Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A nuclear poly(ADP-ribose) polymerase (PARP) is activated by gamma-irradiation and consequently synthesizes poly(ADP-ribose) by binding to DNA strand-breaks. This property suggests that PARP is a DNA strand-break-signal generator. Meanwhile, the cell-cycle arrest occurs in G1 and G2 phases following gamma-irradiation. We found that PARP inhibitors including 3-aminobenzamide (3-AB) suppressed G1 arrest and enhanced G2 arrest following gamma-irradiation. These observations suggested that PARP is critical for the induction of G1 arrest and is also involved in the regulation of G2 arrest. Furthermore, the effects of 3-AB on the G1-arrest signal-transduction pathway were also studied. We found that p53 stabilization following gamma-irradiation was not inhibited but the p53-responsive transient increases of WAF1/CIP1/p21 and MDM-2 mRNA were suppressed by 3-AB. Therefore, it is suggested that PARP participates in G1-arrest signal-transduction pathway through the modulation of WAF1/CIP1/p21 and MDM-2 mRNA expression.
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PMID:Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following gamma-irradiation. 757 30

In response to DNA damage, in particular DNA strand breaks, the proposed roles for normal tumour suppressor protein p53 are to increase the period of time available for DNA repair prior to replication, or to direct damaged cells into programmed cell-death. Since treatment of mammalian cells with (+/-)-anti-benzo[a]pyrene diolepoxide [(+/-)-anti-BPDE] --a mixture of metabolites comprising the most reactive (+)-anti-enantiomer of the full environmental carcinogen benzo[a]pyrene--has been shown to result in induction of DNA repair processes and consequently in DNA strand break formation, the aim of the present study was to investigate whether p53 accumulation is induced in (+/-)-anti-BPDE-treated phytohaemagglutinin-stimulated human peripheral blood lymphocytes (PBLs). Both immunocytochemical and immunoblot analysis indicated that treatment of PBLs with (+/-)-anti-BPDE results in p53 accumulation. Optimal accumulation was observed at 2.5 microM, while no increase of p53 levels was observed at concentrations < 2.5 microM and > 10 microM. Further, (+/-)-anti-BPDE-induced p53 accumulation in PBLs was found to be time-dependent with accumulation up to 24 h after the onset of treatment. Treatment of PBLs with 2.5 microM of (+/-)-anti-BPDE and 1 mM of 3-aminobenzamide, an inhibitor of the DNA strand break-dependent enzyme poly(ADP-ribose) polymerase, resulted in increased p53 levels, in comparison to cells treated with (+/-)-anti-BPDE alone. This combination also potentiated the frequency of (+/-)-anti-BPDE-induced micronuclei. These findings suggest that (+/-)-anti-BPDE-induced DNA strand break formation is responsible for the observed p53 accumulation. It is unlikely that poly(ADP-ribose) polymer formation is a prerequisite in the process of p53 accumulation, as triggered by DNA strand-break inducing agents like (+/-)-anti-BPDE. It is hypothesized that p53-dependent pathways may be activated in phytohaemagglutinin-stimulated human peripheral blood lymphocytes exposed ex vivo to (+/-)-anti-BPDE.
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PMID:Inhibition of poly(ADP-ribose) polymerase increases (+/-)-anti-benzo [a]pyrene diolepoxide-induced micronuclei formation and p53 accumulation in isolated human peripheral blood lymphocytes. 758 97

We have used two different approaches to study the consequences of NAD/poly(ADP-ribose) deficiency on p53 expression and its activity in V79-derived cell lines. In the first approach, we have used two cell lines that are deficient in poly(ADP-ribose) (pADPR) synthesis because of deficiency in the enzyme poly(ADP-ribose) polymerase (PARP). In a second approach, we have used a cell line that is deficient in NAD/pADPR metabolism due to unavailability of NAD, the substrate for PARP. These NAD/PARP-deficient cell lines exhibit a significant reduction in both baseline p53 expression and its activity compared to their parental V79 cells. Furthermore, etoposide, a topoisomerase II inhibitor that was shown to cause an increase in p53 expression and subsequent apoptosis in V79 cells, failed to produce any significant increase in p53 expression or apoptotic DNA fragmentation in NAD/PARP-deficient cell lines. Thus, our studies suggest that NAD/pADPR synthesis may be involved in the regulation of p53 and its dependent pathways.
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PMID:Involvement of NAD-poly(ADP-ribose) metabolism in p53 regulation and its consequences. 764 Nov 78

