Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sulfate substitutes for phosphate in the transitory uncoupling of rat liver mitochondria induced by hydrazine when beta-hydroxybutyrate is the substrate. A high level of sulfate in the absence of added phosphate induces a pseudo state three of the mitochondria. Uncoupling is inhibited by rutamycin. Thus sulfate is activated by the mechanism usually utilized by phosphate, and the target for hydrazine is the bond holding electrophilic sulfate. ATP, ADP, PPi, and Mg++ protect against hydrazine, presumably by causing a conformational change of the phosphorylating enzymes which participate in oxidative phosphorylation. Arsenate also could substitute for phosphate in the transitory uncoupling induced by hydrazine. Uncoupling is again inhibited by rutamycin; thus arsenate is also activated by the enzymic mechanism usually utilized by phosphate. Since sulfate is known to enhance the carcinogenicity of certain carcinogens, these results expand the experimental confluence between oxidative phosphorylation and chemical carcinogenesis and also serve to explain at least in part the "toxic" effects of sulfate. Because of the analogous results with arsenate and sulfate, it is suggested that arsenate, like sulfate, may enhance the carcinogenicity of other carcinogens. The data are compatible with epidemiological studies which implicate some role in carcinogenesis for sulfate (often measured as a sulfur dioxide equivalent) and arsenate.
 ...
PMID:The mitochondrial activation of sulfate and arsenate and their role in carcinogenesis. 42 26

Promotion of 'initiated' JB6 epidermal cells to the tumor phenotype can be effected by 12-O-tetradecanoylphorbol-13-acetate treatment, by stimulation of epidermal growth factor (EGF) receptor activity with EGF or transforming growth factor alpha and by exposure to the isoquinoline derivative H7. When these cells were incubated with pertussis toxin (PTX), induction of anchorage-independent growth by all four promoting substances was suppressed. The inhibition is specific since cell proliferation is not affected, suggesting that activation of a Gi protein is essential for promotion of the epidermal cells. This interpretation is strongly supported by the observation that the wasp poison mastoparan, which is known to mimic receptor-mediated activation of certain Gi proteins, also promoted anchorage independence. Immunological data and partial amino acid sequence analysis of ADP-ribosyl alpha i isolated from PTX-treated JB6 cells indicate that a Gi-2 protein is a mediator to tumor promotion in this system. The inhibitory action of 4-bromophenacyl bromide may point to a coupling of the Gi protein to phospholipase A2. From our data we infer that promoters induce the tumor phenotype in 'initiated' JB6 epidermal cells by activating epigenetically the same Gi protein that in a number of adrenal and ovarian tumors appears to be persistently activated by mutational events.
Carcinogenesis 1992 Dec
PMID:Epigenetic activation of Gi-2 protein, the product of a putative protooncogene, mediates tumor promotion in vitro. 147 50

In previous studies we demonstrated that liver poly(ADP ribose) polymerase (pADPRP) activity was lost in animals exposed to N-2-acetylaminofluorene (2AAF) according to the Teebor and Becker experimental model (Cancer Res 31:1-3, 1971). In addition, we used the resistant hepatocyte model of Solt and Farber (Nature 263:702-703, 1976) to further investigate pADPRP activity during the multistep process of liver carcinogenesis. A marked depletion of the catalytic protein was evidenced after 2AAF exposure, confirming previous results and indicating a specific effect of 2AAF on this nuclear enzyme that controls conformational changes of chromatin and regulates several catalytic activities in the nucleus. The levels of pADPRP mRNA, measured by northern blot analysis using both experimental models, indicate that the enzyme depletion is not due to a loss of transcript. Moreover, these data indicate that pADPRP depletion, caused by 2AAF, was also maintained during liver compensatory growth, which is known to induce a rapid and marked increase in pADPRP activity and protein level. Treatment of 2AAF-exposed animals with N-acetyl-L-cysteine not only efficiently protected against DNA damage, but also prevented a rapid depletion of the catalytic protein. Interestingly, these data indicate that the marked loss of liver pADPRP occurred during the promotion step induced by 2AAF feeding and that this loss was observed using different models for experimental hepatocarcinogenesis. This phenomenon can be ascribed to a highly defective transcript that cannot be correctly translated into the specific protein or to a rapid degradation of the translated protein.
 ...
PMID:Influence of poly(ADP ribose) polymerase depletion on promotion of liver carcinogenesis. 155 9

