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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly ADP-ribosylation is a post-translational modification of chromatin proteins catalyzed by the enzyme poly-ADPR transferase (poly-ADPRT) and affects the structure as well as the functional properties of chromatin. It is of particular relevance in carcinogenesis, as it represents an epigenetic mechanism for modulation of gene expression. In the present study, A431 cells were exposed to tumor promoters phorbol-12-myristate-13-acetate (PMA), benzoyl peroxide (BP), mezerein and 6-keto-lithocholic acid (KA), and their effect on poly-ADP-ribosylation was studied. All these tumor promoters increased the activity of poly-ADPRT in these cells--PMA 2.3-fold, BP and mezerein 2.2-fold each and KA 1.3-fold. The enzyme inhibitor 3-amino benzamide (3AB) partially prevented the stimulation of poly-ADPRT by these promoters. There was a concomitant decrease in NAD levels, the substrate for poly-ADPRT. The decrease was 44% for PMA, 46% for BP, 21% for KA and 34% for mezerein. The induction of poly-ADP-ribose synthesis by PMA and BP appears to be mediated at least in part by active oxygen species, as they induced an increase in superoxide anions and anti-oxidants prevented the increase of poly-ADPRT activity to varying extents.
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PMID:A comparative study on the effect of tumor promoters on poly ADP-ribosylation in A431 cells. 212 Jan 35

The repair of DNA damage in eukaryotic cells is closely coupled with local changes of chromatin structure such that newly synthesized repair patches transiently appear in 'free' DNA domains with increased accessibility to enzymatic and chemical probes. We have isolated these domains from mammalian cells repairing bulky DNA adducts. During the first 3 h of repair, excision of adducts occurred exclusively in free DNA and was closely linked with the appearance of newly synthesized repair patches. Following depletion of chromatin-bound poly(ADP-ribose), the repositioning of repair patches into these domains was completely blocked, although overall repair patch synthesis was unaltered. Concomitantly, DNA adducts were no longer excised and tended to accumulate in free DNA domains. Our results suggest a tight coupling of the excision step with the formation of free DNA domains by a mechanism involving poly ADP-ribosylation of chromatin proteins.
Carcinogenesis 1990 Jul
PMID:Uncoupling of DNA excision repair and nucleosomal unfolding in poly(ADP-ribose)-depleted mammalian cells. 237 83

Effects of ATP and some other nucleotides (AMP, ADP, CTP, GTP, UTP and dATP) on reparative DNA synthesis and repair patch ligation in bleomycin-pretreated permeable mouse sarcoma cells were studied. Reparative DNA synthesis was significantly stimulated by 2.5 mM ATP, ADP or dATP. The stimulation was observed on both DNA polymerase alpha- and beta-dependent reparative DNA synthesis. ATP concentration required for repair patch ligation was much lower than that required for the stimulation of reparative DNA synthesis. An apparent Km value for ATP of the repair patch ligation was about 40 microM. ADP supported repair patch ligation after being converted into ATP by adenylate kinase in permeable cells.
Carcinogenesis 1987 Oct
PMID:Effects of ATP and other nucleotides on DNA repair synthesis in bleomycin-pretreated permeable mouse sarcoma cells. 244 62

This paper reports studies on the binding of aflatoxin B1 (AFB1) to rat liver nuclear proteins in vivo and in vitro, and its effect on RNA synthesis. Two hours after rats (200 g) were given a single i.p. injection of 300 micrograms AFB1 containing 50 microCi [3H]AFB1/100 g body wt, AFB1 was found bound to the free nuclear proteins (29.7 pmol/mg protein), histones (20.3 pmol/mg protein) and chromatin-bound non-histone proteins (13.8 pmol/mg protein). The binding of AFB1 to histones was further studied in vitro. We found that for a given type of histone, the binding level varied greatly depending on the conditions used. Under both in vivo and in vitro conditions, however, H3 was always the most efficient substrate, and H4/H2B always the least efficient substrates for AFB1 binding. These results suggest that the binding preference was mainly related to the intrinsic properties of the histone type, and was little affected by the geometric arrangement of the histones in chromatin. Using nuclear proteins added to the RNA synthesizing system in vitro, we found that only the histone fraction had a strong inhibitory effect. Further studies, however, indicated that this inhibition was not due to histones per se, but rather to poly-ADP-ribosylated histones present in the histone preparations. No detectable difference in effect was found between control and AFB1-bound nuclear proteins on RNA synthesis. Moreover, higher levels of AFB1 binding to histones did not potentiate the inhibitory effect. We therefore conclude, and in direct support to our previous correlation studies (see the preceding paper), that the binding of AFB1 to nuclear proteins has no inhibitory effect on RNA synthesis.
Carcinogenesis 1988 Apr
PMID:The binding of aflatoxin B1 to rat liver nuclear proteins and its effect on DNA-dependent RNA synthesis. 245 74

