Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “PARPs”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed1996

The PARP promoter of Trypanosoma brucei is developmentally regulated in a chromosomal context.

African trypanosomes are extracellular protozoan parasites that are transmitted from one mammalian host to the next by tsetse flies. Bloodstream forms express variant surface glycoprotein (VSG); the tsetse fly (procyclic) forms express instead the procyclic acidic repetitive protein (PARP). PARP mRNA is abundant in procyclic forms and almost undetectable in blood-stream forms. Post-transcriptional mechanisms are mainly responsible for PARP mRNA regulation but results of nuclear run-on experiments suggested that transcription might also be regulated. We measured the activity of genomically-integrated PARP, VSG and rRNA promoters in permanently-transformed blood-stream and procyclic form trypanosomes, using reporter gene constructs that showed no post-transcriptional regulation. When the constructs were integrated in the rRNA non-transcribed spacer, the ribosomal RNA and VSG promoters were not developmentally regulated, but integration at the PARP locus reduced rRNA promoter activity in bloodstream forms. PARP promoter activity was 5-fold down-regulated in bloodstream forms when integrated at either site. Regulation was probably at the level of transcriptional initiation, but elongation through plasmid vector sequences was also reduced.

Animals↗
PubMed1999

Inhibition of PARP prevents oxidant-induced necrosis but not apoptosis in LLC-PK1 cells.

Oxidant-induced cell injury has been implicated in the pathogenesis of several forms of acute renal failure. The present studies examined whether activation of poly(ADP-ribose)polymerase (PARP) by oxidant-induced DNA damage contributes to oxidant injury of renal epithelial cells. H2O2 exposure resulted in an increase in PARP activity and decreases in cell ATP and NAD content. These changes were significantly inhibited by 10 mM 3-aminobenzamide (3-ABA), a PARP inhibitor. In contrast, H2O2-induced DNA damage was not prevented by 3-ABA. Exposure of LLC-PK(1) cells to 1 mM H2O2 for 2 h induced necrotic cell death as measured by increased lactate dehydrogenase (LDH) release. 3-ABA completely prevented the H2O2-induced LDH release. Live/dead fluorescent staining confirmed the protection by 3-ABA. These results are consistent with the view that oxidant-induced DNA damage activates PARP and that the subsequent ATP and NAD depletion contribute to necrotic cell death. Of note, although protected from necrosis, cells treated with H2O2 and 3-ABA underwent apoptosis as evidenced by DNA fragmentation and bis-benzimide staining. In conclusion, activation of PARP contributes to oxidant-induced ATP depletion and necrosis in LLC-PK1 cells. However, PARP inhibition may target cells toward an apoptotic form of cell death.

Animals↗
PubMed2006

Partial protection against collagen antibody-induced arthritis in PARP-1 deficient mice.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear DNA-binding protein that participates in the regulation of DNA repair and maintenance of genomic integrity. In addition, PARP-1 has a role in several models of inflammation disease, where its absence or inactivation confers protection. The aim of this study was to analyze the impact of selective PARP-1 suppression in collagen antibody-induced arthritis. We show that PARP-1 deficiency partially reduces the severity of arthritis, although the incidence of disease was similar in control and deficient mice. Decreased clinical scores were accompanied by partial reduction of histopathological findings. Interestingly, quantitative real-time PCR and ELISA analysis revealed that the absence of PARP-1 down-regulated IL-1beta and monocyte chemotactic protein 1 expression in arthritic joints whereas tumor necrosis factor-alpha transcription was not impaired. Our results provide evidence of the contribution of PARP-1 to the progression of arthritis and identify this protein as a potential therapeutic target for the treatment of rheumatoid arthritis.

Animals↗
PubMed2006

The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors.