Okadaic acid (OA) is a specific and strong inhibitor of protein phosphatases 1 and 2A present in eukaryotes, and a potent promoter of carcinogenesis in mouse skin. In this study, we examined the mutagenicity of OA. OA did not induce mutations in S. typhimurium TA100 and TA98, with or without a microsomal metabolic activation system. However, it was strongly mutagenic to Chinese hamster lung (CHL) cells without a microsomal activation system, as shown using diphtheria toxin (DT) resistance (DTr) as a selective marker. Treatment of CHL cells with OA at 17.5 ng/ml induced 164 DTr mutants per 10(6) survivors. A plot of the mutation frequency against the OA concentration gave a concave curve, and the mutant frequency was calculated to be 5500/10(6) survivors/micrograms, with OA in the dose range of 10-15 ng/ml. This value was about 680 times that of ethyl methanesulfonate (EMS), and comparable to that of 2-amino-N6-hydroxyadenine, one of the strongest known mutagens. Elongation factor 2 (EF-2) obtained from 4 DTr clones was not ADP-ribosylated by DT fragment A. PCR-direct sequencing revealed that the hot spot of EF-2 for EMS mutagenesis in CHO-K1 cells, the first letter of codon 717, was not a hot spot for OA mutagenesis in CHL cells.
 ...
PMID:Mutation induction by okadaic acid, a protein phosphatase inhibitor, in CHL cells, but not in S. typhimurium. 165 41

Effects of 3-aminobenzamide (ABA) on pancreatic carcinogenesis after initiation by N-nitrosobis(2-oxopropyl)amine (BOP) were investigated in Syrian hamsters. Animals were given BOP at a dose of 70 mg/kg body weight by subcutaneous injection and following a 2-week recovery period, were administered basal diet or basal diet containing 0.5, 0.75 and 1.5% ABA for 30 weeks. While the incidences of resultant pancreatic lesions, including hyperplasia, atypical hyperplasia and carcinoma, induced by BOP were not significantly influenced by ABA treatment, the mean numbers of those pancreatic lesions were significantly decreased in a dose-dependent way. The results therefore suggested the possible involvement of poly(ADP-ribosyl)ation in the post-initiation phase of pancreatic carcinogenesis in hamsters.
 ...
PMID:Effects of 3-aminobenzamide on the post-initiation phase of N-nitrosobis(2-oxopropyl)amine induced pancreatic carcinogenesis in Syrian hamsters. 176 98

