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)

Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.
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PMID:Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. 1582 66

Poly(ADP-ribose) polymerases (PARPs) are involved in the regulation of many cellular functions. Three consequences of the activation of PARP1, which is the main isoform of the PARP family, are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of pro-inflammatory genes. Consequently, pharmacological inhibitors of PARP have the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce parenchymal cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications). The first ultrapotent novel PARP inhibitors have now entered human clinical trials. This article presents an overview of the principal pathophysiological pathways and mechanisms that are governed by PARP, followed by the main structures and therapeutic actions of various classes of novel PARP inhibitors.
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PMID:Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. 1586 71

Ageing of organisms is among the most complex processes currently known. Understanding the molecular mechanism of physiological ageing is one of the most essential issues in biology and medicine because it is not possible to predict when and how a certain individual will start ageing. In the past centuries human life expectancies increased. Extension of life span is associated with increased susceptibility to a number of chronic diseases. Insight into the cellular and molecular targets of the ageing process would offer the opportunity to prevent at least some of the destructive processes. In the present paper the involvement of two tumor suppressor proteins: wild-type p53 and poly(ADP-ribose)polymerase-1 (PARP-1) in the regulation of cellular senescence and physiological ageing was reviewed. Moreover, the interaction and cross-talk between p53 and PARP1-1 was discussed.
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PMID:Physiological ageing: role of p53 and PARP-1 tumor suppressors in the regulation of terminal senescence. 1607 92

The genes encoding the BRCA1 and BRCA2 tumor suppressors are the most commonly mutated in human familial breast cancers. Both have separate roles in the maintenance of genomic stability through involvement in homologous recombination, an error-free process enabling cells to repair DNA double-strand breaks. We have previously shown that cre-mediated conditional deletion of Brca2 within the mouse small intestine sensitizes the tissue to DNA damage. Eventually, the tissue repopulates via stem cells in which recombination at the floxed Brca2 allele has not taken place. In this study, we have treated Brca2-deficient small intestine with a potent small-molecule inhibitor of poly(ADP-ribose) polymerase 1 (PARP1), an enzyme predominantly involved in the recognition of DNA single-strand breaks. Brca2 deficiency rendered otherwise normal cells exquisitely sensitive to PARP inhibition, resulting in very high levels of apoptosis as early as 6 hours after treatment, with evidence for repopulation of the tissue at 12 hours. Furthermore, the intestines of animals treated with serial injections of the inhibitor repopulated very rapidly in comparison with those from untreated mice. Our results represent the first in vivo demonstration that inhibition of PARP1 activity confers exquisite sensitivity to death in physiologically normal Brca2-deficient cells, suggesting that such a regimen may be extremely potent prophylactically in women heterozygous for the BRCA2 gene, as well as against established tumors lacking functional BRCA2.
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PMID:Efficient deletion of normal Brca2-deficient intestinal epithelium by poly(ADP-ribose) polymerase inhibition models potential prophylactic therapy. 1628 96

Sustained activation of poly(ADP-ribose) polymerase-1 (PARP-1) and extracellular signal-regulated kinases 1/2 (ERK1/2) both promote neuronal death. Here we identify a direct link between these two cell death pathways. In a rat model of hypoglycemic brain injury, neuronal PARP-1 activation and subsequent neuronal death were blocked by the ERK1/2 inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059). In neuron cultures, PARP-1-mediated neuronal death induced by N-methyl-d-aspartate, peroxynitrite, or DNA alkylation was similarly blocked by ERK1/2 pathway inhibitors. These inhibitors also blocked PARP-1 activation and PARP-1-mediated death in astrocytes. siRNA down-regulation of ERK2 expression in astrocytes also blocked PARP-1 activation and cell death. Direct effects of ERK1/2 on PARP-1 were evaluated by using isolated recombinant enzymes. The activity of recombinant human PARP-1 was reduced by incubation with alkaline phosphatase and restored by incubation with active ERK1 or ERK2. Putative ERK1/2 phosphorylation sites on PARP-1 were identified by mass spectrometry. Using site-directed mutagenesis, these sites were replaced with alanine (S372A and T373A) to block phosphorylation, or with glutamate (S372E and T373E) to mimic constitutive phosphorylation. Transfection of PARP-1 deficient mouse embryonic fibroblasts with the mutant PARP-1 species showed that the S372A and T373A mutations impaired PARP-1 activation, whereas the S372E and T373E mutations increased PARP-1 activity and eliminated the effect of ERK1/2 inhibitors on PARP-1 activation. These results suggest that PARP1 phosphorylation by ERK1/2 is required for maximal PARP-1 activation after DNA damage.
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PMID:Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2. 1662 22

