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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor promoter phorbol-12-myristate-13-acetate (PMA) increases the level of poly ADP-ribosylation of chromosomal proteins in mouse embryo fibroblasts C3H10T1/2. The poly ADP-ribosylated nuclear proteins fall into the following molecular weight classes: 40, 48, 61, 77, 92, 158, 200 kd. Preincubation with catalase reduced the poly ADP-ribose (ADPR) substitution of all these proteins essentially to control levels. Western blot analysis with antibody directed against ADPR transferase indicates that the major acceptors are ADP-ribose transferase (116 kd) itself and its proteolytic degradation products of 20-25, 45 and 72-95 kd. Poly ADP-ribosylation of these proteins is suppressed by cycloheximide, 3-aminobenzamide, antipain and catalase. The latter three inhibitors possess anti-promotional activities in certain in vitro cell culture systems. Auto-poly ADP-ribosylation of ADPR transferase and its proteolytic cleavage as well as the poly ADP-ribosylation of other chromosomal proteins may play a role in the modulation of gene expression by PMA.
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PMID:Non-histone chromosomal protein acceptors for poly(ADP)-ribose in phorbol-12-myristate-13-acetate treated mouse embryo fibroblasts (C3H10T1/2). 393 85

Transformation of mouse C3H 10T1/2 cells by X-irradiation in vitro was blocked by the addition of 1 mM 3-aminobenzamide, an inhibitor of polyadenosine diphosphoribose (poly[ADP-ribose]) synthesis immediately after irradiation. 3-Aminobenzamide also inhibited an increase in the frequency of transformants caused by the addition of the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate, 7 days after irradiation. These results demonstrate a role for poly(ADP-ribose) synthesis during the initiation and promotion stages of transformation. From previous studies it is known that poly(ADP-ribose) synthesis is stimulated by the DNA damage caused by X rays during initiation. During promotion, however, 12-O-tetradecanoylphorbol-13-acetate acted as a mitogen but did not induce detectable DNA damage, and we could detect no stimulation of poly(ADP-ribose) synthetase. The roles of poly(ADP-ribose) during initiation and during promotion must, therefore, be significantly different.
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PMID:Antagonistic action of a tumor promoter and a poly(adenosine diphosphoribose) synthesis inhibitor in radiation-induced transformation in vitro. 394 68

The tumor promoter phorbol-12-myristate-13-acetate (PMA) increases the poly ADP-ribosylation of acid extractable (0.2N H2SO4) nuclear proteins in mouse embryo fibroblasts C3H10T1/2. Catalase suppresses the reaction by approximately 50%. Polyacrylamide gel electrophoresis reveals that the core histones H2B, A24 and H3d serve as major poly ADP-ribose acceptors. Smaller amounts of poly ADP-ribose are associated with histones H2A/H3 and H1. Poly ADP-ribosylation of histones may change the nucleosomal structure and function and play a role in PMA induced modulation of gene expression in promotion.
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PMID:Poly ADP-ribosylation of histones in tumor promoter phorbol-12-myristate-13-acetate treated mouse embryo fibroblasts C3H10T1/2. 406 47

Poly(ADP-ribose) polymerases from Ehrlich ascites tumor cells, pig thymus, and HeLa S3 cells were purified by chromatography on DNA-agarose and Blue Sepharose. A molecular mass of 112000 Da was found for all three polymerases. Fragmentation of polyacrylamide-gel-embedded polymerases with cyanogen bromide, and subsequent analysis of the fragments by polyacrylamide gradient gel electrophoresis, showed great similarities with regard to fragment sizes. The amino acid composition of the pig thymus enzyme was very similar to that of the polymerase from Ehrlich ascites tumor cells, and the terminal amino group appeared to be blocked. The HeLa polymerase electrofocused in two peaks at pH 8.8 and 5.5, while the Ehrlich ascites tumor cells and the pig thymus enzyme focused in single peaks at pH 9.4 and 9.6 respectively. Removal of residual DNA by treatment with hydroxyapatite abolished these differences in apparent isoelectric points; all three polymerases focused at pH 9.8. No important differences were found with regard to the effect of a number of substances on the synthesis of poly(ADP-ribose). Apparent Michaelis constants for NAD of 41 microM, 48 microM, and 34 microM were found for polymerase from Ehrlich ascites tumor cells, pig thymus, and HeLa S3 cells, respectively. All these results indicate that the three polymerases, which represented the major poly(ADP-ribose) polymerase activity in the organisms investigated, are closely related proteins.
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PMID:A comparison of purified poly(ADP-ribose) polymerases from Ehrlich ascites tumor cells, pig thymus, and HeLa S3 cells. 628 Oct 3

