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

The principal target amino acid residue for covalent binding of metabolically activated [3H]benzo[a]pyrene (B[a]P) to histone 1 (H1) has been identified. Highly purified calf thymus H1 was modified by incubation with [3H]B[a]P in the presence of rat liver microsomes. The relative distribution of [3H]B[a]P versus specific amino acids among the N-bromo-succinimide peptides of H1 suggested that lysine may be the target. This was tested by selectively blocking the nucleophilic amino groups of lysine by amidination prior to [3H]B[a]P binding. Increasing levels of amidination of H1 resulted in corresponding decreases in the reactivity of this histone toward [3H]B[a]P. Amidination of 93% of the lysines blocked 87% of the [3H]B[a]P binding indicating that lysine was the principal target. N-terminal amino acid sequencing of [3H]B[a]P-modified H1 confirmed that lysine residues had bound [3H]B[a]P.
Carcinogenesis 1982
PMID:Lysines of histone 1 represent the principal target for covalent binding of microsomally activated benzo[a]pyrene in vitro. 681 81

Dimethylnitrosamine given after partial hepatectomy reduces the synthesis of DNA, histone, and, to a lesser extent, of nonhistone proteins, the inhibition being general rather than for specific nuclear proteins. The extent of inhibition of macromolecular synthesis is greatest when the carcinogen is given a few hours after the operation. As a higher incidence of hepatocellular carcinoma is induced when dimethylnitrosamine is injected later, during the wave of DNA replication, it appears that inhibition of nuclear protein synthesis is not a relevant factor in carcinogenesis, unless it relates to loss of a specific non-histone protein present in small amounts. Analysis of sequentially extracted groups of non-histone proteins by 2D electrophoresis did not reveal any changes produced by treatment with dimethylnitrosamine. Animals fed a diet containing diethylnitrosamine showed an increased incorporation of amino acid into histone. Electrophoretic analysis of non-histone proteins revealed two reproducible effects of feeding the carcinogenic diet: relative to the bulk of nuclear non-histone protein, there was a reduction in the amount of a slightly basic 65000 mol. wt. polypeptide, and an increase in the level of a high molecular weight protein that was almost undetectable in material from normal rats. As these changes were not induced by partial hepatectomy of normal animals, it is possible that they are related to malignancy rather than to the associated increase in cell replication.
Carcinogenesis 1983 Sep
PMID:The behaviour of nuclear proteins during nitrosamine-induced carcinogenesis. 688 31

Nuclear protein methylation was studied in regenerating rat liver by giving [methyl-3H]methionine 45 h after partial hepatectomy. Ethionine, a liver carcinogen, has been shown to alter the methylation patterns in a basic protein (histone) fraction, as well as an acidic protein (non-histone) fraction present in a 0.25 N HCl nuclear extraction. The proteins present in the 0.25 N HCl extraction were separated by chromatography using a Bio-Rex 70 cation exchange column. Polyacrylamide gel electrophoresis and total amino acid analysis showed the first protein fraction contained acidic large molecular weight non-histone proteins, while the second fraction contained basic small molecular weight histone proteins. Both fractions were then hydrolyzed, and the amino acids chromatographed on an Aminex A-5 cation exchange column. The histones were found to contain epsilon-N-mono, di and trimethyllysine derivatives; whereas the non-histone fraction contained these lysine derivatives and additional basic amino acid identified as NG,NG-dimethylarginine. Ethionine (0.5 mg/g body weight) was found to inhibit in vivo methylation of lysine to form epsilon-N-mono, di and trimethyllysine, 46, 52 and 68%, respectively. The formation of NG,NG-dimethylarginine was inhibited by 85%. Ethylation of these proteins was also studied by giving [ethyl-3H]ethionine. After hydrolysis, the non-histones were found to contain a labeled lysine and arginine derivative, but in the histone fraction only labeled lysine was found.
Carcinogenesis 1982
PMID:Ethionine inhibits in vivo methylation of nuclear proteins. 709 6

The interaction of aflatoxin B2 (AFB2) in vivo with rat liver nuclear macromolecules was examined in an attempt to correlate this binding with biological potency. The incorporation of [3H]AFB2 residues into rat liver histones and DNA was determined 2, 24 and 48 h following administration of a single i.p. dose of 1 mg [3H]AFB2/kg body weight. At each time point, histone H1 and the total histone fraction contained 5--30-fold more [3H]AFB2 moieties than did DNA on a weight basis. Analytical reversed-phase h.p.l.c. of the acid hydrolysis products resulting from AFB2 binding to DNA revealed that 85% of the radioactivity co-chromatographed with the major aflatoxin B1-DNA adduct, 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1. These studies revealed an apparent correlation between AFB2 derived binding to DNA in vivo in rats and its potency as a toxin and carcinogen in this species.
Carcinogenesis 1981
PMID:Interaction of aflatoxin B2 with rat liver DNA and histones in vivo. 732 36