The impact of human chorionic gonadotropin (hCG) on prostate carcinoma viability was investigated. Treatment of LNCaP and PC-3 cells with hCG modestly reduced cell viability within 96 h. Treatment of cells with hCG followed by exposure to ionizing radiation enhanced radiosensitivity. Exposure of LNCaP cells to hCG promoted activation of epidermal growth factor receptor (ERBB1) via a Galpha(i)-, mitogen-activated protein kinase kinase (MEK)1/2-, and metalloprotease-dependent paracrine mechanism, effects that were further enhanced after radiation exposure, and that were causal in prolonged intense activation of poly(ADP-ribose) polymerase (PARP). Inhibition of ERBB1, MEK1, or PARP1 function suppressed the radiosensitizing properties of hCG. Radiosensitization was also, in part, dependent upon c-Jun NH2-terminal kinase 1/2 signaling. PARP1-dependent radiosensitization was suppressed by a pan-caspase inhibitor and by knockdown of apoptosis-inducing factor expression. Inhibition of phosphatidylinositol 3-kinase, expression of dominant-negative AKT, or treatment with the HMG CoA reductase inhibitor lovastatin suppressed AKT phosphorylation and enhanced the cytotoxic effects of hCG. The enhancing effect of lovastatin was reproduced by incubation with a geranylgeranyl transferase inhibitor and blocked by coexposure to geranylgeranyl pyrophosphate. Treatment with hCG and lovastatin decreased expression of BCL-(XL) and XIAP, and increased expression of IkappaB. The cytotoxic effects of hCG were enhanced by expression of dominant-negative IkappaB, and they were abolished by coexpression of activated AKT. Expression of activated AKT maintained BCL-(XL) levels in cells expressing dominant-negative IkappaB. The promotion of hCG lethality by lovastatin was abolished by overexpression of BCL-(XL), and was dependent upon activation of caspase-9. Thus, hCG, in combination with radiation and lovastatin, may represent a novel approach to kill prostate cancer cells.
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PMID:Human chorionic gonadotropin modulates prostate cancer cell survival after irradiation or HMG CoA reductase inhibitor treatment. 2741 95

Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that is rapidly activated by DNA strand breaks and signals the presence of DNA lesions by attaching ADP-ribose units to chromatin-associated proteins. The therapeutic applications of PARP inhibitors in potentiating the killing action of ionizing radiation have been well documented and are attracting increasing interest as a cancer treatment. However, the initial kinetics underlying the recognition of multiple DNA lesions by PARP1 and how inhibition of PARP potentiates the activity of DNA-damaging agents are unknown. Here we report the spatiotemporal dynamics of PARP1 recruitment to DNA damage induced by laser microirradiation in single living cells. We provide direct evidence that PARP1 is able to accumulate at a locally induced DNA double strand break. Most importantly, we observed that the rapid accumulation of MRE11 and NBS1 at sites of DNA damage requires PARP1. By determining the kinetics of protein assembly following DNA damage, our study reveals the cooperation between PARP1 and the double strand break sensors MRE11 and NBS1 in the close vicinity of a DNA lesion. This may explain the sensitivity of cancer cells to PARP inhibitors.
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PMID:PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. 1802 84

