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)

Cell death in B cell terminal differentiation rapidly follows cell cycle arrest in IL-6 differentiation of EBV-immortalized, IgG-bearing human lymphoblastoid cells in vitro. G1 arrest is now found to coincide with repression of EBNA2 and LMP1, two EBV genes essential for B cell transformation, without activation of the viral lytic cycle. IL-6-differentiated B cells die by apoptosis, as evidenced by increases in Annexin V binding activity, PARP cleavage, and chromatin disorganization. Expression of Mcl-1, a Bcl-2 family member, was specifically induced during IL-6 differentiation and down-regulated during apoptosis. Thus, IL-6 reverses EBV immortalization and activates the terminal differentiation program in IgG-bearing human B lymphoblastoid cells, including regulation of an anti-apoptotic gene to coordinate differentiation, cell cycle arrest, and cell death.
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PMID:Reversal of EBV immortalization precedes apoptosis in IL-6-induced human B cell terminal differentiation. 939 Jun 90

Signal transduction pathways involving the c-Raf protein kinase are frequently activated in tumor cells. We have addressed the relevance of this activation by a loss-of-function approach. An anti-sense phosphorothioate oligonucleotide (ODN) specifically targeted against c-raf mRNA (Monia et al., 1996a) was used to block c-Raf protein expression in four different cell lines derived from lung, cervical, prostate and colon carcinomas. Concomitant with the abrogation of c-Raf expression we observed the occurrence of classical apoptotic markers, including chromatin condensation, inter-nucleosomal DNA cleavage, annexin V binding and cleavage of PARP, which was followed by cell death, affecting most of the cell population. This induction of apoptosis occurred independent of the p53 status of the cell. These findings demonstrate that c-Raf can protect tumor cells from undergoing programmed cell death, and suggest that the interference with c-Raf expression or function by ODNs or specific drugs could represent a powerful means for improving the efficacy of anti-cancer therapy.
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PMID:Abrogation of c-Raf expression induces apoptosis in tumor cells. 958 88

The anti-tumor drug Flavopiridol is a potent inhibitor of cyclin-dependent kinases (cdks). As a consequence, Flavopiridol-treated cells arrest in both G1 and G2, but Flavopiridol has also been shown to be cytotoxic for some tumor cell lines. The underlying molecular events are, however, unclear. We now show that Flavopiridol induces apoptosis in human umbilical vein endothelial cells (HUVECs), as judged by the occurrence of classical apoptotic markers, including chromatin condensation, internucleosomal cleavage, DNA fragmentation (TUNEL assay), annexin V binding and poly(ADP-ribose) polymerase (PARP)-cleavage. Such induction of apoptosis occurs with equal efficiency in both proliferating and G0/G1-arrested cells. Because growth-arrested HUVECs lack cdk2 activity and contain high levels of the cdk inhibitor p27, our observations suggest that cell cycle regulated cdks may not be the only critical target for Flavopiridol-induced apoptosis. Surprisingly, A549 lung carcinoma cells were clearly dependent on cell proliferation for the induction of cell death, pointing to cell type-related differences in the mechanism of Flavopiridol action.
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PMID:Cell cycle-independent induction of apoptosis by the anti-tumor drug Flavopiridol in endothelial cells. 963 6

C2-ceramide, a cell-permeable analogue of ceramide, induced significant, dose- and time-dependent death in human retinoblastoma Y79 cells. Dying cells strongly displayed the morphology of apoptosis as characterized by microscopic evidence of cell shrinkage, membrane blebbing, nuclear and chromatin condensation and degeneration of the nucleus into membrane-bound apoptotic bodies. Upon induction of apoptosis Y79 cells evidence early phosphatidylserine externalization, as shown by annexin V-FITC. Apoptosis was also assessed by monitoring changes in cell granularity by staining with the combined fluorescent dyes acridine orange and ethidium bromide. C2-ceramide induced these morphological changes without a concomitant production of oligonucleosomal fragments responsible for the DNA ladder and without changes in p53 protein level. Apoptosis was accompanied by accumulation of a modified Bcl-2 protein with a slower-mobility form, and by proteolytic cleavage of PARP. The effect seemed to be specific for C2-ceramide, as C2-dihydroceramide, or other amphiphilic lipid analogues, or products of ceramide hydrolysis were ineffective. The effect also depended on mRNA and protein synthesis as it was markedly inhibited by actinomycin D and cycloheximide. Sphingomyelinase and interleukin-1beta, which are known to activate the sphingomyelin turnover leading to ceramide generation, also induced apoptosis mimicking the effects of ceramide. These findings propose ceramide as an activator of the suicidal program in Y79 cells.
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PMID:Induction of programmed cell death in human retinoblastoma Y79 cells by C2-ceramide. 974 6

