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)

Betulinic acid (BA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases). FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-XL conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, Bax and Bcl-xs, two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.
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PMID:Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. 986 49

Ewing's sarcoma (EWS) cells accumulate elevated steady-state levels of poly (ADP-ribose) polymerase (PARP) mRNA and protein. To understand the molecular mechanisms underlying PARP upregulation, we cloned and analysed the 5'-flanking region of the PARP gene from EWS cells. Nucleotide sequence analysis demonstrated no variations in the PARP promoter region in EWS cells. The PARP promoter encompasses multiple binding motifs for the ETS transcription factor. We have also observed that there is a coordinated up-regulation of the expression of both PARP and ETS1, relative to cells of other human tumor types expressing lower levels of PARP. Transient co-expression of ETS1 in EWS cells resulted in a strong enhancement of PARP-promoter activity. The participation of ETS in the regulation of PARP gene expression was further demonstrated in EWS cells stably transfected with Ets1 antisense cDNA constructs. Antisense-mediated down-regulation of endogenous ETS1 resulted in the inhibition of PARP expression in EWS cells, and sensitized these cells to ionizing radiation. These data provide support for ETS regulation of PARP expression levels, and implicate ETS transcription factors in the radiation response of EWS cells.
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PMID:Regulation of the human poly(ADP-ribose) polymerase promoter by the ETS transcription factor. 1043 18

Ewing's sarcoma (EWS) cells contain significantly higher levels of poly(ADP-ribose) polymerase (PARP) mRNA, protein and enzymatic activities than any other eukaryotic cells. Evidence from our laboratory showed that increased transcription, rather than mRNA stability, contributes to the elevated PARP levels. It has been proposed that alterations in the normal turnover rate of PARP may also contribute to the total cellular PARP content as well as to the apoptotic response of Ewing's sarcoma cells to ionizing radiation. To address this possibility, we compared the turnover of PARP in EWS cells (A4573), which contain high PARP and are relatively radiosensitive, with that in laryngeal squamous cell carcinoma cells (SQ-20B), which have low PARP and are radioresistant. Results showed that PARP turnover parameters are nearly identical in both cells types. These data conclusively demonstrate that PARP turnover is not a determinant of either the elevated PARP content or the radiation response of EWS cells.
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PMID:Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells. 1195 22

Ewing's sarcoma (EWS) cells contain levels of poly(ADP-ribose) polymerase (PARP) significantly higher than other eukaryotic cells. Previously, we cloned the PARP gene promoter region from EWS cells, showed that it contained multiple ETS-binding sites and demonstrated a positive regulation of PARP by ETS1. We now report that, contrary to ETS1, EWS/FLI-1, an aberrant ETS transcription factor present in most EWS cells, is a negative effector of PARP transcription. Because PARP levels have been associated with cellular resistance or sensitivity to genotoxic agents, we studied the effect of modifying PARP levels in EWS cells on their response to DNA damage by modulating the expression of ETS1 or EWS/FLI-1 using antisense methodology. Results show that stable down-regulation of ETS1 increases the resistance of EWS cells to various genotoxic agents, whereas down-regulation of EWS/FLI-1 has pro-apoptotic effects. Because down-regulation EWS/FLI-1 does not dramatically change PARP levels, these results suggest a direct effect for EWS/FLI-1 in the DNA damage response of EWS cells. Since expression of the aberrant fusion proteins by EWS cells is essential for maintaining their neoplastic phenotype, our results suggest that the use of antisense oligonucleotides in combination with chemotherapeutic agents or radiation may be doubly effective by causing both an increase in sensitivity to therapeutic agents and a simultaneous down-regulation, or reversion, of the neoplastic phenotype of EWS cells.
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PMID:Differential regulation of the response to DNA damage in Ewing's sarcoma cells by ETS1 and EWS/FLI-1. 1197 49

