system induced Bax protein expression and apoptosis even in these Bcl-2 transfected cell lines. Taken together, our results suggest that this Bax expression system might represent a useful gene therapy strategy when applied to the treatment of prostate cancer and its efficacy would be independent of the Bcl-2 status and androgen sensitivity of these cancers.
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PMID:A recombinant adenovirus expressing wild-type Bax induces apoptosis in prostate cancer cells independently of their Bcl-2 status and androgen sensitivity. 1217 Jul 76

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is an active constituent of Rheum palmatum, and showed inhibitory activity on lipopolysaccharide-induced NO production in our previous study. However, the apoptosis-inducing activity of emodin has remained undefined. Among three structurally related anthraquinones, including emodin, physcion, and chrysophanol, emodin showed the most potent cytotoxic effects on HL-60 cells, accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including an increase in DNA ladder intensity, morphological changes, appearance of apoptotic bodies, and an increase in hypodiploid cells. Emodin at apoptosis-inducing concentrations causes rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity, according to cleavage of caspase 3 substrates poly(ADP-ribose) polymerase and D4-GDI proteins, the appearance of cleaved caspase 3 fragments being detected in emodin- but not physcion- or chrysophanol-treated HL-60 cells. A decrease in the anti-apoptotic protein, Mcl-1, was detected in emodin-treated HL-60 cells, whereas other Bcl-2 family proteins including Bax, Bcl-2, Bcl-XL, and Bad remained unchanged. The caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor, Ac-YVAD-CHO, attenuated emodin-induced DNA ladders, associated with the blockage of PARP and D4-GDI cleavage. Free radical scavenging agents including NAC, catalase, SOD, ALL, DPI, L-NAME and PDTC showed no preventive effect on emodin-induced apoptotic responses, whereas NAC, CAT and PDTC prevented HL-60 cells from ROS (H(2)O(2))-induced apoptosis through inhibition of caspase 3 cascades. Induction of catalase, but not SOD, activity was detected in emodin-treated HL-60 cells by in gel activity assays, and H(2)O(2)-induced intracellular peroxide level was significantly reduced by prior treatment of emodin in HL-60 cells. Our experiments provide evidence that emodin is an effective apoptosis inducer in HL-60 cells through activation of the caspase 3 cascade, but that it is independent of ROS production.
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PMID:Emodin induces apoptosis in human promyeloleukemic HL-60 cells accompanied by activation of caspase 3 cascade but independent of reactive oxygen species production. 1244 60

Flavonoids were demonstrated to possess several biological effects including antitumor, antioxidant, and anti-inflammatory activities in our previous studies. However, the effect of glycosylation on their biological functions is still undefined. In the present study, the apoptosis-inducing activities of three structure-related flavonoids including aglycone quercetin (QUE), and glycone rutin (RUT; QUE-3-O-rutinoside), and glycone quercitrin (QUI; QUE-3-O-rhamnoside) were studied. Both RUT and QUI are QUE glycosides, and possess rutinose and rhamnose at the C3 position of QUE, respectively. Results of the MTT assay showed that QUE, but not RUT and QUI, exhibits significant cytotoxic effect on HL-60 cells, accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including an increase in DNA ladder intensity, morphological changes, apoptotic bodies, and an increase in hypodiploid cells by flow cytometry analysis. QUE, but not RUT or QUI, caused rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity, according to cleavage of caspase 3 substrates poly(ADP-ribose) polymerase (PARP) and D4-GDI proteins, and the appearance of cleaved caspase 3 fragments being detected in QUE- but not RUT- or QUI-treated HL-60 cells. A decrease in the anti-apoptotic protein, Mcl-1, was detected in QUE-treated HL-60 cells, whereas other Bcl-2 family proteins including Bax, Bcl-2, Bcl-XL, and Bag remained unchanged. The caspase 3 inhibitor, Ac-DEVD-FMK, but not the caspase 1 inhibitor, Ac-YVAD-FMK, attenuated QUE-induced cell death. Results of DCHF-DA assay indicate that no significant increase in intracellular peroxide level was found in QUE-treated cells, and QUE inhibited the H(2)O(2)-induced intracellular peroxide level. Free radical scavengers N-acetyl-cysteine (NAC) and catalase showed no prevention of QUE-induced apoptosis. In addition, QUE did not induce apoptosis in an mature monocytic cell line THP-1, as characterized by a lack of DNA ladders, caspase 3 activation, PARP cleavage, and an Mcl-1 decrease, compared with those in HL-60 cells. Our experiments provide evidence to indicate that the addition of rutinose or rhamnose attenuates the apoptosis-inducing activity of QUE, and that the caspase 3 cascade but not free radical production is involved.
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PMID:Differential apoptosis-inducing effect of quercetin and its glycosides in human promyeloleukemic HL-60 cells by alternative activation of the caspase 3 cascade. 1287 37

