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)

p53 and poly(ADP-ribose) polymerase (PARP) are both DNA damage recognition proteins and can be functionally activated by DNA strand breaks. To understand the functional interaction between these two proteins, the effects of a PARP inhibitor, 3-aminobenzamide (3AB), on the p53 pathway were investigated in human glioblastoma cells with different p53 status. Consistent with previous studies, irradiation with gamma-rays induced both p53 and WAF1 accumulation in A-172 cells (wtp53) but not in T98G cells (mp53). However, the presence of 3AB but not its analog suppressed radiation-induced accumulation of wtp53 and the expression of WAF1 and MDM2. Similar results were also obtained from U87MG, another human glioblastoma cell line with wtp53 status. Northern blotting analysis showed that 3AB inhibited the gamma-ray-induced WAF1 gene expression. Moreover, 3AB but not its analog inhibited irradiation-induced activation of sequence-specific DNA binding of wtp53 as detected using 32P-labeled or biotin-labeled p53 consensus sequence (p53CON). However, immunoblotting with an anti-poly(ADP-ribose) antibody showed that p53 proteins of the p53CON-bound fraction did not contain poly(ADP-ribose) (PAR). These findings suggested that poly(ADP-ribosyl)ation is required for rapid accumulation of p53, activation of p53 sequence-specific DNA binding and its transcriptional activity after DNA damage.
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PMID:Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation. 987 88

Chemotherapeutic agents and gamma-irradiation used in the treatment of brain tumors, the most common solid tumors of childhood, have been shown to act primarily by inducing apoptosis. Here, we report that activation of the CD95 pathway was involved in drug- and gamma-irradiation-induced apoptosis of medulloblastoma and glioblastoma cells. Upon treatment CD95 ligand (CD95-L) was induced that stimulated the CD95 pathway by crosslinking CD95 via an autocrine/paracrine loop. Blocking CD95-L/receptor interaction using F(ab')2 anti-CD95 antibody fragments strongly reduced apoptosis. Apoptosis depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3 like proteases) as it was almost completely abrograted by the broad range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. Apoptosis was mediated by cleavage of the receptor proximal caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3, Apopain) resulting in cleavage of the prototype caspase substrate PARP. Moreover, CD95 was upregulated in wild-type p53 cells thereby increasing responsiveness towards CD95 triggering. Since activation of the CD95 system upon treatment was also found in primary medulloblastoma cells ex vivo, these findings may have implications to define chemosensitivity and to develop novel therapeutic strategies in the management of malignant brain tumors.
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PMID:Activation of the CD95 (APO-1/Fas) pathway in drug- and gamma-irradiation-induced apoptosis of brain tumor cells. 1020 87

Poly(ADP-ribose) glycohydrolase (PARG) digests poly(ADP-ribose), which is synthesized by poly(ADP-ribose) polymerase (PARP) after DNA damage. We mapped the human poly(ADP-ribose) glycohydrolase gene to chromosome 10q11.23-21.1 by fluorescence in situ hybridization analysis. Since chromosomal rearrangements in thyroid papillary carcinoma and loss of heterozygosity in glioblastoma are frequently observed in this region, genetic alteration of PARG could be implicated in these diseases.
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PMID:The human poly(ADP-ribose) glycohydrolase maps to chromosome 10q11.23-21.1 by fluorescence in situ hybridization. 1036 63

Malignant brain tumors are the most common solid tumors in children. The overall prognosis for this group of patients is still poor, emphasizing the importance of more effective therapies. Betulinic acid (Bet A) has been described as a novel cytotoxic compound active against melanoma and neuroblastoma cells. Here we report that Bet A was active against medulloblastoma and glioblastoma cell lines. In addition, Bet A exerted cytotoxic activity against primary tumor cells cultured from patients in 4 of 4 medulloblastoma-tumor samples tested and in 20 of 24 glioblastoma-tumor samples. Since a small percentage of primary-glioblastoma-tumor cells (4/24) did not respond to Bet-A treatment, resistance to Bet A might occur. Induction of apoptosis by Bet A involved mitochondrial perturbations, since inhibition of the mitochondrial permeability transition by the mitochondrion-specific inhibitor bongkrekic acid (BA) reduced Bet-A-induced apoptosis. In addition, mitochondria undergoing Bet-A-induced permeability transition triggered DNA fragmentation in isolated nuclei. Cytochrome c was released from mitochondria of Bet-A-treated cells, and might be involved in activation of caspases. Following treatment with Bet A, caspase-8, caspase-3 and PARP were proteolytically processed. Inhibition of caspase cleavage by the broad-range caspase inhibitor zVAD.fmk strongly reduced Bet-A-induced apoptosis, indicating that apoptosis was mediated by activation of caspases. Since Bet A did not exhibit cytotoxicity against murine neuronal cells in vitro, these findings suggest that Bet A may be a promising new agent for the treatment of medulloblastoma and glioblastoma cells that clearly warrants further pre-clinical and clinical evaluation.
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PMID:Betulinic acid: a new cytotoxic agent against malignant brain-tumor cells. 1039 62