We here report an alternatively spliced form of PARP lacking exon 5 of the Drosophila PARP gene encoding the auto-modification domain. The alternative form of PARP (PARP II) consists 804 amino acids with a molecular weight of 92.3 kDa. The deduced amino acid sequence of PARP II was completely matched to that of PARP I encoded by a full-length Drosophila PARP cDNA, except it lacks the region corresponding to the auto-modification domain. To examine the function of PARP II, stable transformants of Rat-1 cells in which PARP II was ectopically expressed by MMTV-LTR were isolated and characterized. After induction with dexamethasone, PARP II transformants showed slower growth and showed morphological changes with loss of spindled shape compared to cells transformed with the vector or PARP I. The PARP II-transformed cells incorporated propidium iodide after induction; however, Annexin V and TUNEL analysis indicated these changes were not due to apoptosis.
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PMID:An alternative form of poly(ADP-ribose) polymerase in Drosophila melanogaster and its ectopic expression in rat-1 cells. 979 Sep 3

The aim of this study was to determine the mechanism of cell death associated with the preferential killing of multidrug-resistant (MDR) cells by the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in a range of MDR human KB carcinoma cell lines selected in different drugs. The D10 values for KB-V1, KB-C1 and KB-A1 (selected in vinblastine, colchicine and doxorubicin respectively) were 1.74, 1.04 and 0.31 mM, respectively, compared with 4.60 mM for the parental cell line (KB-3-1). The mechanism of cell death was identified as apoptosis, based on nuclear morphology, annexin V binding and poly(ADP-ribose) polymerase (PARP) cleavage. 2DG induced apoptosis in the three MDR cell lines in a dose- and time-dependent manner and did not induce necrosis. PARP cleavage was detected in KB-C1 cells within 2 h of exposure to 50 mM 2DG and slightly later in KB-A1 and KB-V1 cells. The relative levels of 2DG sensitivity did not correlate with the levels of multidrug resistance or with the reduced levels of the glucose transporter GLUT-1 in these cells. We speculate that a 2DG-stimulated apoptotic pathway in MDR KB cells differs from that in normal KB cells.
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PMID:2-Deoxy-D-glucose preferentially kills multidrug-resistant human KB carcinoma cell lines by apoptosis. 983 79

The major objective of our study was to define the mechanism by which mercuric chloride (HgCl2) induces human T-cell death. Human peripheral blood T-cells were exposed to 0-40 microm HgCl2 and then analyzed for biochemical and molecular features of T-cell apoptosis. HgCl2-treated cells exhibited increased Hoechst 33258 fluorescence while maintaining their ability to exclude the vital stain 7-aminoactinomycin D. To further evaluate cell death and distinguish between apoptosis and necrosis, translocation of phosphatidylserine to the outer layer of the plasma membrane (annexin V binding), DNA fragmentation (TUNEL assay), and cleavage of poly (ADP-ribose) polymerase (PARP) were assessed. In the presence of 20-40 microm HgCl2, T-cells exhibited increased annexin V binding (28%) and DNA fragmentation (31%). HgCl2-dependent PARP cleavage was also observed by Western blot analysis. Because degradative changes associated with apoptosis are often preceded by disruption of mitochondrial function, HgCl2-treated cells were assessed for disruption of the mitochondrial transmembrane potential (DeltaPsim) and development of the mitochondrial permeability transition state. Using DiOC6(3), we demonstrated that HgCl2 exposure resulted in a decrease in the DeltaPsim. Because a decline in DeltaPsim can disturb the intracellular pH (pHi), we used the fluorescent probe, SNARF-1, to assess intracellular acidification. Treatment of T-cells with HgCl2 resulted in reduced pHi from 7.0 to 6.7. Concomitant with these observations, the fluorescent probe, hydroethidine, was utilized to demonstrate that uncoupled mitochondrial electron transport resulted in increased reactive oxygen species (ROS) generation. Interestingly, in spite of these alterations to mitochondrial function, translocation of cytochrome c to the cytosol was not detected; this correlated with enhanced bcl-2 levels in HgCl2-treated cells. In conclusion, HgCl2 exposure results in oxidative stress and activation of death signaling pathways leading to apoptosis. Collectively, our studies indicate that individual mercurial species are capable of inducing T-cell death by activating specific apoptotic cascades.
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PMID:Mercuric chloride induces apoptosis in human T lymphocytes: evidence of mitochondrial dysfunction. 987 95