Mononuclear leukocytes from 151 patients with cancer of various organs and from 467 apparently cancer-free individuals were exposed, in vitro, to H2O2 (100 microM) and the effects of the exposure on the activity of adenosine diphosphate ribosyl transferase (ADPRT) were determined. First, the reproducibility of this test procedure was established as satisfactory, by comparing the results of assays performed independently by two investigators, and by measuring ADPRT in cells from two individuals over a 9-week period. The test data were analyzed by multiple linear regression, and the correlation of cancer diagnosis, age, sex and smoking habits with ADPRT values was determined. The strongest correlate was cancer diagnosis. We considered categorizing ADPRT values as high and low, with a cut-off value that would substantially distinguish cancer from cancer-free individuals. When a cut-off value of 1200 c.p.m. TCA ppt [3H]NAD+/5 x 10(5) cells was applied to the complete test material, it was found that ADPRT values from cancer patients were more frequently below the cut-off than values from disease-free individuals: the relative risk estimate (odds ratio) was 13.8. When a similar analysis was done on values from lung cancer patients and smoking disease-free individuals, the odds ratio was 73.5. However, a cut-off value of 2000 c.p.m. TCA ppt [3H]NAD+/5 x 10(5) cells was most effective in distinguishing lung cancer patients (the largest cancer group, n = 96) from smoking non-cancer individuals: that value provided better sensitivity (85%) and specificity (81%) than other cut-off values tested in the range 1200-2000 c.p.m. Further, in the case of lung cancer, possible effects of anatomical site, and of staging and pathology on ADPRT values was analyzed by the chi-squared test: no significant associations were found. These data support the value of the ADPRT test in detecting early stage lung cancer regardless of location or pathological type.
Carcinogenesis 1989 Sep
PMID:Adenosine diphosphate ribosyl transferase responses to a standardized dose of hydrogen peroxide in the mononuclear leukocytes of patients with a diagnosis of cancer. 250 4

The author reviews the problem of the pattern of lipid peroxidation in cancer cells with special reference to a comparison between normal liver cells and hepatomas both transplanted and induced by diethylnitrosamine. It is stated that the loss of lipid peroxidation is proportional to the degree of de-differentiation of hepatoma cells. During carcinogenesis, however, the loss is already evident at the stage of preneoplastic nodules. A common feature of all tumors, independently of the extent of the loss of peroxidation in basal conditions, is the lack of further stimulation by ADP/iron or by ascorbate/iron. As regards the reasons for the decline in lipid peroxidation, they are certainly not unique. An important cause is the low activity of the enzymes of the monooxygenase microsomal chain. Another very important one is the change in lipid composition of membranes, with a marked decrease in polyunsaturated fatty acids, which are the main substrate for lipid peroxidation. It has been shown that enrichment of membranes of hepatomas with arachidonic acid results in restoration of stimulation of peroxidation by ascorbate/iron, but not with ADP/iron. The last type of stimulation mostly reflects the behaviour of the monooxygenase chain, whereas ascorbate/iron-induced stimulation does not require the presence of an efficient cytochrome P450-chain. Another cause for decreased lipid peroxidation in tumors is the increased rigidity of membranes, due to the large increase in cholesterol content: this prevents to some extent the influx of oxygen inside the membranes. Yet another cause is the presence of increased amounts of antioxidants in both cytosol and membranes. The main toxic product of lipid peroxidation, 4-hydroxynonenal, has been found to elicit several actions at extremely low concentrations. In fact, 4-hydroxynonenal stimulates chemotaxis of polymorphonuclear leukocytes, stimulates plasma membrane adenylate cyclase, stimulates plasma membrane guanylate cyclase, and stimulates phospholipase C. The last three enzymes involve the action of G-proteins. The effect of the aldehyde is present at less than micromolar concentrations, which may occur inside the cells in certain conditions. Moreover, at concentrations from 10(-6) to 10(-7) M, the aldehyde is able to block oncogene c-myc expression in the human erythroleukemic K562 cell line, which at the same time becomes able to express the gamma-globin gene. These facts are discussed with reference to a possible biological meaning of the loss of lipid peroxidation in tumors.
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PMID:Lipid peroxidation and cancer: a critical reconsideration. 251 Mar 83

Oxidants can act at multiple stages of carcinogenesis. While they cause genetic damage and are cytotoxic, they also activate cellular pathways which alter gene expression, growth, and differentiation. Certain pathways used by polypeptide growth factors and hormones are also activated by oxidants. For example, oxidants stimulate the phosphorylation of the ribosomal subunit S6, the phosphotransferase activity of protein kinase C, and induce its translocation to the plasma membrane. On the genomic level, oxidants increase the transcription of the growth-competence-related protooncogenes c-fos and c-myc. In addition to these growth factor-type reactions, oxidants induce pathways which are unique to them. Poly ADP-ribosylation of chromosomal proteins is of particular relevance to oxidant carcinogenesis. It represents an epigenetic consequence of DNA-breakage. Both histones and nonhistone proteins are poly ADP-ribosylated in response to oxidants. Among non-histones, ADPR-transferase, topoisomerase I, and the fos oncoprotein were identified as acceptors. Inhibition of poly ADP-ribosylation suppressed the oxidant-induced transcription of c-fos. Since fos oncoprotein serves as a transcriptional regulator, we speculate that its poly ADP-ribosylation and that of other chromosomal proteins plays a role in the modulation of gene expression in response to oxidative stress.
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PMID:Mechanisms of action of oxidant carcinogens. 269 47