Development of necrosis is a characteristic feature of glioblastoma but its pathogenesis remains poorly understood. The process of poly(ADP-ribosyl)ation in response to DNA damage is mediated by poly(ADP-ribose) polymerase (PARP) and results in NAD+ depletion. The consequent ATP and energy depletion may result in cell necrosis. Therefore PARP activation is a potential candidate for a regulatory role in the pathogenesis of necrosis in glioblastoma. This study investigated whether there might be a relationship between both PARP expression and poly(ADP-ribosyl)ation, and necrosis in glioblastoma. The pattern of expression of PARP and of poly(ADP-ribose) groups in an archival series of glioblastoma was examined using immunohistochemistry. These parameters were also studied in multicellular tumour spheroids, derived from human glioma cell lines in which central necrosis develops with increasing spheroid diameter. Poly(ADP-ribose) groups were expressed in peri-necrotic tumour cells in glioblastoma. In the spheroid model poly(ADP-ribosyl)ation was seen centrally in pre-necrotic and necrotic cells with increasing spheroid diameter. PARP was widely expressed in viable tumour cells in the glioblastoma sections. In the spheroids, PARP expression, which was initially diffuse, became confined to the outer proliferative zone with increasing diameter. The pattern of expression of poly(ADP-ribose) groups in the spheroids and in glioblastoma raises the possibility that poly(ADP-ribosyl)ation may play a role in the development of necrosis in glioma. The high basal PARP expression in both glioblastoma and the spheroids suggests that this enzyme may have additional roles in glioma cell biology.
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PMID:Expression of poly(ADP-ribose) polymerase and distribution of poly(ADP-ribosyl)ation in glioblastoma and in a glioma multicellular tumour spheroid model. 1112 19

Staurosporine, a protein kinase and etoposide, a topoisomerase II inhibitor, are known to enhance apoptosis. The differential effects of these agents on T98G glioblastoma and SK-N-SH neuroblastoma, cell lines both derived from human tumors, have not been determined. We assessed cellular viability, DNA fragmentation and laddering, chromatin condensation, and Poly(ADP-ribose) polymerase (PARP) cleavage induced by these agents at a series of concentrations and times. In addition, to gain an understanding of the mechanism by which these agents work, we measured Protein Kinase C (PKC) activity. Staurosporine induced significant alterations in all apoptotic parameters tested in both cell lines. Etoposide induced apoptotic alterations similar to those caused by staurosporine in neuroblastoma but produced no detectable apoptotic changes in glioblastoma cells. Etoposide induced membrane but not cytosolic PKC activity in neuroblastoma but had no effect on PKC activity in glioblastoma. Our results show that the induction of apoptosis is cell type dependent. PKC activity appears to be crucial in the initiation of apoptosis.
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PMID:Differential responses of human neuroblastoma and glioblastoma to apoptosis. 1145 93

Tissue factor pathway inhibitor-2 (TFPI-2) is a 32 kDa serine protease inhibitor found at high levels in extracellular matrix. Recombinant human TFPI-2 has recently been shown to be a strong inhibitor of trypsin, plasmin, plasma kallikrein, and factor XIa amidolytic activity. Earlier studies in our laboratory showed that the expression of TFPI-2 is lost during tumor progression in human gliomas. We stably transfected this protease inhibitor in multiform glioblastoma cell line (SNB-19) and in low-grade glioma cell line (Hs683) in sense and antisense orientation respectively. This confirmed that the upregulation/down-regulation of TFPI-2 plays a significant role in the invasive behavior of human gliomas both in vitro and in vivo models. Collectively, these results suggested an idea to determine whether TFPI-2 is necessary for cell survival and inhibition of tumor formation in nude mice, due to apoptosis of intracerebrally injected SNB-19 cells. In the present study we determined p-ERK levels and found that they are decreased in TFPI-2 over-expressed clones (SNB-19) and increased in TFPI-2 down-regulated clones (Hs683). We also checked the levels of BAX/BCl-2, caspases (for e.g., 9, 7, 3, 8), PARP, cytochrome-c and Apaf-1. Moreover, the increase of apoptosis in vitro is associated with increased and decreased expression of apoptotic protein BAX in sense clones (SNB-19) and antisense clones (Hs683) respectively, when compared to controls and vice versa with Bcl-2 the anti-apoptotic protein. Caspases (9, 7 and 3), cytochrome-c, Apaf-1 and PARP levels are increased in SNB-19 and decreased in Hs683. Caspase 8 was not expressed in either cell line. Caspases 9 and 3 activity assay revealed higher activity in sense clones (SNB-19) but lesser in antisense clones (Hs683) compared to controls. This is the first report of TFPI-2 playing a novel role in cell survival in human gliomas.
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PMID:A novel role of tissue factor pathway inhibitor-2 in apoptosis of malignant human gliomas. 1149 41