Oncogenic transformation of hamster embryo cells and mouse C3H 10T1/2 can be modified by a variety of agents and conditions which alter events at early stages of initiation and at later stages of promotion. Inhibition of poly(ADP-ribose) synthesis by low concentrations of benzamide and 3-aminobenzamide inhibits the induction of transformation by ultraviolet light, X-rays, and chemical carcinogens as well as inhibiting the enhancement of transformation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The suppression of transformation by the benzamides is observed under conditions where the inhibitors reduce poly(ADP-polymerization) by about 75%, have no influence on damage induced by X-rays or alkylating chemicals and enhance sister chromatid exchanges. A modification of the physiological state of the cells by rendering them hypothyroid also results in an inhibition of transformation by radiation and chemical carcinogens and a suppression of promotion by teleocidin and TPA. When thyroid hormone is added to the medium radiogenic transformation and its dramatic enhancement by the tumor promoters is observed, with teleocidin being over 100 times as effective as a promotor as TPA. Our results suggest that mechanisms regulating initiation and promotion are associated with alterations in poly(ADP-ribosylation), causing changes in gene control and expression and may differ from those associated with the induction of sister chromatid exchanges. The results also suggest that genetic events taking place in both the early events (initiation) and late events (promotion) in malignant transformation are highly dependent on the presence of thyroid hormones.
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PMID:Critical biochemical and regulatory events in malignant transformation in vitro. 639 89

Three types of ADP-ribosyl proteins (poly(ADP-ribose) conjugates, NH2OH sensitive and NH2OH resistant mono(ADPR) conjugates) could be found in all eukaryotic cells so far studied. They changed independently under various conditions and showed an uneven subcellular distribution suggesting independent functions. Treatment of Ehrlich ascites tumor (EAT) cells with monofunctional or cross-linking alkylating agents led to rapid fragmentation of DNA and depletion of NAD while poly(ADPR) polymerase activity showed a retarded increase. Endogenous amounts of poly(ADPR) groups increased 4- to 30-fold, depending on dose, with the same initial kinetics as the loss of NAD and the appearance of DNA strand breaks. Turnover of poly(ADPR) was determined from the decay rate of the polymer after the addition of benzamide to alkylated cells. At peak elevation of poly(ADPR), an apparent half-life of about 1 min was obtained (control cells: t/2 much greater than 3 hr). There was also an accumulation of nuclear mono(ADPR) conjugates with a half-life of about 10 min. In contrast to in vitro experiments, histone H1 in vivo proved to be only a minor acceptor of ADPR groups in rat liver and in hepatoma cells. It carried less than 0.2% of total monomeric, and less than 2% of total polymeric ADPR residues. Alkylation of cells increased mono(ADP-ribosyl)ation of histone H1 to a much higher degree than poly(ADP-ribosyl)ation. Addition of benzamide to alkylated cells inhibited poly(ADPR) formation and NAD depletion, but interfered with neither DNA fragmentation nor with DNA resealing. Nevertheless, benzamide was a very effective co-cytostatic.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional aspects of mono- and poly(ADP-ribosyl)ation: subcellular distribution and ADP-ribosyl turnover under conditions of repair and 'starvation'. 665 28

Treatment of Ehrlich ascites tumor cells with the trifunctional alkylating agent 2,3-5-tris(ethyleneimino)benzoquinone-1,4 (triaziquonum) led to rapid fragmentation of DNA and depletion of NAD while poly(ADP-ribose) synthetase activity showed a retarded increase. Poly(ADP-ribosyl) residues in treated cells increased 4- to 30-fold, but transiently, and in a dose-dependent manner, exhibiting the same initial kinetics as the loss of NAD and the appearance of DNA strand breaks when determined by the nucleoid method. Although the amounts of "activated ADP-ribosyl" groups present in the substrate NAD (80 nmol/10(8) cells) exceeded by far basal and triaziquonum-induced poly(ADP-ribosyl) groups (up to 250 pmol/10(8) cells), accelerated formation of the polymer, nevertheless, may explain at least partially the loss of NAD seen under these conditions. Addition of benzamide, a potent inhibitor of poly(ADP-ribose) synthetase, to triaziquonum-treated cells effected an immediate drop of poly(ADP-ribose) to basal values. The data indicate a biphasic decay, the half-life of greater than 85% of the polymeric ADP-ribosyl groups exhibiting a t1/2 less than 1 min under these conditions, while the residual fraction died away with t1/2 approximately 6 min. Treatment with the DNA fragmenting agent also led to a 9-fold increase of nuclear mono(ADP-ribosyl) groups, while cytoplasmic mono(ADP-ribosyl) protein conjugates were not significantly affected. The apparent half-life of nuclear mono (ADP-ribosyl) protein conjugates (8-10 min) at peak elevation was definitely longer than that of poly(ADP-ribosyl) residues. This result is consistent with the interpretation that accumulation of mono(ADP-ribosyl) groups is due to a retarded removal of the primary ADP-ribosyl group from the acceptor protein by a separate mono(ADP-ribosyl) protein glycohydrolase, being the rate-limiting step in the overall turnover of poly(ADP-ribosyl) residues.
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PMID:DNA fragmentation and NAD depletion. Their relation to the turnover of endogenous mono(ADP-ribosyl) and poly(ADP-ribosyl) proteins. 681 30