BRCA1 and BRCA2 mutations are responsible for most familial breast carcinomas. Recent reports carried out in non-cancerous mouse BRCA1- or BRCA2-deficient embryonic stem (ES) cells, and hamster BRCA2-deficient cells have demonstrated that the targeted inhibition of poly(ADP-ribose) polymerase (PARP-1) kills BRCA mutant cells with high specificity. Although these studies bring hope for BRCA mutation carriers, the effectiveness of PARP-1 inhibitors for breast cancer remains elusive. Here we present the first in vivo demonstration of PARP-1 activity in BRCA1-deficient mammary tumors and describe the effects of PARP-1 inhibitors (AG14361, NU1025, and 3-aminobenzamide) on BRCA1-deficient ES cells, mouse and human breast cancer cells. AG14361 was highly selective for BRCA1-/- ES cells; however, NU1025 and 3-aminobenzamide were relatively non-selective. In allografts of naïve ES BRCA1-/- cells there was either partial or complete remission of tumors. However, in allografts of mouse, BRCA1-/- mammary tumors, there was no tumor regression or remission although a partial inhibition of tumor growth was observed in both the BRCA1-/- and BRCA1+/+ allografts. In human tumor cells, PARP-1 inhibitors showed no difference in vitro in limiting the growth of mammary tumors irrespective of their BRCA1 status. These results suggest that PARP-1 inhibitors may non-specifically inhibit the growth of mammary tumors.

Aged↗
PubMed2006

PARP-1 inhibitors: are they the long-sought genetically specific drugs for BRCA1/2-associated breast cancers?

Recent studies demonstrated that PARP-1 [poly(ADP-ribose) polymerase-1] inhibitors kill breast cancer associated gene-1 and -2 (BRCA1/2) deficient cells with extremely high efficiency while BRCA+/- and BRCA+/+ cells are relatively non-responsive to the treatment. It was therefore proposed that PARP-1 inhibitors might be the long-sought genetically specific drugs that are both safe and effective for treating BRCA1/2-associated breast cancers. However, a report published in a recent issue of the International Journal of Biological Sciences revealed that PARP-1 inhibitors, although able to kill naïve BRCA1 mutant cells with high specificity both in vitro and in vivo, exhibit minimal specificity in inhibiting the growth of mouse mammary tumor cells irrespective of their BRCA1 status in allograft nude mice. Non-specific inhibition in human BRCA1+/+, BRCA1+/-, and BRCA1-/- breast cancer cells by PARP-1 inhibitors was also observed. Additional mutations occurring during cancer progression may be a culprit, although the exact cause for the resistance of BRCA1-/- breast cancer cells to PARP-1 inhibitors remains elusive. These findings suggest that PARP inhibition may serve as an approach for the prevention of BRCA related breast cancer and may be useful in combination with other chemotherapeutic agents in the treatment of breast cancer.

Journal Article↗
PubMed2001

PARP inhibitors.

Poly(ADP-ribose) polymerase (PARP) catalyzes the biochemical conversion of nicotinamide adenine dinucleotide (NAD+) to poly(ADP-ribose) and nicotinamide, which is a weak feedback inhibitor of the enzyme. Early designs of PARP inhibitors were primarily based on mimicking the structure of nicotinamide and resulted in the identification and widespread use of benzamide analogs as PARP inhibitors. Recent searches for more potent and specific PARP inhibitors, facilitated by the crystal structure of the catalytic domain of PARP, led to several families of amide and lactam derivatives with multiple ring systems. New PARP inhibitors have shown efficacies in several animal disease models of cancer, ischemia and inflammation.

Journal Article↗
PubMed2006

Quantitative correlation between cellular proliferation and nuclear poly (ADP-ribose) polymerase (PARP-1).

Treatment of cells with lysophosphatidyl choline and centrifugal extraction can separate poly (ADP-ribose) synthetase (PARP-1) and DNA synthetase activities, permitting the experimental analysis and comparison of both multienzyme systems. Only PARP-1 is being assayed by our system. Ca(2+) and Mg(2+) have minor activating effects, and added histones are without activating action. Short end-blocked dsDNAs at nM concentrations and spermine at mM concentrations are maximally activating coenzymes of poly (ADP-ribose) synthesis. Comparison of non-proliferating non-malignant cells with rapidly growing cancer cells demonstrates that rates of poly (ADP-ribose) synthesis and DNA synthesis are highest in pre-confluent non-malignant cells and in proliferating cancer cells, and lowest in contact-inhibited non-malignant cells. Rates of poly (ADP-ribose) synthesis correlate with the number of enzymatically activable PARP-1 molecules per cell, determined under Vmax conditions where activity is linearly proportional to enzyme protein. Contact-inhibited non-malignant cells exhibit only trans-ADP-ribosylation that is not affected by ATP, while rapid growth, especially in cancer cells, demonstrates extensive auto-poly (ADP)-ribosylation that is strongly inhibited by ATP at concentrations present in cells exhibiting normal bioenergetics. Rates of mRNA synthesis in non-proliferating non-malignant cells and in cancer cells were indistinguishable, indicating that the differences observed between cellular phenotypes are most likely due to reassembly of PARP-1 molecules in nuclei to homo-dimers (in cancer cells) and hetero-dimers (in non-cancer cells). A specific inhibitor and an inactivator of PARP-1 each inhibit DNA synthesis when intact cancer cells are pretreated with these drugs. Direct addition of these drugs to permeabilized cells performing DNA synthesis has no effect on DNA synthesis. The most striking diagnostic signal for cancer cells is activation of PARP-1 and of DNA synthesis.