Arsenite (NaAsO(2)) has been shown to produce vascular dysfunction in many studies. Arsenite-induced damage to vascular endothelial cells represents one of the possible mechanisms causing leakage of the vascular endothelial barrier. To explore arsenite-induced vascular endothelial damage, we used primary porcine aortic endothelial cells (PAECs) as an in vitro system to test the effects of arsenite on signal transduction pathways and apoptosis. Here we demonstrated that arsenite exposure induced apoptosis accompanied by the occurrence of apoptotic signals including degradation of poly(ADP-ribose) polymerase (PARP) and CPP32 (cleavage/activation) and DNA ladder formation. By using the luciferase reporter assay, we demonstrated that arsenite exposure differentially activated two redox-sensitive transcription factors, NF-kappaB and AP-1. Lower levels of arsenite exposure (25 microM NaAsO(2), 24 h) induced co-activation of NF-kappaB and AP-1, accompanied by 9% total apoptosis. In contrast, higher levels of arsenite exposure (40 microM NaAsO(2), 24 h) induced higher levels of AP-1 activation, accompanied by 45% total apoptosis. Blockade of NF-kappaB or JNK activity further enhanced arsenite-induced apoptosis. Upregulation of JNK activity showed no effect on arsenite-induced apoptosis. Based on these data, we propose that activation of redox-sensitive transcription factors, NF-kappaB and AP-1, plays a very important role in the protection of PAECs from arsenite-induced apoptosis.
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PMID:The protective role of NF-kappaB and AP-1 in arsenite-induced apoptosis in aortic endothelial cells. 1294 53

N-Tosyl-L-phenylalanyl chloromethyl ketone (TPCK), a chymotrypsin-like serine protease inhibitor, affected apoptosis in human monocytic THP.1 cells differently dependent on both the concentration used and the apoptotic stimulus. TPCK (50 - 75 microM) induced both biochemical and ultrastructural changes characteristic of apoptosis, including proteolysis of poly (ADP-ribose) polymerase (PARP) and lamins together with formation of large kilobase pair fragments of DNA, particularly of 30 - 50 and 200 - 300 kilobase pairs in length but without internucleosomal cleavage of DNA. The induction of apoptosis by TPCK also involved the processing of CPP32 and Mch 3 to their catalytically active subunits. Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.FMK), an ICE-like protease inhibitor, completely prevented all the biochemical and morphological changes induced by TPCK demonstrating the involvement of ICE-like proteases in the execution phase of apoptosis. Lower concentrations of TPCK (5 - 20 microM) prevented internucleosomal cleavage of DNA induced by other apoptotic stimuli. TPCK (10 microM) inhibited cell death induced by etoposide but potentiated that induced by cycloheximide demonstrating that it differentially affected apoptosis in THP.1 cells dependent on the stimulus used. These results are consistent with at least three distinct TPCK targets, one being important for cell survival, the second in facilitating internucleosomal cleavage of DNA and the third in the modulation of apoptosis induced by different apoptotic stimuli.
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PMID:Apoptosis in human monocytic THP.1 cells involves several distinct targets of N-tosyl-L-phenylalanyl chloromethyl ketone (TPCK). 1455 72

Caspases have been shown to play a crucial role in apoptosis induced by various deleterious and physiologic stimuli. In this study, we show for the first time that photodynamic therapy (PDT), using benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) as the photosensitizer, induces the complete cleavage and subsequent activation of caspase-3 (CPP32/Yama/Apopain) but not caspase-1 (ICE) in human promyelocytic leukemia HL-60 cells. Poly(ADP-ribose) polymerase (PARP) and the catalytic subunit of DNA dependent protein kinase (DNA PK(CS)) were cleaved within 60 min of light activation of BPD-MA. The general caspase inhibitor Z-Asp-2,6 dichlorobenzoyloxymethylketone (Z-Asp-DCB) blocked PARP cleavage while the serine protease inhibitors 3,4-dichloroisocoumarin (DCI) and N-tosyl-lysyl chloromethyl ketone (TLCK) blocked the cleavage of caspase-3 suggesting that they act upstream of caspase-3 activation. All three inhibitors were able to block DNA fragmentation that was induced by treatment with BPD-MA followed by light application. These studies demonstrate that protease activity, particularly that of caspase-3, is triggered in HL-60 cells treated with lethal levels of BPD-MA and visible light.
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PMID:Photodynamic therapy induces caspase-3 activation in HL-60 cells. 1455 76

We explored whether hypoxic preconditioning minimizes oxidative injury induced by overdistension/emptying in the rat bladder. For hypoxic preconditioning, female Wistar rats were placed in a hypobaric chamber (380 Torr) 15 h day(-1) for 28 days. Overdistension was induced by infusion of two times the threshold volume of saline into the bladder and was maintained for 1 or 2 h, followed by drainage/emptying. During overdistension (ischaemia) and emptying (reperfusion) periods, a bursting increase of reactive oxygen species (ROS) from the bladder was originated from the large numbers of infiltrating leucocytes and scattered resident cells, including urothelial, submucosal, and smooth muscle cells. ROS impaired the voiding function by a reduction of bladder afferent and efferent nerve activity and bethanecol- or ATP-induced detrusor contraction. ROS enhanced pro-apoptotic mechanisms, including increases in the Bax/Bcl-2 ratio, CPP32 expression, and poly(ADP-ribose) polymerase (PARP) fragments with subsequent apoptotic cell formation in the insulted bladders. Hypoxia preconditioning up-regulated Bcl-2 expression in the bladder and significantly reduced the levels of ROS and apoptosis detected in the overdistension/emptying bladders and preserved partial voiding function. Bcl-2 up-regulation by hypoxia preconditioning contributes protection against overdistension/emptying-induced oxidative stress and injury in the bladder.
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PMID:Hypoxia preconditioning attenuates bladder overdistension-induced oxidative injury by up-regulation of Bcl-2 in the rat. 1460 4