Both increased cell proliferation and apoptosis play important roles in the malignant growth of glioblastomas. We have demonstrated recently that the differential expression of protein kinase C (PKC)-eta increases the proliferative capacity of glioblastoma cells in culture; however, specific functions for this novel PKC isozyme in the regulation of apoptosis in these tumors has not been defined. In the present study of several glioblastoma cell lines, we investigated the role of PKC-eta in preventing UV- and gamma-irradiation-induced apoptosis and in caspase-dependent signaling pathways that mediate cell death. Exposure to UV or gamma irradiation killed 80% to 100% of PKC-eta-deficient nonneoplastic human astrocytes and U-1242 MG cells, but had little effect on the PKC-eta-expressing U-251 MG and U-373 MG cells. PKC-eta appears to mediate resistance to irradiation specifically such that when PKC-eta was stably expressed in U-1242 MG cells, more than 80% of these cells developed resistance to irradiation-induced apoptosis. Reducing PKC-eta expression by transient and stable expression of antisense PKC-eta in wild-type U-251 MG cells results in increased sensitivity to UV irradiation in a fashion similar to U-1242 MG cells and nonneoplastic astrocytes. Irradiation of PKC-eta-deficient glioblastoma cells resulted in the activation of caspase-9 and caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and a substantial increase in subdiploid DNA content that did not occur in PKC-eta-expressing tumor cells. A specific inhibitor (Ac-DEVD-CHO) of caspase-3 blocked apoptosis in PKC-eta-deficient U-1242 MG cells. The data demonstrate that resistance to UV and gamma irradiation in glioblastoma cell lines is modified significantly by PKC-eta expression and that PKC-eta appears to block the apoptotic cascade at caspase-9 activation.
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PMID:Protein kinase C-eta regulates resistance to UV- and gamma-irradiation-induced apoptosis in glioblastoma cells by preventing caspase-9 activation. 1177 28

Primary or acquired resistance to current treatment protocols remains a major concern in clinical oncology and may be caused by defects in apoptosis programs. Since recent data suggest that TRAIL can bypass apoptosis resistance caused by Bcl-2, we further investigated the role of Bcl-2 in TRAIL-induced apoptosis. Here we report that overexpression of Bcl-2 conferred protection against TRAIL in neuroblastoma, glioblastoma or breast carcinoma cell lines. Bcl-2 overexpression reduced TRAIL-induced cleavage of caspase-8 and Bid indicating that caspase-8 was activated upstream and also downstream of mitochondria in a feedback amplification loop. Importantly, Bcl-2 blocked cleavage of caspases-9, -7 and -3 into active subunits and cleavage of the caspase substrates DFF45 or PARP. Also, Bcl-2 blocked cleavage of XIAP and overexpression of XIAP conferred resistance against TRAIL indicating that apoptosis was also amplified through a feedforward loop between caspases and XIAP. In contrast, in SKW lymphoblastoid cells, TRAIL-induced activation of caspase-8 directly translated into full activation of caspases, cleavage of XIAP, DFF45 or PARP and apoptosis independent of Bcl-2 overexpression, although Bcl-2 similarly inhibited loss of mitochondrial membrane potential and the release of cytochrome c, AIF and Smac from mitochondria in all cell types. By demonstrating a cell type dependent regulation of the TRAIL signaling pathway at different level, e.g. by Bcl-2 and by XIAP, these findings may have important clinical implication. Thus, strategies targeting the molecular basis of resistance towards TRAIL may be necessary in some tumors for cancer therapy with TRAIL.
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PMID:Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. 1194 12

Temozolomide (TZM) is a novel methylating agent currently under investigation for treatment of recurrent high-grade gliomas. Although TZM generates a wide spectrum of methyl adducts, its cytotoxicity has been attributed to mismatch repair (MR)-mediated processing of O(6)-methylguanine:T mispairs. N3-methyladenine and N7-methylguanine adducts are promptly repaired by the base excision repair system, unless a poly(ADP-ribose) polymerase (PARP) inhibitor is combined to TZM. In this case, the repair process of N-methylpurines cannot be completed and the deriving DNA strand breaks contribute to cytotoxicity. In this study, we investigated the influence on cell growth and cell cycle of treatment with TZM + PARP inhibitor in glioma cells characterized by different susceptibility to TZM. The results indicated that PARP inhibitor increases growth inhibition induced by TZM in either p53-wild-type or p53-mutant glioblastoma cells, as early as 24 h after drug exposure. The enhancing effect exerted by PARP inhibitor was particularly evident in glioma cells characterized by a defective expression of MR, since these cells are tolerant to O(6)-methylguanine damage and show low sensitivity to TZM. In O(6)-alkylguanine-DNA alkyltransferase (OGAT)-deficient and MR-proficient tumor cells bearing wild-type p53, the drug combination markedly reduced cell accumulation in the G(2)/M phase of cell cycle and induction of the G(2) checkpoint regulator Chk1 kinase. In short-term cultures of glioma cells derived from surgical specimens, PARP inhibitor enhanced chemosensitivity to TZM and this effect was especially evident in OGAT-proficient tumors. Thus, a pharmacological strategy based on the interruption of N-methylpurine repair might represent a novel strategy to restore or increase glioma sensitivity to TZM.
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PMID:Poly(ADP-ribose) polymerase inhibitor increases growth inhibition and reduces G(2)/M cell accumulation induced by temozolomide in malignant glioma cells. 1223 42


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