Poly(ADP-ribose) polymerase-1 (PARP-1) is an ubiquitous DNA-binding protein involved in the cellular response to various genotoxic agents. Excessive PARP-1 activation is known to lead to the depletion of intracellular NAD+ and ATP pools and hence to threat cell survival. Therefore, PARP-1 could be involved in neuronal death and contribute to the development of diabetic polyneuropathy (DPN). This study addressed the association of Leu54Phe and Val762Ala polymorphisms of PARP-1 with DPN in Russian type 1 diabetic (T1D) patients. Eighty-six T1D patients with severe DPN and 93 T1D patients with no clinical signs of DPN have been studied by a polymerase chain reaction restriction fragment length polymorphism approach. Using Fisher's exact test revealed the association of the Phe54 and Val762 variants of PARP-1 (odds ratio (OR), 1.66 and 2.88, respectively) with increased risk of DPN in T1D. These results suggest that the PARP1 gene is involved in the pathogenesis of diabetic neuropathy in a Russian population. Additionally, a logistic regression analysis revealed a significant association between the neurological variances such as vibration detection threshold (OR, 2.08), vibration and temperature perception thresholds (OR, 1.32 and 1.67, respectively), and sensory and motor nerve conduction velocities (OR, 2.34 and 2.58, respectively), with DPN.
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PMID:Leu54Phe and Val762Ala polymorphisms in the poly(ADP-ribose)polymerase-1 gene are associated with diabetic polyneuropathy in Russian type 1 diabetic patients. 1805 8

The influence of de novo synthesis of nicotinamide adenine dinucleotide (NAD) through the kynurenine (KYN) pathway of tryptophan (TRP) degradation on gene transcription of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production in chicken interferon gamma (ChIFN-gamma)-stimulated and non-stimulated chicken macrophage cell line HD11 was investigated. Interferon gamma up regulation of iNOS transcription and NO production was dependent on an undisturbed flow through the KYN pathway. Inhibition of indoleamine-2,3-dioxygenase, the rate-limiting enzyme of TRP catabolism, by 1-methyl-l-tryptophan (1-mTRP) down regulated both iNOS gene transcription and NO production. Addition of KYN to 1-mTRP-treated, ChIFN-gamma-stimulated macrophages circumvented the down regulation of iNOS transcription and NO production. Inhibition of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair, replication and transcription, which cleaves NAD into nicotinamide and ADP-ribose, down regulated iNOS gene transcription and NO production in ChIFN-gamma-stimulated HD11 cells. Our results suggest that prevention of NAD depletion in HD11 cells by ChIFN-gamma-mediated induction of IDO facilitates iNOS transcription and NO production. This effect is most likely a result of PARP1 automodification in the presence of NAD, known to facilitate transcription by changing chromatin structure and to allow NFkappaB binding to iNOS promoter which is hindered by direct protein-protein interaction between NFkappaB and unmodified PARP1.
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PMID:The role of tryptophan metabolism in iNOS transcription and nitric oxide production by chicken macrophage cells upon treatment with interferon gamma. 1808 71

Majority of chemotherapeutic agents inhibit tumor growth by inducing apoptosis or necrosis. The DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), kills cells by necrosis through massive production of DNA strand breaks and subsequent over-activation of PARP. Inhibition of PARP, either through PARP1 genetic ablation or through small molecule PARP inhibitors, protected MNNG-induced cell death in certain cell types including MEF and primary cortical cultures. We report here that a potent PARP inhibitor, ABT-888, facilitates the induction of apoptotic cell death in HeLa cells treated with MNNG. Although the release of cytochrome c from mitochondria to cytosol was observed in HeLa cells treated with either MNNG alone or the combination of MNNG and ABT-888 (MNNG/ABT-888), apoptosis is observed only in HeLa cells treated with MNNG/ABT-888. Bcl-2 family proteins regulate the release of cytochrome c. Downregulation of Bax and Bak by their corresponding siRNAs or overexpression of Bcl-xl inhibited the release of cytochrome c from mitochondria to cytosol, and inhibited apoptosis induced by MNNG/ABT-888. Further examination indicates that ATP concentration is greatly reduced in HeLa cells treated with MNNG alone, but not in HeLa cells treated with MNNG/ABT-888. Reduction of ATP concentration by F0F1-ATP synthase inhibitor oligomycin A renders HeLa cells resistant to the apoptosis induction by treatment with MNNG/ABT-888. Unlike in HeLa cells, ABT-888 protected MNNG induced cell death in normal human fibroblasts. Our study provides evidence that PARP activity determines the fate of HeLa cells by regulating the level of ATP after treatment with MNNG.
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PMID:Poly (ADP-ribose) polymerase activity regulates apoptosis in HeLa cells after alkylating DNA damage. 1872 May 55


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