Animals↗
PubMed2003

Are poly(ADP-ribosyl)ation by PARP-1 and deacetylation by Sir2 linked?

Poly(ADP-ribose) polymerase-1 (PARP-1) safeguards genomic integrity by limiting sister chromatid exchanges. Overstimulation of PARP-1 by extensive DNA damage, however, can result in cell death, as prolonged PARP-1 activation depletes NAD(+), a substrate, and elevates nicotinamide, a product. The decline of NAD(+) and the rise of nicotinamide may downregulate the activity of Sir2, the NAD(+)-dependent deacetylases, because deacetylation by Sir2 is dependent on high concentration of NAD(+) and inhibited by physiologic level of nicotinamide. The Sir2 deacetylase family has been implicated in mediating gene silencing, longevity and genome stability. It is conceivable that poly(ADP-ribosyl)ation by PARP-1, which is induced by DNA damage, could modulate protein deacetylation by Sir2 via the NAD(+)/nicotinamide connection. The possible linkage of the two ancient pathways that mediate broad biological activities may spell profound evolutionary roles for the conserved PARP-1 and Sir2 gene families in multicellular eukaryotes.

Animals↗
PubMed2004

PolyADP-ribose polymerase-1 (PARP-1) and the evolution of learning and memory.

PARP-1 is a multifunctional enzyme that can modulate gene expression. Cohen-Armon et al.(1) found that a homologue of PARP-1 is activated in the Aplysia nervous system as the animal responds to an aversive stimulus, which leads to sensitization, and during a more complex form of learning that involves feeding behavior. Significantly, inhibiting PARP-1 activation blocked the learning. Several key pathways in Aplysia neurons are activated both during learning and after injury, suggesting that mechanisms of learning evolved from primitive responses to injury. Since PARP-1 is evolutionarily conserved as a responder to various forms of stress, the finding that PARP-1 is activated during learning supports this idea.

Animals↗
PubMed2005

Co-localization of PARP-1 and lamin B in the nuclear architecture: a halo-fluorescence- and confocal-microscopy study.

A functional interaction between poly(ADP-ribose) polymerase-1 (PARP-1) and lamin B has recently been proposed by nuclear fractionation, crosslinking, and immunoprecipitation experiments. Here we use fluorescence microscopy to verify and extend these findings. We analyze nuclear halo preparations by fluorescence in situ immuno staining (FISIS), which shares attributes with traditional nuclear fractionation techniques, and by confocal laser scanning microscopy (CLSM). The results agree in that a major part of the enzyme co-localizes with lamin B under physiological conditions, where PARP-1 only has basal activity. After DNA damage and the associated activation of PARP-1, and during the subsequent entry into apoptosis, dramatic changes occur: a gradual release of the enzyme from the lamina, accompanied by its accumulation in nucleoli. Our observations are in line with biochemical evidence for lamin B-PARP-1 interactions under physiological conditions and suggest ways by which these interactions are modified to support PARP-functions in damage and its fate in apoptosis.

Animals↗
PubMed1998

Prolongation of the p53 response to DNA strand breaks in cells depleted of PARP by antisense RNA expression.