The induction of apoptosis following topoisomerase inhibitors proceeds in at least three distinct steps: (1) induction of cleavable complexes (potentially lethal damage), (2) topoisomerase-induced DNA damage, and (3) a presently unknown sequence of events that must either lead to cell cycle arrest (G2-block, differentiation) or apoptosis. DNA degradation provides a convenient way to quantify apoptosis in HL-60 cells. Extensive apoptosis can be induced rapidly in undifferentiated HL-60 cells without prevention by cycloheximide or actinomycin D. Therefore, HL-60 cells appear to express constitutively the apoptotic machinery that may be kept under control of a yet unknown repressor. The absence of the tumor suppressor p53 and the presence of bcl-2 are in contrast with the sensitivity of these cells to apoptosis. Agents that modify chromatin structure (zinc, poly[ADPribose] inhibitors, spermine) can block DNA fragmentation without affecting cell survival. By contrast macrophage-like differentiation by phorbol esters suppresses apoptosis without affecting topoisomerase-induced DNA damage. Better understanding of the apoptotic regulation in the widely used and characterized HL-60 cell line should allow the identification of new mechanisms and parameters of cellular sensitivity and resistance to the cytotoxic activity of anticancer agents.
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PMID:Apoptosis induced by DNA topoisomerase I and II inhibitors in human leukemic HL-60 cells. 785

Nitric oxide (NO)-releasing compounds cause apoptotic cell death in RAW 264.7 macrophages. This is confirmed morphologically by chromatin condensation and biochemically by DNA laddering. With use of spontaneously decomposing NO donors known as NONOates we show that the integral of concentration over time accounts for the NO-donor damaging ability. A 30-min exposure to the rapidly decomposing NO-donor diethylamine-nitric oxide complex (DEA-NO) causes irreversible damage and apoptotic cell death after 6 to 8 h. For intermediate NO releasers like sodium nitroprusside, S-nitrosoglutathione (GSNO), and spermine-NO removal of the NO-donating compound halts fragmentation to a certain degree. The relatively stable diethylenetriamine-nitric oxide complex initiates fragmentation only after prolonged exposure. NO-mediated apoptotic signaling in macrophages neither decreases cellular NAD+, nor causes a drop in APT. Consistently, membrane integrity measured by lactate dehydrogenase release is preserved and inhibitors of poly(ADPribose) polymerase, like 3-aminobenzamide, are noneffective. The level of the tumor suppressor p53 increases in response to NO donors like GSNO and effectively senses NO intoxication in macrophages. GSNO removal concomitantly allows p53 to decline with only a small percentage of cells showing DNA fragmentation. Contrary, massive damage initiated by a 1-h exposure to DEA-NO is irreversible, with persistent p53 levels. NO-mediated apoptotic cell death in RAW 264.7 macrophages correlates with the degree of p53 accumulation, probably sensing the integrity of the genome.
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PMID:Nitric oxide (NO) in apoptotic versus necrotic RAW 264.7 macrophage cell death: the role of NO-donor exposure, NAD+ content, and p53 accumulation. 861 78

Poly(ADP-ribosyl)ation of mutant and wild-type p53 was studied in transformed and nontransformed rat cell lines constitutively expressing the temperature-sensitive p53135val. It was found that in both cell types at 37.5 degrees C, where overexpressed p53 exhibits mutant conformation and cytoplasmic localization, a considerable part of the protein was poly(ADP-ribosyl)ated. Using densitometric scanning, the molecular mass of the modified protein was estimated as 64 kD. Immunofluorescence studies with affinity purified anti-poly(ADP-ribose) transferase (pADPRT) antibodies revealed that, contrary to predictions, the active enzyme was located in the cytoplasm, while in nuclei chromatin was depleted of pADPRT. A distinct intracellular localization and action of pADPRT was found in the cell lines cultivated at 32.5 degrees C, where p53 adopts wild-type form. Despite nuclear coexistence of both proteins no significant modification of p53 was found. Since the strikingly shared compartmentalization of p53 and pADPRT was indicative of possible complex formation between the two proteins, reciprocal immunoprecipitation and immunoblotting were performed with anti-p53 and anti-pADPRT antibodies. A poly(ADP-ribosyl)ated protein of 116 kD constantly precipitated at stringent conditions was identified as the automodified enzyme. It is concluded that mutant cytoplasmic p53 is tightly complexed to pADPRT and becomes modified. At 32.5 degrees C binding to DNA of p53 or its temperature-dependent conformational alteration might prevent an analogous modification of the tumor suppressor protein.
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PMID:ADP-ribosylation of p53 tumor suppressor protein: mutant but not wild-type p53 is modified. 883 78