Incubation of Ehrlich ascites tumor cells in their own ascites fluid induced a reversible metabolic adaptation to these "starvation" conditions which was associated with a fragmentation of DNA. Endogenous poly(ADP-ribose) residues also increased, reaching within 1-3 h values 6-10 times higher than in cells taken directly from the mouse peritoneum. The NAD content changed only slightly while dimethyl sulfate-induced accumulation of poly(ADP-ribose) (10-fold within 30 min) was associated with a rapid depletion of NAD (85% lost at 30 min). Nevertheless, turnover of poly(ADP-ribose) as measured by the decay rate of the polymer upon addition of benzamide was dramatically stimulated in both situations, reaching apparently identical half-lives (t 1/2 approximately equal to 1 min) in "starved" and in alkylated cells. However, since penetration of benzamide into the nucleus may be the rate-limiting factor in these studies, turnover of poly(ADP-ribose) in dimethyl sulfate-treated cells may still be much higher than that in "starved" cells. In cells treated with dimethyl sulfate, suppression of poly(ADP-ribose) synthesis by benzamide did not interfere with DNA fragmentation or with DNA resealing as determined by the nucleoid procedure. By contrast, starvation induced a type of DNA incision that was prevented by benzamide. It is proposed that starvation-induced scission of DNA occurs at specific ("regulatory?") sites requiring poly(ADP-ribose) formation to take place, while fragmentation of DNA at random as seen with alkylating agents is associated with, but not dependent on, increased poly(ADP-ribosyl)ation.
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PMID:Stimulation of poly(ADP-ribosyl)ation during Ehrlich ascites tumor cell "starvation" and suppression of concomitant DNA fragmentation by benzamide. 683 44

The amount of elongation factor 2 (EF-2) associated with different ribosomal fractions (mono- and polyribosomes) isolated from a methylcholanthrene-induced sarcoma is estimated during tumor growth (exponential and plateau phase of growth). Direct EF-2 quantification is obtained by a modification of the method of the diphtheria toxin-catalyzed transfer of (14C)ADP-ribose from (14C)NAD+ to the enzyme. Data reported show that the amount of EF-2 associated with the monoribosomal fraction changes during tumor growth, and particularly, that this amount increases when the tumor cells enter into the plateau phase. In contrast, the EF-2 content of the polyribosomal fraction does not change during the different phases of tumor growth. Data also show that the amount of EF-2 bound to the monoribosomal fraction isolated from tumor cells is significantly and constantly lower than that of the corresponding fraction isolated from reticulocytes or hepatocytes. Moreover the tumor monoribosomes generated by the polyribosome breakdown induced by the "starvation" procedure did not show significant changes in their EF-2 content with respect to monoribosomes isolated from tumor cells maintained in physiological conditions. Besides, tumor monoribosomes generated by the polyribosome breakdown induced by puromycin or by running-off treatment exhibit a relevant increase of the EF-2 content. In these conditions the amount of EF-2 associated with the monoribosomes is similar to that associated with the monoribosomes of control cells (hepatocytes and reticulocytes). Results are discussed in view of a possible regulative role of the EF-2 enzyme in the ribosomal cycle of eukaryotic cells.
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PMID:Association of elongation factor 2 with ribosomes during growth of a murine ascitic tumor. 685 May 53

5'-AMP antigens were synthesized by conjugation of N6-carboxymethyl-5'-AMP (Cm65'-AMP) to native or methylated serum albumin. Injection of the antigens resulted in antibodies with high affinity and specificity for 5'-AMP in all animals, thus allowing discrimination against 3'(2')-AMP even when present at 10(4)-10(5) times higher concentrations. This specificity was comparable to that of anti 5'-AMP antibodies raised against Cm65'-AMP serum albumin antigens formed in situ from Cm6ADP-ribose serum albumin conjugates by intracellular or pericellular phosphodiesterases. The hapten in the Cm65'-AMP-methylated serum albumin conjugate appeared to be bound almost exclusively via the N6-position. Due to the free exposure of the 5'-phosphate group in this antigen, the resulting antibodies discriminated 5'-AMP derivatives substituted at the phosphate group more efficiently than derivatives with modifications in the adenine ring. It also led to the concomitant formation of adenosine-specific antibodies due presumably to dephosphorylation of the antigen by phosphatases present in the recipient animals. The conjugates formed from Cm65'-AMP and native serum albumin, which appeared to be linked to a large extent via carboxyl groups of the protein and hydroxyl groups of the ribose, recognized modifications in the adenine ring much better than substitutions at the phosphate group. However, in spite of these relatively small differences in specificity, all three types of antibodies could be used successfully to quantitate by radioimmunoassay protein-bound ADP-ribose in adult rat liver and NAD+-NADH in Ehrlich ascites tumor cells as shown by the excellent agreement of the values obtained with the three antisera.
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PMID:Determination of 5-AMP in the presence of excess 3'(2')-AMP with the aid of antibodies raised against n6-carboxymethyl-5'-AMP conjugates. Use for the quantitation of pyridine nucleotides and of protein-bound ADP-ribose. 721 30


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