Poly(ADP-ribose) polymerase (PARP) has strong affinity for DNA strand breaks and cycles on and off the DNA ends to allow DNA repair. A DNA-binding domain of PARP (PARP-DBD) acts as a dominant-negative mutant by binding to DNA strand breaks irreversibly and sensitizing mammalian cells to DNA-damaging agents. Therefore, expression of PARP-DBD in prostate carcinoma cells offers a strategy to achieve sensitization to genotoxic treatments. Toward this end, we developed recombinant plasmids expressing the PARP-DBD under the control of the 5'-flanking sequences of the human prostate-specific antigen (PSA) gene. Tissue specificity of PARP-DBD expression in human tumor cells was confirmed using the PSA-producing (LNCaP) and PSA-negative (PC-3) prostate cancer cells, as well as cells of nonprostate origin, Ewing's sarcoma (A4573 cells). LNCaP cells stably transfected with the PSA-regulated cDNA for PARP-DBD exhibit an androgen-dependent induction of PARP-DBD expression as determined by Western blotting, reverse transcription-PCR, and in situ immunofluorescence. Furthermore, we found that PARP-DBD sensitized LNCaP cells to DNA-damaging agents, such as ionizing radiation and etoposide. Androgen (R1881) -dependent stimulation of PARP-DBD expression resulted in a 2-fold growth inhibition in LNCaP cells as compared with controls, and an augmented apoptotic cell death in response to ionizing radiation or etoposide. Taken together, the plasmid vector developed in this study permits the expression of the human PARP-DBD in an androgen-inducible and PSA-dependent fashion, and sensitizes prostatic adenocarcinoma cells to DNA-damaging treatments. These results provide proof-of-principle for a novel therapeutic strategy for the treatment of prostate cancer.
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PMID:Gene therapy for prostate cancer by targeting poly(ADP-ribose) polymerase. 1246 Sep 2

The Ewing's sarcoma family of tumours (ESFT) are small round cell tumours characterized by the non-random EWS-ETS gene rearrangements. We have previously demonstrated that ESFT are highly sensitive to fenretinide-induced death, effected in part through a reactive oxygen species (ROS)-dependent pathway. Here, we demonstrate for the first time that the sensitivity of ESFT cells to fenretinide-induced cell death is decreased following downregulation of the oncogenic fusion protein EWS-Fli1; siRNA targeting EWS-Fli1 attenuated fenretinide-induced cell death in cell lines expressing EWS-Fli1, but not EWS-ERG. This decrease in cell death was independent of the level of ROS produced following exposure to fenretinide, but was effected through EWS-Fli1-dependent modulation of p38(MAPK) activity. Furthermore, inhibition of p38(MAPK) activity and knockdown of EWS-Fli1 reduced fenretinide-induced mitochondrial permeabilization, cytochrome c release, caspase and PARP cleavage, consistent with the hypothesis that p38(MAPK) is critical for activation of the death cascade by fenretinide in ESFT cells. These data demonstrate that expression of EWS-Fli1 enhances fenretinide-induced cell death in ESFT and that this is effected at least in part through modulation of p38(MAPK) activity.
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PMID:The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38(MAPK) activity. 1770 May 34

Bortezomib (VELCADE), formerly known as PS-341, is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo anti-tumor activity. Bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma. In this report, we examined the sensitivity of cell lines derived from Ewing's sarcoma-family of tumors (ESFT) to Bortezomib. Five ESFT-derived cell lines, TC-71, TC-32, SK-N-MC, A4573 and GRIMES, were highly sensitive to Bortezomib (IC(50) = 20 to 50 nM), and underwent cell cycle arrest and apoptosis following drug treatment. Bortezomib-induced apoptosis was associated with activation of caspase 3, cleavage of PARP and induction of p27 and p21 expression. Moreover, Bortezomib exhibited synergistic activity against the TC-71 and TC-32 cell lines when combined with TRAIL. Our results suggest that Bortezomib might be a useful agent for treatment of ESFT, when used alone or in combination with TRAIL.
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PMID:Proteasome inhibitor Bortezomib induces cell cycle arrest and apoptosis in cell lines derived from Ewing's sarcoma family of tumors and synergizes with TRAIL. 1822 18