Poly(ADP-ribose) is a naturally occurring nuclear macromolecule resembling nucleic acids. It is synthesized from NAD+ on histones and a few other nuclear proteins. Its function, although not completely understood, might be to alter chromatin structure and to regulate the activity of proteins involved in the metabolism of DNA strand breaks such as ligase II, and topoisomerase I. In addition, poly(ADP-ribose) modifies proteins involved in gene expression such as acetylated histones. HMG proteins, and T antigen. The enzyme poly(ADP-ribose) polymerase responsible for this modification has the unique property of requiring nicks or free ends on the DNA for its activity and of being automodified. The automodified enzyme, presumably found at the vicinity of DNA strand breaks at damaged chromatin sites, could remove histones from DNA and attract enzymes that have an affinity for poly(ADP-ribose) such as ligase II or poly(ADP-ribose) glycohydrolase, the polymer-degrading enzyme. Alterations in chromatin structure alter gene expression and seem to be involved in repair, replication, and recombination and in changing DNA superhelical density, intermediate steps in molecular carcinogenesis. Experiments with cells in culture and laboratory animals show that inhibition of poly(ADP-ribosylation) alters transformation and tumorigenicity brought about by a great number of carcinogenic agents. Cancer can be caused by the accumulation of unrepaired DNA strand breaks in the cell accelerating gene rearrangements, deletions, insertions and amplifications. Repair of DNA strand breaks shows an absolute dependence upon the rapid synthesis and degradation of poly(ADP-ribose). The polymer has a very short half life indeed. Data are reviewed on changes in chromatin structure and function caused by histone and nonhistone poly(ADP-ribosylation). The link of this modification to transformation, tumorigenesis, development, replication and gene expression is examined. A model is proposed to explain the effect of poly(ADP-ribosylation) on chromatin structure at the molecular level. Mono- and oligo(ADP-ribosylated) histones present in nuclei under physiological conditions are proposed to functions, like acetylated histones, in maintaining chromatin loops into transcriptionally active structures. On the other hand, poly(ADP-ribosylated) histones and poly(ADP-ribosylated) enzymes such as DNA and RNA polymerases, suggested to be modified from in vitro studies, might only appear in cells that have been heavily damaged by carcinogen. Their function might be to remove histones from DNA in order to facilitate repair and to shut down transcription and replication.
 ...
PMID:Relation between carcinogenesis, chromatin structure and poly(ADP-ribosylation) (review). 190

Damage of 3T3 fibroblasts as induced by short-term co-cultivation with O2(-)-producing granulocytes, stimulated by 12-O-tetradecanoyl-phorbol-13-acetate (TPA), was compared with that induced by treatment with enzymically generated O2- and with the alkylating agent dimethyl sulfate. The action of stimulated granulocytes was different in several aspects: (a) DNA fragmented by the products of TPA-stimulated granulocytes showed a biphasic alkaline elution pattern while fragmentation induced by alkylation or by enzymically produced O2- was monophasic. (b) Poly(ADP-ribosyl)ation of nuclear proteins after treatment with TPA-stimulated granulocytes exhibited a lag phase and was, in most experiments, less pronounced than after equitoxic dimethyl sulfate treatment. (c) 3-Aminobenzamide, the most widely used inhibitor of ADP-ribosylation, partially protected target cells from the cytotoxic effects of TPA-stimulated granulocytes, while it enhanced alkylation-induced and O2(-)-induced cytotoxicity. Protection by 3-aminobenzamide in the granulocyte system was apparently not mediated by an inhibition of nuclear poly(ADP-ribosyl)ation. Other inhibitors, like benzamide and nicotinamide, augmented cytotoxicity of TPA-stimulated granulocytes. The unique effect of 3-aminobenzamide in this system appeared to relate to TPA-induced adhesion of the neutrophils to surfaces. In the presence of 1 mM 3-aminobenzamide, but not of benzamide, the adhesion of stimulated granulocytes to 3T3 monolayer cultures was markedly reduced or even abolished. This effect was also seen in granulocyte preparations depleted of monocytes. Since 3-aminobenzamide at the doses applied does not inhibit TPA-induced superoxide production in isolated granulocytes, its specific anticytotoxic effect appears to result from a 'dilution' of granulocyte-derived damaging agents into the medium. Our data suggest that prevention of granulocyte adhesion is likely to reduce tissue damage and carcinogenesis in areas of chronic inflammation.
 ...
PMID:3-Aminobenzamide inhibits cytotoxicity and adhesion of phorbol-ester-stimulated granulocytes to fibroblast monolayer cultures. 201 15