Nickel(II) compounds are established human carcinogens, but the molecular mechanisms underlying their activity are only partially known. One mechanism may include mediation by nickel of promutagenic oxidative DNA damage that depends on Ni(II) binding to chromatin. To characterize such binding at the histone moiety of chromatin, we synthesized the peptide CH3CO-Cys-Ala-Ile-His-NH2 (L), a model of the evolutionarily conserved motif in histone H3 with expected affinity for transition metals, and evaluated its reactivity toward Ni(II). Combined spectroscopic (UV/vis, CD, NMR) and potentiometric measurements showed that, at physiological pH, mixtures of Ni(II) and L yielded unusual macrochelate complexes, NiL and NiL2, in which the metal cation was bound through Cys and His side chains in a square-planar arrangement. Above pH 9, a NiH-3L complex was formed, structurally analogous to typical square-planar nickel complexes. These complexes are expected to catalyze oxidation reactions, and therefore, coordination of Ni(II) by the L motif in core histone H3 may be a key event in oxidative DNA base damage observed in the process of Ni(II)-induced carcinogenesis.
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PMID:Interactions of nickel(II) with histones. Stability and solution structure of complexes with CH3CO-Cys-Ala-Ile-His-NH2, a putative metal binding sequence of histone H3. 754 50

DNA damage is an important effect of treatment of cells and organisms with chemical carcinogens. Although much has been learned from in vitro studies of the reaction of carcinogens with purified DNA, in vivo the DNA is associated with a variety of histone and non-histone proteins in a complex and dynamic structure known as chromatin. The covalent interactions of bulky chemical carcinogens with chromatin are reviewed. Differences from bulk genomic DNA in adduct density are found in replicating, transcribing and nuclear matrix-bound DNA regions, and between DNA in nucleosome cores and linker DNA regions. These differences range from 2- to 3-fold for linker versus core, to approximately 8-fold close to a replication fork. Much remains to be done to determine the influences of non-histone proteins and higher order chromatin structure on carcinogen binding.
Carcinogenesis 1995 Sep
PMID:Interaction of bulky chemical carcinogens with DNA in chromatin. 755 47

In this report the effects of single doses of ionizing radiation on the mRNA expression of several proteins involved in multiple drug resistance were analyzed. Murine NIH 3T3 cells treated with single doses of 5, 10 and 20 Gy during the time interval from 1.5 to 72 h after irradiation were compared with their corresponding controls at the same points of time. The glutathione S-transferase-pi (GST pi) level was elevated in cells treated with 10 or 20 Gy from 24 to 72 h after irradiation compared with the control. Topoisomerase II alpha and thymidylate synthase were decreased in irradiated cells 24-72 h after exposure. These down-regulations were associated with cellular proliferation, determined by mRNA expression of the proliferation marker histone 3. Irradiated cells exhibited no alteration in the P-glycoprotein or glutathione peroxidase mRNA content. The finding that GST pi mRNA was overexpressed after irradiation was validated by investigations on a human lung carcinoma cell line (LXF 289) on the mRNA and protein level. Thus, our results indicate that irradiation alters the expression of proteins involved in multidrug resistance and may, therefore, play a role in clinical drug response.
Carcinogenesis 1995 Sep
PMID:Effects of single doses of irradiation on the expression of resistance-related proteins in murine NIH 3T3 and human lung carcinoma cells. 755 53

Short-chain fatty acids (SCFAs: acetate, propionate, n-butyrate) arising in the large bowel during bacterial fermentation of dietary fibre and starch have paradoxical effects on colonic epithelial proliferation. While the three major SCFAs stimulate proliferation of normal crypt cells, n-butyrate and, to a lesser degree, propionate inhibit growth of colon cancer cell lines. At the molecular level, n-butyrate causes histone acetylation, favours differentiation, induces apoptosis and regulates the expression of various oncogenes. To understand the complex effects of SCFAs on carcinogenesis, it is important to study the intermediate stages of the adenoma-carcinoma sequence where a "switch" from stimulation to suppression of cell proliferation must occur.
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PMID:Role of short-chain fatty acids in the prevention of colorectal cancer. 757 95

Nuclear organizer regions (NORs) code for ribosomal RNA and are associated with non-histone nucleoproteins, which can be identified by silver staining (AgNORs). AgNORs have been correlated to proliferative activity of tumors and hence may be prognosis-related. The present study evaluates AgNOR counts in inflammatory lesions of the uterine cervix, cervical intra-epithelial neoplasia, and invasive cervical squamous carcinoma. Significant variation in AgNOR counts were observed between the three study groups, with invasive carcinoma showing maximum counts. Further, a highly significant positive correlation was observed between AgNOR counts and tumor progression. These results therefore suggest that AgNOR counts may be of significance in the evaluation of cervical carcinogenesis and could elaborate histopathological diagnosis of cervical lesions.
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PMID:Argyrophilic nucleolar organizer regions (AgNORs) in inflammatory pre-malignant and malignant lesions of the uterine cervix. 836 93

The involvement of ADP-ribosylation has been investigated by comparing the extent of ADP-ribosylation in two different stages of oral cancer with that of the corresponding normal oral tissue. Poly(ADP-ribose) synthetase(PADPRS), the enzyme that is responsible for this type of posttranslational covalent modification, was assayed first by measuring 14C-ADP-ribose incorporation into different acceptor proteins of the tissue homogenate. The results clearly indicate an increase in PADPRS activity during oral carcinogenesis. After observing this increased pattern in total tissue, further experiments were conducted to check the extent of ADP-ribosylation in purified nuclei. The data of this experiment also indicates a progressive increase in the extent of ADP-ribosylation with increase in malignancy of oral tissue. Further analysis of an ADP-ribosylation of chromosomal proteins indicates that the increased pattern of ADP-ribosylation is mainly attributed to histones and not to non-histone chromosomal proteins. Our investigation suggests that ADP-ribosylation may play a role in oral cancer and may be used as a potential tumour marker.
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PMID:Increased ADP-ribosylation of histones in oral cancer. 840 95


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