The observation that 3-aminobenzamide, which inhibits a variety of ADP-ribose transferases, prolongs the gamma-irradiation-induced increase in intracellular p53 concentration suggested that one or more of such enzymes may determine the duration of the p53 response during G1 arrest. The role of poly(ADP-ribose) polymerase (PARP), an abundant nuclear enzyme activated by DNA strand breaks, in the p53 response to y-irradiation was investigated in Burkitt's lymphoma AG876 cells stably transfected with an inducible PARP antisense construct. Immunoblot analysis revealed that the cellular content of PARP was reduced to virtually undetectable levels after incubation of transfected cells for 72 h with the inducer dexamethasone. In noninduced antisense cells, the p53 concentration reached a maximum 2 h after exposure to 6.3 Gy of gamma-radiation and returned to control values by 4 h. In contrast, the p53 response in PARP-depleted antisense cells peaked at 4 h, with the levels of p53 remaining elevated for up to 12 h after y-irradiation. The maximal increase in p53 concentration was similar in both induced and noninduced cells. These results thus indicate that PARP activity, in part, determines the duration, but not the magnitude, of the p53 response to DNA damage.

Burkitt Lymphoma↗
PubMed2006

[The apoptosis marker enzyme poly-(ADP-ribose) polymerase (PARP) in systemic lupus erythematosus].

The enzyme poly-(ADP-ribose) polymerase (PARP) is localized within the cell nucleus and catalyzes DNA-repair. During programmed cell death (apoptosis), PARP is enzymatically cleaved. Detection of the cleavage products is characteristic for apoptosis. In patients with systemic lupus erythematosus (SLE), the highly ordered signal transduction cascade of apoptosis is disturbed. SLE patients show reduced PARP activity . PARP cleavage products are mainly found in association with either antinuclear and/or anti-dsDNA antibodies. In addition, serum samples from SLE patients and other autoimmune diseases display anti-PAR and anti-PARP autoantibodies.

Antibodies, Antinuclear↗
PubMed1996

Reactive oxygen intermediate(s) (ROI): common mediator(s) of poly(ADP-ribose)polymerase (PARP) cleavage and apoptosis.

HL-60 acute myeloblastic and U937 monoblastoid leukaemic cell lines both cleave poly(ADP-ribose)polymerase (PARP), at the onset of apoptosis, in response to a wide range of cytotoxic agents. This appears to be a common feature of leukaemic cell apoptosis. However, in the chronic myelogenous leukaemic (CML) derived cell line, K562, no such cleavage was detectable. This correlated with previous findings that this cell line is particularly resistant to apoptosis induced by cytotoxic agents. Proteolytic cleavage of PARP and the subsequent progression to apoptosis was inhibited by two protease inhibitors NEM and IOD. As both PARP cleavage and DNA fragmentation appeared closely linked in these cell lines, anti-oxidants (previously shown to be effective inhibitors of DNA fragmentation and apoptosis) were also demonstrated to prevent PARP cleavage. These results combine to suggest that ROI may mediate PARP cleavage, DNA fragmentation and the eventual apoptosis of these cells following cytotoxic insult.

Antioxidants↗
PubMed2006

KIF4 motor regulates activity-dependent neuronal survival by suppressing PARP-1 enzymatic activity.

In brain development, apoptosis is a physiological process that controls the final numbers of neurons. Here, we report that the activity-dependent prevention of apoptosis in juvenile neurons is regulated by kinesin superfamily protein 4 (KIF4), a microtubule-based molecular motor. The C-terminal domain of KIF4 is a module that suppresses the activity of poly (ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme known to maintain cell homeostasis by repairing DNA and serving as a transcriptional regulator. When neurons are stimulated by membrane depolarization, calcium signaling mediated by CaMKII induces dissociation of KIF4 from PARP-1, resulting in upregulation of PARP-1 activity, which supports neuron survival. After dissociation from PARP-1, KIF4 enters into the cytoplasm from the nucleus and moves to the distal part of neurites in a microtubule-dependent manner. We suggested that KIF4 controls the activity-dependent survival of postmitotic neurons by regulating PARP-1 activity in brain development.

Animals↗
PubMed2004

Identification of autoantibody against poly (ADP-ribose) polymerase (PARP) fragment as a serological marker in systemic lupus erythematosus.