BST-1 is an ectoenzyme expressed on human bone marrow Stromal cells and myeloid lineage cells, having both ADP-ribosyl cyclase and cyclic ADP-ribose (cADPR) hydrolase activities. In mouse, BST-1 is also expressed on lymphoid progenitors. We isolated chromosomal DNA segments of the human BST-1 gene. The human BST-1 gene consisted of nine exons and eight introns. The length of each exon was very similar to that of the Aplysia ADP-ribosyl cyclase gene. The flanking region of the BST-1 gene contained several potential binding sites for nuclear factors, NF-kappa B, p53, NF-IL6, CREB, PEA3, E2A, C/EBP, AP3, AP2 and SP1 and consensus sequences for gamma-IRE and ISRE like element.
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PMID:Genomic structure of human BST-1. 903 Sep 74

Signals of etoposide (ETO) induced apoptosis were studied in a human (B) lymphoma cell line, HT58. Morphology and DNA fragmentation assays proved the appearance of apoptosis after a short ETO treatment (4 hours). Modulation of signal components of this apoptotic pathway resulted the following a) phorbol ester (PMA) or heat shock inhibited apoptosis, which was prevented by staurosporine b) 3-amino-benzamide, a potent poly(ADP-ribose)polymerase inhibitor, had no significant effect; c) cysteine reactive compounds, such as iodoacetamide and phenylarsine oxide, as well as protease inhibitor TPCK were very active inhibitors of apoptosis; d) protein synthesis inhibitor, cycloheximide, potentiated cell death; e) the ETO-induced p53 protein overexpression had neither enhancing nor protecting effect on the apoptotic process. In conclusion, in the majority of HT58 lymphoma cells the apoptotic machinery is "primed" (the components are already expressed) and ETO-induced apoptosis is regulated by STA sensitive phosphorylation and proteolysis by cystein proteases, but not affected by ADP-ribozylation or p53.
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PMID:Modulation of apoptosis signaling in etoposide-treated lymphoma cells. 925 89

Poly-ADP-ribose polymerase (PARP) and p53 are both induced by DNA damage and each has been proposed to mediate the normal cellular response to damage. We find that embryo fibroblasts from PARP-null mice have a approximately twofold lower basal level of p53 and that the induction of p53 in response to DNA damage or nucleotide depletion is more than twofold less than in normal mouse cells. These factors combine to decrease the induced level of the p53 protein in PARP-deficient cells by 4-5-fold, compared to normal cells. However, there is virtually no decrease in the induction of p53 activity in PARP-deficient cells, as assayed with a p53-responsive promoter. Furthermore, cells lacking PARP arrest normally in G1 after DNA damage, in contrast to cells lacking p53, where this checkpoint is absent. Other p53-dependent properties, such as the mitotic spindle checkpoint and permissivity for gene amplification, are also normal in PARP-deficient cells. We conclude that the induced level of the p53 protein is governed by a combination of PARP-dependent and PARP-independent pathways and that the activation of p53 is largely PARP-independent. The results are consistent with a model in which the regulation of gene expression by p53 involves both increases in the amount of the protein and activation of p53 as a transcription factor.
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PMID:Defective induction but normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase. 928 57

The tumor suppressor gene p53 is expressed in the contrasting cell fates apoptosis and proliferation. We examined whether the transactivation of the p53 target genes, waf1 and mdm2, is dependent on the cause of p53 induction in human peripheral blood mononuclear cells (PBMC). Both apoptosis triggered by the purine analog 2-chlorodeoxyadenosine (CdA) and growth stimulation by the mitogen phytohemagglutinin (PHA) induced a comparable level and time course of p53 mRNA expression. Both stimuli led also to an increase of p53 protein levels. The cytotoxic agent, but not the mitogen, led to transactivation of waf1 and mdm2 within 18 h. Transactivation was followed by apoptosis of 89% of the PBMC within 48 h. The c-myc oncogene and poly(ADP-ribose)polymerase (PARP), which also have a dual function in proliferation and apoptosis, showed an early induction by both CdA and PHA. These results add further evidence that growth stimulation and DNA damage-induced apoptosis share early gene activation pathways in normal cells. However, since p53 does selectively translate into transactivation of target genes depending on the cause of induction, this function of p53 seems to be regulated by additional factors, which are closely related to the ultimate fate of the cell.
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PMID:Type of inducing signal regulates transactivation by p53. 936 63


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