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1
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Differential effects of heterocyclic amines on poly[ADP-ribose] polymerase-1 and mono-ADP-ribosyltransferase A

100%
Banasik M., Stedeford T., Strosznajder R. P., Hsu C.-H., Tanaka S., Ueda K.
Journal of Physiology and Pharmacology. Supplement
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2006
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tom 57
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nr 4
15-22
Heterocyclic amines (HCAs) have been shown to be carcinogenic in a variety of experimental systems. The purpose of the present study was to determine the in vitro effect of HCAs on the activity of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1). HCAs were also tested on the arginine-specific mono-ADP-ribosyltransferase A (MART-A), an enzyme involved in signal transduction and cytoskeletal realignment. 3-Amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) at 1 mM caused a 134% increase in PARP-1 activity and a 93% decrease in activity at 5 mM (IC50 = 2.2 mM). This dual effect is unique among inhibitors of this enzyme. On the other hand, Trp-P-2 activated MART-A at all concentrations tested, the peak being at 3 mM (>171% increase). In contrast, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) inhibited concentration-dependently both enzymes, PARP-1 (IC50 = 0.22 mM) and MART-A (IC50 = 2.8 mM). With nine other HCAs tested, predominantly inhibitory effects were observed. These results may assist our understanding of the carcinogenic mechanism of action and the dose-dependency of HCAs in animal bioassays.
2
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Poly(ADP-ribose) polymerase-1 is a novel nuclear target for cholinergic receptor signaling in the hippocampus

100%
Strosznajder R. P., Jesko H., Adamczyk A.
Journal of Physiology and Pharmacology. Supplement
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2005
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tom 56
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nr 4
209-213
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair and transcription regulation. The aim of this study was to investigate the role of PARP-1 in muscarinic cholinergic receptor signaling. Our data indicate that activation of muscarinic cholinergic receptors by carbachol (1mM) in the presence of GTPS evoked a significant enhancement of PARP activity in the adult rat hippocampus. Moreover, TMB-8 (10µM), an antagonist of inositol 1, 4, 5 trisphosphate (IP3) receptor prevented the activation of PARP-1, which indicates that IP3 /Ca2+ signaling is involved in this pathway. The diacylglycerol (DAG)-regulated protein kinase C (PKC) inhibitor (GF109203X) (1µM) only slightly enhanced PARP activity in hippocampal nuclear fractions, which suggests that DAG/ PKC is not involved in PARP activation.
3

Advantage of a baculovirus expression system for protein-protein interaction studies. Involvement of posttranslational phosphorylation in the interaction between wt p53 protein and poly[ADP-ribose] polymerase-1

100%
Schmid G., Wojciechowski J., Wesierska-Gadek J.
Acta Biochimica Polonica
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2005
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tom 52
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nr 3
We recently observed an interaction between poly(ADP-ribose) polymerase-1 (PARP-1) and the tumor suppressor p53 protein. However, more extensive studies on both proteins, especially those on characterization of their domains involved in the interaction were difficult due to very low expression levels of p53 in mammalian cells. Therefore, we generated recombinant proteins for such studies. To clarify which domains of human PARP-1 and of human wild-type (wt) p53 were involved in this protein-protein interaction, we generated baculoviral constructs encoding full length or distinct functional domains of both proteins. Full length PARP-1 was simultaneously coexpressed in insect cells with full length wt p53 protein or its distinct truncated fragments and vice versa. Reciprocal immunoprecipitation of Sf9 cell lysates revealed that the central and carboxy-terminal fragments of p53 each were sufficient to confer binding to PARP-1, whereas the amino-terminal part harbouring the transactivation functional domain was dispensable. On the other hand, the amino-terminal and central fragments of PARP-1 were both necessary for complex formation with p53 protein. Since the most important features of p53 protein are regulated by phosphorylation, we addressed the question whether its phosphorylation is essential for the binding between the two proteins. Baculovirally expressed wt p53 was post-translationally modified. At least six distinct p53 isomers were resolved by immunoblotting following two-dimensional separation of baculovirally expressed wt p53 protein. Using specific phospho-serine antibodies, we identified phosphorylation of baculovirally expressed p53 protein at five distinct sites. To define the role of p53 phosphorylation, pull-down assays using untreated and dephosphorylated p53 protein were performed. Dephosphorylated p53 failed to bind PARP-1, indicating that complex formation between the two proteins was regulated by phosphorylation of p53. The marked phosphorylation of p53 at Ser392 observed in unstressed cells suggests that the phosphorylated carboxy-terminal part of p53 undergoes complex formation with PARP-1 resulting in masking of the NES and thereby preventing its export.
4

Poly[ADP-ribose] polymerase in base excision repair: always engaged, but not essential for DNA damage processing