OBJECTIVES: By utilizing serological analysis of a recombinant cDNA expression library (SEREX), we previously found that autoantibodies to poly (ADP-ribose) polymerase (PARP) are specifically present in the sera of patients with SLE. In this study, recombinant proteins of various domains of PARP were used to determine the PARP domain that is associated with SLE. METHODS: We produced four recombinant PARP proteins, which contained various PARP domains, and then carried out enzyme linked immunosorbent assay (ELISA) using these recombinant proteins to identify domains useful for SLE diagnosis. The recombinant proteins used in this analysis were; ADPNF (amino acids 1-234), ET-L2 (amino acids 339-680), ET-L3 (amino acids 681-1014), and ADPCF (amino acids 300-1014). RESULT: ELISA with ADPNF or ET-L2 showed low sensitivity in the sera of patients with SLE (14.3% and 17.0% respectively), whereas ELISA with ET-L3 or ADPCF showed high sensitivity in the sera of patients with SLE (34.0% and 49.1%, respectively). Autoantibodies to ADPCF were not found in the sera of patients with rheumatoid arthritis (0/30), systemic sclerosis (0/30) or healthy donors (0/54) and were rarely found in polymyositis/dermatomyositis (1/30) and Sjogren syndrome (1/14). Autoantibodies to ADPCF were closely associated with the presence of an oral ulcer in SLE (P=0.03, by the chi-square test). CONCLUSION: The high sensitivity and specificity shown by autoantibodies to ADPCF protein could be used as a valuable serologic maker for the diagnosis of SLE.

Adult↗
PubMed2006

PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3beta pathway.

The inhibition of glycogen synthase kinase-3beta (GSK-3beta) via phosphorylation by Akt or protein kinase C (PKC), or the activation of mitogen-activated protein kinase (MAPK) cascades can play a pivotal role in left ventricular remodeling following myocardial infarction. Our previous data showed that MAPK and phosphatidylinositol-3-kinase/Akt pathways could be modulated by poly(ADP-ribose)polymerase (PARP) inhibition raising the possibility that cardiac hypertrophic signaling responses may be favorably influenced by PARP inhibitors. A novel PARP inhibitor (L-2286) was tested in a rat model of chronic heart failure following isoproterenol-induced myocardial infarction. Subsequently, cardiac hypertrophy and interstitial collagen deposition were assessed; additionally, mitochondrial enzyme activity and the phosphorylation state of GSK-3beta, Akt, PKC and MAPK cascades were monitored. PARP inhibitor (L-2286) treatment significantly reduced the progression of postinfarction heart failure attenuating cardiac hypertrophy and interstitial fibrosis, and preserving the integrity of respiratory complexes. More importantly, L-2286 repressed the hypertrophy-associated increased phosphorylation of panPKC, PKC alpha/betaII, PKC delta and PKC epsilon, which could be responsible for the activation of the antihypertrophic GSK-3beta. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3beta intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure.

Animals↗
PubMed2003

NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that is involved in DNA repair and activated by DNA damage. When activated, PARP-1 consumes NAD(+) to form ADP-ribose polymers on acceptor proteins. Extensive activation of PARP-1 leads to glycolytic blockade, energy failure, and cell death. These events have been postulated to result from NAD(+) depletion. Here, we used primary astrocyte cultures to directly test this proposal, utilizing the endogenous expression of connexin-43 hemichannels by astrocytes to manipulate intracellular NAD(+) concentrations. Activation of PARP-1 with the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) produced NAD(+) depletion, glycolytic blockade, and cell death. Cultures incubated in high (10mM) extracellular concentrations of NAD(+) after MNNG exposure showed normalization of intracellular NAD(+) concentrations. Repletion of intracellular NAD(+) in this manner completely restored glycolytic capacity and prevented cell death. These results suggest that NAD(+) depletion is the cause of glycolytic failure after PARP-1 activation.

Animals↗
PubMed2003

PARP-1, a determinant of cell survival in response to DNA damage.

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a primary role in the process of poly(ADP-ribosyl)ation. This posttranslational modification of nuclear proteins is activated in response to DNA damage. Having been studied for more than 30 years, PARP-1 is now known to be implicated in several crucial cellular processes: DNA replication, transcription, DNA repair, apoptosis, and genome stability. In this review, we focus on recent findings suggesting that PARP-1 participates in DNA damage signaling in cell death. Of clinical relevance is its role in cancer therapy, irradiation, and chemotherapy, all of which may cause DNA damage and overactivate PARP-1, resulting in inflammation caused by necrosis. Therefore, we will discuss how inhibition of PARP-1 may enhance the efficiency of cancer therapy.

Cell Survival↗