The prevention of cancer by agents in our diet has led to the concept that oxygen radicals are a necessary component of a variety of human cancers including breast, colon and prostatic cancer. These cancers are putatively promoted by estradiol, bile acids and androgens. Epidemiological studies have shown that these cancers are suppressed in vegetarian populations. Vegetable components that may be responsible for this cancer prevention are Vitamin A, retinoids and protease inhibitors (PIs). These agents have been shown to suppress the formation of hydrogen peroxide in promoter-induced neutrophils. They also have been shown to block two-stage carcinogenesis and breast cancer when fed to animals. PIs also suppress experimentally-induced colon cancer and spontaneous liver cancer. Moreover, a new series of cancer-preventive agents, Sarcophytols (isolated by Fujiki and co-workers), are capable of suppressing two-stage carcinogenesis, breast and colon cancers in rodents when given in low concentrations. Sarcophytols were also active suppressors of H2O2 formation of 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced neutrophils. These observations point to an essential role of oxygen radicals in carcinogenesis. Suppression of the oxygen radical response of neutrophils in relation to cancer preventive agents is a facile assay of these important substances. The mechanism of action of oxygen radicals in promoting carcinogenesis is a multiple one, including: (1) activation of oncogenes, (2) modification of DNA bases, and (3) formation of single-strand breaks leading to poly(ADP)ribose polymerase activation.
 ...
PMID:Prevention of cancer by agents that suppress oxygen radical formation. 206 Aug 47

The catalytic activity of the nuclear enzyme poly(ADP-ribose) polymerase (NAD+ ADP-ribosyl transferase, EC 2,4,2,30) is totally dependent upon the presence of DNA strand breaks. Having isolated a full-length cDNA for the polymerase, we have now evaluated the effect of endogenously and exogenously induced DNA strand breaks on the transcriptional control of this enzyme. During retinoic acid or dimethyl-sulfoxide-induced differentiation of HL-60 human leukemia cells, which may involve DNA breaks as well as other changes in chromatin, mRNA levels for the polymerase increased very early and remained high for up to 48 h after which it decreased to pre-induced levels. Polymerase transcript levels did not change, however, during the induction of DNA strand breaks by dimethylsulfate, a variety of other alkylating agents, X-irradiation, or UV-irradiation in several mammalian cell lines. It appears that in sharp contrast to the catalytic requirement of the polymerase, the induction of transcription of the polymerase gene may not be a strand-break-dependent process. The noninducibility of the polymerase gene following DNA damage suggested that there may be adequate levels of the polymerase in the cells to cope with DNA damage. To test this hypothesis we examined the efficacy of DNA repair in Cos cells engineered to overexpress the polymerase. Although there was a slight augmentation of the repair rate, this increase was apparent only after very high levels of DNA damage and only at early repair times. After a longer repair period, the extent of repair in control cell was similar to that in the cell overexpressing the polymerase. We thus conclude that the basal levels of the polymerase are adequate for significant amounts of DNA damage.
Carcinogenesis 1990 Jan
PMID:Expression of the poly(ADP-ribose) polymerase gene following natural and induced DNA strand breakage and effect of hyperexpression on DNA repair. 210 80

The effects of inhibitors of poly(ADP-ribose)polymerase, 3-aminobenzamide (ABA), luminol and 3-methoxybenzamide (MBA) on the rat liver tumor promotion activity of phenobarbital (PB) were assessed. Fischer 344 male rats were initiated with N-nitrosodiethylamine (200 mg/kg) and placed on either basal diet, diet containing 0.05% PB, diet containing various doses of the inhibitors alone or diet containing 0.05% PB plus various doses of inhibitors for 10 weeks, and then killed. Quantitation of the development of glutathione S-transferase placental form-positive foci revealed that ABA at doses of 2 and 1.5, but not 1%, significantly inhibited the PB promotion activity. Luminol dose-dependently reduced PB promotion at doses of 3 and 6% but exerted no effects at the 1 and 2% levels. MBA also demonstrated a dose-dependent inhibitory influence at doses of 1 and 2%. The results are thus strongly suggestive of an involvement of poly ADP-ribosylation in the mechanisms underlying liver tumor promotion by PB.
Carcinogenesis 1990 Oct
PMID:Possible involvement of poly ADP-ribosylation in phenobarbital promotion of rat hepatocarcinogenesis. 211 7


1 2 3 4 5 6 7 8 9 10 Next >>