Resistance to conventional chemotherapy is a major problem in several paediatric tumours. One explanation for this is that tumour cells are unable to engage apoptosis after cytotoxic drug-induced damage. Inhibitor of apoptosis proteins (IAPs) function by inhibiting both effector (9) and initiator (3 and 7) caspases. Repression of the widely expressed X-linked IAP (XIAP) by RNAi sensitises adult tumour cells to cytotoxics in vitro. Antisense oligonucleotide (ASO)-induced down-regulation of XIAP is effective at inducing cell death and delaying the growth of adult tumour cells as xenografts and these agents are currently in phase II clinical trials. The importance of XIAP in paediatric tumours has not been characterised but high expression correlates with poor survival in childhood AML. We have used the novel XIAP ASO (AEG35156) to evaluate the effects of down-regulation of XIAP in paediatric tumour cells. Here, we show that AEG35156 can down-regulate XIAP in a number of paediatric cell lines including models of osteosarcoma, rhabdomyosarcoma and Ewing's sarcoma. Cell death assays demonstrated a higher proportion of dead cells after XIAP down-regulation by ASO and these cells displayed increased levels of cleaved caspase-3 and cleaved PARP, showing cell death was due to apoptosis. In long-term clonogenic assays, XIAP ASO sensitised 791T osteosarcoma cells to doxorubicin, etoposide and vincristine. The work presented here suggests that AEG35156, as a monotherapy or in combination with cytotoxic agents, may be of benefit in the treatment of paediatric tumours.
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PMID:Down-regulation of XIAP by AEG35156 in paediatric tumour cells induces apoptosis and sensitises cells to cytotoxic agents. 2128 65

We reported previously that Ewing's sarcoma (ES) cells respond to ionizing radiation exposure by arrest in G(2)/M phase and induction of apoptosis which occurs in conjunction with poly(ADP-ribose) polymerase (PARP) proteolytic cleavage. ES cells (A4573 cell line) do not express immunodetectable levels of Bcl-2. To determine if expression of Bcl-2 could modulate radiation-induced ES cell death, we have stably transfected A4573 cells with a full-length human bcl-2 cDNA. Expression of Bcl-2 protein rendered ES cells relatively resistant to radiation-induced apoptosis. Moreover, the anti-apoptotic activity of Bcl-2 was directly related to levels of its expression in different ES clones. Cell cycle characteristics were similar for both parental and Bcl-2 expressing ES cells following radiation treatment, although bcl-2 transfectants exhibited a more protracted G(2)/M phase arrest and lower rate of apoptosis after release from the block. Constitutive expression of Bcl-2 resulted in about two-fold inhibition of PARR cleavage in ES cells dying after ionizing radiation exposure. These data support a role for Bcl-2 protein as a negative regulatory element of PARP proteolysis at the early stages of radiation-induced apoptosis in ES cells.
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PMID:Expression of the human Bcl-2 increases resistance of Ewing's sarcoma cells to apoptosis and inhibits poly(ADP-ribose) polymerase cleavage induced by radiation. 2154 49

We have cloned a 3.0 kb SalI-Sau3AI fragment containing 5' upstream sequences of a human poly(ADP-ribose) polymerase (PARR) pseudogene from the Ewing's sarcoma (ES) cell line A4573. The nucleotide sequence of the entire cloned fragment has been determined. Nucleotide sequence homology and Southern hybridization analysis of a panel of human/hamster somatic cell hybrids allowed us to map the PARP 5' sequences to human chromosome 13. Because it has been reported that the duplication of a 193 bp within the PARP sequences on chromosome 13 results in a 2.7/2.5 kb HindIII restriction fragment length polymorphism (RFLP), defined as A/B allele polymorphism, and that an elevated B allele frequency has been proposed to be associated with predisposition to cancer, we have analyzed ES cell lines for the presence of PARR-linked polymorphisms on chromosome 13. Using a probe from the cloned 5' PARP sequences, we found that ES cells homozygous (A/A) and heterozygous (A/B) for the 2.7/2.5 kb HindIII RFLP also differ in the organization of the genomic region upstream of the PARP pseudogene sequences. HindIII fragments of about 6.3, 10.5 and 22.0 kb were detected in A/B heterozygous cell lines (A4573 and SK-ES-1), whereas the A/A homozygous TC-106 ES cells showed fragments of about 6.6, 11.0 and 24.0 kb. This novel rearrangement on chromosome 13 may provide an additional marker to investigate cancer predisposition in human populations.
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PMID:Identification of a rearrangement in the 5' upstream region of the poly(ADP-ribose) polymerase pseudogene on chromosome 13 in Ewing's sarcoma cells. 2159 28


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