Nonsteroidal antiinflammatory agents (NSAIA) have been shown to exert potent chemopreventive activity against colon, lung, and breast cancers. In this study, we show that at pharmacological concentrations (1 to 3 mmol/L) sodium salicylate (Na-Sal) can potently induce programmed cell death in several human myeloid leukemia cell lines, including TF-1, U937, CMK-1, HL-60, and Mo7e. TF-1 cells undergo rapid apoptosis on treatment with Na-Sal, as indicated by increased annexin V binding capacity, cpp-32 (caspase-3) activation, and cleavage of poly (ADP-ribose) polymerase (PARP) and gelsolin. In addition, the expression of MCL-1, an antiapoptotic member of the BCL-2 family, is downregulated during Na-Sal-induced cell death, whereas the expression of BCL-2, BAX, and BCL-XL is unchanged. Z-VAD, a potent caspase inhibitor, prevents the cleavage of PARP and gelsolin and rescues cells from Na-Sal-induced apoptosis. In addition, we show that Na-Sal accelerates growth factor withdrawal-induced apoptosis and synergizes with daunorubicin to induce apoptosis in TF-1 cells. Thus, our data provide a potential mechanism for the chemopreventive activity of NSAIA and suggest that salicylates may have therapeutic potential for the treatment of human leukemia.
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PMID:Sodium salicylate activates caspases and induces apoptosis of myeloid leukemia cell lines. 1009 Sep 50

We have investigated the possibility of the involvement of PARP in apoptosis, independently of its enzymatic activity. We thus transfected PARP(-)/(-)A11 cells with a DNA construct encoding the PARP DNA-binding domain (DBD) fragment or mutants DBDbd(-), defective in DNA binding to DNA strand breaks, and DBDcl(-), resistant to caspase-3 cleavage. We found that in the absence of PARP, while expression of DBD has only a marginal effect, expression of the mutants strongly inhibits the apoptosis induced by staurosporine, as measured by the binding of annexin V. Moreover, the mutants, but not DBD, inhibit the cleavage of DNA PKcs, suggesting inhibition of activation of caspase-3. In addition, the mutant transfectants are fractionally less susceptible to low doses of an alkylating agent than the DBD transfectant or the original A11 line. The results suggest that the DBD fragment of PARP, apart from its classical role of nick detection and DNA binding, participates in complexes involved in upstream events leading to activation of the caspase cascade.
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PMID:Inhibition of apoptosis of a PARP(-)/(-)cell line transfected with PARP DNA-binding domain mutants. 1043 94

The tumor suppressor gene product p53 can bind to and inhibit the helicase activity of the multisubunit transcription-repair factor TFIIH. We previously reported that p53-mediated apoptosis is attenuated in primary human fibroblasts from individuals with Xeroderma Pigmentosum (XP) that harbor mutations in the TFIIH DNA helicases XPD or XPB. In this study we show that apoptosis is reduced and delayed in three XPD lymphoblastoid cell lines (LCLs), but not in an XPD heterozygote LCL, after exposure to doxorubicin, a DNA-damaging agent and topoisomerase II inhibitor frequently used in cancer therapy. Apoptosis was assessed by quantitation of Annexin V binding to exposed phosphatidylserine residues and by caspase-mediated cleavage of Poly(ADP)Ribose Polymerase (PARP). Apoptosis induced by doxorubicin was suppressed in LCLs retrovirally transduced with the Human Papillomavirus 16 E6 oncoprotein, consistent with the hypothesis that this is a p53-dependent process. PARP cleavage was not delayed in XPD LCLs in response to anti-Fas (CD95) antibody-mediated apoptosis, thus, the defect in the apoptotic pathway in these cells lies upstream of caspase activation. Similar changes in the expression of apoptosis-effector genes, p53, and p53-responsive genes p21Cip1/WAF-1/Sid1 (p21), gadd45, bcl-2 and bax were observed in normal and XPD LCLs after treatment with doxorubicin, indicating that delayed apoptosis was not a consequence of defective transcription of these genes. Thus, our studies provide further support to the hypothesis that XPD and p53 can functionally interact in a p53-mediated apoptotic pathway.
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PMID:Drug-induced apoptosis is delayed and reduced in XPD lymphoblastoid cell lines: possible role of TFIIH in p53-mediated apoptotic cell death. 1046 15


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