100%
Allinson S. L., Dianova I. I., Dianov G. L.
Acta Biochimica Polonica
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2003
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tom 50
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nr 1
Poly(ADP-ribose) polymerase (PARP-1) is an abundant nuclear protein with a high affinity for single- and double-strand DNA breaks. Its binding to strand breaks pro­motes catalysis of the covalent modification of nuclear proteins with poly(ADP-ribose) synthesised from NAD+ . PARP-1-knockout cells are extremely sen­sitive to alkylating agents, suggesting the involvement of PARP-1 in base excision re­pair; however, its role remains unclear. We investigated the dependence of base exci­sion repair pathways on PARP-1 and NAD+ using whole cell extracts derived from normal and PARP-1 deficient mouse cells and DNA substrates containing abasic sites. In normal extracts the rate of repair was highly dependent on NAD+ . We found that in the absence of NAD+ repair was slowed down 4-6-fold after incision of the abasic site. We also established that in extracts from PARP-1 deficient mouse cells, repair of both regular and reduced abasic sites was increased with respect to normal extracts and was NAD+ -independent, suggesting that in both short- and long-patch BER PARP-1 slows down, rather than stimulates, the repair reaction. Our data support the pro­posal that PARP-1 does not play a major role in catalysis of DNA damage processing via either base excision repair pathway.
5

Role of poly[ADP-ribose] polymerase in the regulation of the stability of wild-type p53 protein and p53-mediated apoptosis

100%
Wesierska-Gadek J.
Cellular and Molecular Biology Letters
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2000
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tom 05
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nr 2
6
Content available remote

Non-Abeta component of Alzheimer's disease amyloid and amyloid beta peptides evoked poly(ADP-ribose) polymerase-dependent release of apoptosis-inducing factor from rat brain mitochondria

84%
Adamczyk A., Czapski G. A., Jesko H., Strosznajder R. P.
Journal of Physiology and Pharmacology. Supplement
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2005
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tom 56
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nr 2
5-13
Amyloid beta peptide (Aß) and non-Aß component of Alzheimer’s disease amyloid (NAC) are involved in pathomechanism of Alzheimer's Disease (AD) and are deposited in the AD brain in the form of senile plaques. However, the mechanism of their neurotoxicity is not fully understood. In this study the sequence of events involved in NAC and Aß peptides evoked toxicity was investigated in brain slices, synaptosomes and in subcellular fractions. Radio-, immunochemical, spectrophotometrical methods and DNA electrophoresis were used in this study. Our data indicated that Aß 1-40 (25 µM) and NAC (10 µM) peptides induced liberation of free radicals and massive DNA damage that lead to activation of DNA bound enzyme poly(ADP-ribose) polymerase-1 (PARP-1). In consequence of these processes apoptosis-inducing factor (AIF) was released from mitochondria and was translocated to nucleus. The inhibitor of PARP, 3-aminobenzamide significantly decreased AIF release from mitochondria and its translocation. Both peptides under the investigated conditions had no effect on caspase-3 activity. Our data indicated that Aß and NAC peptides stimulate AIF-dependent apoptotic pathway that seems to be caspase independent process. The inhibition of PARP-1 may protect the brain against Aß and NAC toxicity.
7

Poly[ADP-ribose] polymerase-1 regulates the stability of the wild-type p53 protein

84%
Wesierska-Gadek J., Schmid G.
Cellular and Molecular Biology Letters
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2001
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tom 06
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nr 2
8
Content available remote

Physiological ageing: role of p53 and PARP-1 tumor suppressors in the regulation of terminal senescence

67%
Wesierska-Gadek J., Ranftler C., Schmid G.
Journal of Physiology and Pharmacology. Supplement
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2005
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tom 56
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nr 2
77-88
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.
9

Effect of aging and oxidative-genotoxic stress on poly[ADP-ribose] polymerase-1 activity in rat brain

67%
Strosznajder R. P., Jesko H., Adamczyk A.
Acta Biochimica Polonica
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2005
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tom 52
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nr 4
Poly(ADP-ribose) polymerase-1 (PARP-1, EC 2.4.2.30), a DNA-bound enzyme, plays a key role in genome stability, but after overactivation can also be responsible for cell death. The aim of the present study was to investigate PARP-1 activity in the hippocampus, brain cortex, striatum and cerebellum in adult (4 months) and aged (24 months) specific pathogen free Wistar rats and to correlate it with PARP-1 protein level and p53 expression. Moreover, the response of PARP-1 in adult and aged hippocampus to oxidative/genotoxic stress was evaluated. Our data indicated a statistically significant enhancement of PARP-1 activity in aged hippocampus and cerebral cortex comparing to adults without statistically significant changes in PARP-1 protein level. The expression of p53 mRNA was elevated in all aged brain parts with the exception of the cerebral cortex. Our data suggest that enhancement of PARP-1 activity and p53 expression in aged brain may indicate higher DNA damage. Our data also indicate that during excessive oxidative/genotoxic stress there is no response of PARP-1 activity in aged hippocampus in contrast to a significant enhancement of PARP-1 activity in adults which may have important consequences for the physiology and pathology of the brain.
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