A significant stimulation of the 24-h (between day 4 and 5 in vitro) new DNA synthetic activity was elicited in primary neonatal rat hepatocytes kept in low-calcium (0.01 mmol/l) HiWoBa2000 synthetic medium by the addition of a single dose (10(-10) mol/l) of each of several tumour promoters [i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA), phenobarbital, nafenopin, saccharin, teleocidin, benzoyl peroxide butylhydroxytoluene (BHT), dichlorodiphenyltrichloroethane (DDT), lindane, clofibrate and melittin]. Even hormones [e.g. epidermal growth factor (EGF), glucagon and insulin at 10(-10) mol/l] and EGF-like acting drugs (i.e. imidazole and indomethacin, at 10(-11) mol/l) similarly enhanced with respect to untreated controls the 24-h flow into S phase of the primary hepatocytes on condition, however, that the cells were incubated in a high- (i.e. 1.8 mmol/l) and not a low-calcium HiWoBa2000 medium. Xenobiotics, peptide mitogens and EGF-like acting drugs also enhanced the in vitro hepatocellular mitotic activity. The growth-stimulatory effects of the aforementioned eleven tumour promoters were entirely suppressed by the simultaneous addition to the growth medium of a fully effective dose (10(-4) - 10(-3) mol/l) of agents, such as 3-aminobenzamide (3-ABA), 3-methoxybenzamide (3-MBA) or nicotinamide (NA), that are known to inhibit the activity of ADP-ribosyl transferase (ADPRT). However, under the same conditions these inhibitors hampered neither the basal DNA synthetic and mitotic activities of spontaneously cycling hepatocytes nor the stimulation of the hepatocellular growth processes evoked by peptide mitogens and EGF-like acting drugs. Quantitative autoradiographic investigations showed that the incorporation of the ADP-ribose precursor and ADPRT substrate [3H]NAD into nuclear macromolecules of gently digitonin-permeabilized hepatocytes was negligible in the untreated cultures, whereas it was strikingly and nearly steadily increased by a 2-, 8- and 24-h exposure to a fully mitogenic dose (10(-10) mol/l) of TPA, thereby revealing that an early, significant and roughly steady activation of the nuclear ADPRT had taken place in the phorbol ester-treated liver parenchymal cells. The simultaneous addition of 3-ABA (10(-4) mol/l) not only fully checked the mitogenic effects of TPA, but even suppressed about two-thirds of the TPA-elicited nuclear incorporation of [3H]NAD by the permeabilized hepatocytes, thus showing that a significant curtailment of the TPA-activated ADPRT did occur is association with the abatement of the mitogenic effects of TPA by this inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1988 Dec
PMID:Inhibitors of ADP-ribosyl transferase suppress the mitogenic actions exerted by tumour promoters, but not those evoked by peptide mitogens, in primary neonatal rat hepatocytes. 297 75

Poly ADP-ribosylation and DNA strand breakage in response to treatment with the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were studied on SV40 minichromosomes in SV40-infected, permeabilized CV-1 monkey cells. After an initial sharp increase in poly ADP-ribosylation, strand breakage and poly ADPR increased proportionately with increasing dose of MNNG. This suggests a cause-effect relationship between the two reactions. The major poly ADP-ribose acceptor of minichromosomes was core histone H2B. In contrast, H2B, H2A, H1 and protein A24 were poly ADP-ribosylated in the nuclear chromatin of the same cells.
Carcinogenesis 1985 Feb
PMID:Poly ADP-ribosylation and DNA strand breakage in SV40 minichromosomes. 298 15

Cell cycle analysis by DNA flow cytofluorimetry and autoradiography has been utilized to investigate the effects of 3-methoxybenzamide (MBA), a potent inhibitor of ADP-ribosylation reactions, on cell cycle progression in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated C3H10T1/2 cells. Following a dose of 6.8 microM MNNG, the presence of MBA resulted in an increased length of S phase from approximately 6.5 h to 10 h and in an accumulation of cells in G2 with a mitosis delay of 12 h. Progression to the next S phase occurred 5-10 times more slowly and the cells ultimately accumulated in G2. Increasing the dose of MNNG resulted in a complete block in cell division in the absence of ADP-ribosylation. These results suggest that ADP-ribosylation reactions, which do not seem to be necessary for DNA excision repair in nondividing cells, are essential for coordinating the events of DNA excision repair with DNA replication and events related to progression through the cell cycle.
Carcinogenesis 1985 May
PMID:Cell cycle perturbations following DNA damage in the presence of ADP-ribosylation inhibitors. 298 7


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