Treatment of HL60 and Jurkat leukaemic cell lines, both not expressing p53, with the new non-covalent DNA minor groove binder alpha-bromoacryloyl-distamycin (PNU 151807), induces apoptosis as shown either morphologically or by DNA laddering formation. We evaluated the p53-independent mechanisms of activation of apoptosis in these cell systems, by determining the levels of different caspases at different times after treatment with PNU 151807. Through Western blotting analysis we could measure the cleavage of the 110 Kd form of PARP in both HL60 and Jurkat cells and correspondingly the activation of CPP32-caspase 3. The levels of caspase-1 did not change at any time after drug treatment. By using the tetrapeptidic sequence recognized by caspase-3 (DEVD-AMC) or by caspase-1 (YVAD-AMC) linked to fluorogenic substrate, we also demonstrated that only the DEVD sequence was recognized and cleaved after drug treatment, while no significant changes were found for YVAD peptides. PNU 151807-induced DNA fragmentation and DEVD-cleavage were both inhibited by concomitant treatment with the specific inhibitor DEVD-CHO, but not by YVAD-CHO, clearly demonstrating the direct activation of caspase-3-like caspases in the induction of programmed cell death in these cell lines after minor groove binder exposure.
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PMID:P53-independent caspase-mediated apoptosis in human leukaemic cells is induced by a DNA minor groove binder with antineoplastic activity. 1463 94

CTLL cells undergo apoptosis when cultured in the absence of IL-2. The IL-1beta-converting-enzyme (ICE)/ caspase family has been implicated as an integral component of some forms of apoptosis. Numerous members of the caspase family have been identified, and it appears as if caspase-3/CPP32 plays a critical role. Previously we demonstrated that ICE/caspase-1 expression increases in CTLL cells during apoptosis; however, inhibition of ICE activity did not abrogate apoptotic death. The purpose of this report is to determine if other members of the caspase family are involved in T cell apoptosis induced by growth factor starvation. We show that cytosolic CPP32-like activity, as measured by the cleavage of DEVD-pNA and poly(ADP-ribose) polymerase (PARP), increases during apoptosis following growth factor deprivation. Cytosolic CPP32-like activity is inhibited in cells treated with the broad spectrum ICE family inhibitor boc-aspartyl(OMe)-fluoromethylketone (D-FMK) and by VAD-FMK and DEVD-FMK which have greater specificity for CPP32-like ICE homologs; however, only the broad spectrum ICE inhibitor D-FMK inhibited apoptosis. Our results suggest that apoptosis induced by growth factor deprivation involves the caspase family, but increased CPP32-like activity is not sufficient to mediate apoptosis induced by IL-2 starvation.
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PMID:Caspase-3/CPP32-like activity is not sufficient to mediate apoptosis in an IL-2 dependent T cell line. 1464 42

The von Hippel-Lindau (VHL) is a known tumor suppressor that binds to alpha-subunits of hypoxia-inducible factors and induces ubiquitin-mediated degradation of the protein in an oxygen-dependent manner. VHL is also involved in the regulation of tumor angiogenesis, glycolysis, cell cycle regulation, and apoptosis. In the present study, we showed that ectopic expression of VHL induces apoptosis in renal cell carcinoma 786-O cells which contain only the mutant VHL, evidenced by TUNEL assay and DAPI staining. Furthermore, biochemical studies indicated that expression of VHL in 786-O cells results in both PARP and CPP32 cleavage, suggesting that VHL-induced apoptosis in 786-O cells is caspase dependent. Moreover, we also observed that apoptosis induced by ectopic VHL expression was associated with up-regulation of p27 as well as Bax, implicating the roles of these two proteins in VHL-induced apoptosis. The up-regulation of p27 and Bax by VHL was specific since we did not detect any changes in the level of other apoptotic factors including Fas and Bcl2 by the expression of VHL. We next examined the effect of VHL expression on the tumor growth of 786-O renal cell carcinoma cells in nude mouse. The results showed that injection of Ad.VHL adenovirus regresses the tumor growth of 786-O cells in nude mouse. The analysis by TUNEL assay as well as DAPI staining of 786-O tumors injected with Ad.VHL showed clear evidence of apoptosis. These results suggest that ectopic VHL expression induces apoptotic response in 786-O VHL mutant cells both in vitro and in vivo.
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PMID:Ectopic expression of von Hippel-Lindau tumor suppressor induces apoptosis in 786-O renal cell carcinoma cells and regresses tumor growth of 786-O cells in nude mouse. 1524 Jan 40


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