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

The complement of nuclear non-histone proteins in epithelial cells of the colon is progressively altered during the course of carcinogenesis induced by 1, 2-dimethylhydrazine, until finally the nuclear proteins of tumor cells are easily distinguishable from those of the surrounding normal tissue. These changes in nuclear protein compostion reflect earlier differences in the rates of synthesis of individual protein species. Radioisotopic double-labeling experiments show that the synthesis of nuclear proteins of molecular weights 44,000 and 62,000 is selectively accelerated within 4 weeks after administration of the carcinogen, long before any morphological indications of malignancy appear.
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PMID:Selective synthesis and accumulation of nuclear non-histone proteins during carcinogenesis of the colon induced by 1, 2-dimethylhydrazine. 121 54

To determine the mechanisms of cell signalling by asbestos in epithelial cells of the respiratory tract, the activity of protein kinase C (PKC) was examined in hamster tracheal epithelial (HTE) cells exposed to mitogenic concentrations of crocidolite asbestos. In the histone phosphorylation assay, asbestos significantly increased activity of PKC associated with the membrane fraction of HTE cells. However, in contrast to 12-O-tetradecanoylphorbol-13-acetate, which caused redistribution of almost all PKC activity from the cytosolic to the membrane fraction, the majority of the PKC activity was associated with the cytosolic fraction at all time periods examined. Asbestos did not inhibit binding of [3H]phorbol-12,13-dibutyrate to intact HTE cells, whereas binding was inhibited by the phorbol compounds phorbol dibutyrate and phorbol dibenzoate. Thus, crocidolite-induced activation of PKC does not appear to be mediated through the same mechanism as classical phorbol ester tumor promoters, compounds which activate PKC by structurally resembling diacylglycerol.
Carcinogenesis 1991 Aug
PMID:Activation of protein kinase C by crocidolite asbestos in hamster tracheal epithelial cells. 165 Feb 93

Previously we have described polyclonal antibodies that recognized a group of nuclear nonhistone proteins whose molecular weights ranged in size from 170 to 220 kDa. These antigenic nonhistone chromosomal proteins are abundant in rat hepatoma chromatin. In this report we discuss the synthesis and cellular localization of these particular proteins during the multistage process of hepatocarcinogenesis. The appearance of these antigenic proteins in rat liver nuclei approximately parallels the appearance of alpha-fetoprotein in the cytosol of hepatocytes. However, the immunoreactivity of antigenic proteins increased steadily even during the prominent dip in the AFP concentration between 50 and 100 days of carcinogenesis. The effect of the tumor promoting agent, phenobarbital, on the synthesis of antigenic nuclear proteins was also studied. The appearance of hepatoma-associated non-histone chromosomal proteins at early stages of tumor promotion during hepatocarcinogenesis was observed. The results of these studies demonstrate that the hepatoma-associated non-histone proteins are expressed not only in hepatoma cells, but also in hepatocyte cells committed to carcinogenesis.
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PMID:The appearance of hepatoma-associated chromosomal non-histone proteins in rat liver after a single dose of 3'-MDAB followed by treatment of phenobarbital. 169 44

To additionally understand the molecular mechanisms and biologic indicators of colonic tumorigenesis through the adenoma-carcinoma sequence, protein kinase C (PKC) activity was examined in the cytosol and particulate fraction of specimen homogenates from 18 human colonic carcinomas and seven coexisting colonic adenomas and was compared with the adjacent normal mucosal tissues. This study showed that PKC activity could be detected precisely using mini DEAE-Sephacel column purification and histone III-S as a substrate. The PKC activity in both colonic adenoma and carcinoma progressively was reduced in the particulate fraction compared with that of the adjacent normal mucosa from each patient (74.9 +/- 11.3 and 42.4 +/- 9.37 versus 112 +/- 16.8 pmol/min/mg, P less than 0.001), although PKC activity in the cytosolic fraction was not significantly different (62.6 +/- 17.7 and 63.1 +/- 8.08 versus 56.4 +/- 7.32 pmol/min/mg) with respect to protein concentration. Both colonic adenomas and carcinomas showed a significant progressive decrease in total particulate PKC activity compared with the adjacent normal mucosa of each patient (13.5 +/- 2.18 and 7.64 +/- 1.35 versus 19.8 +/- 2.74 pmol/min/g tissue, P less than 0.001) and no difference in total cytosolic PKC activity (15.2 +/- 3.80 and 16.5 +/- 2.02 versus 14.6 +/- 1.81 pmol/min/g tissue). Among PKC activities in carcinomas, there was no difference related to histologic type, Dukes' staging, or carcinoembryonic antigen values. Among PKC activities in colonic adenomas, a significant decrease in particulate PKC correlated with size. The specific PKC activity in the particulate fraction decreased with advancing adenoma size (P less than 0.05). This study showed that colonic carcinogenesis might be associated with alterations in cellular levels of PKC activity and that the decrease in particulate PKC activity in the adenoma had a possible correlation with adenoma size.
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PMID:Protein kinase C activity in human colonic adenoma and colorectal carcinoma. 172 70

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.
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PMID:Relation between carcinogenesis, chromatin structure and poly(ADP-ribosylation) (review). 190

In two-stage mouse skin carcinogenesis initiated by 7,12-dimethylbenz[alpha]anthracene (DMBA), cepharanthine inhibited the tumor promoting activity of 12-O-tetradecanoyl phorbol-13-acetate (TPA). Since Ca2(+)-phospholipid-dependent protein kinase (PKC) was shown to be an intracellular target of TPA, effects of cepharanthine on the activity of this enzyme were investigated Cepharanthine also inhibited the phosphorylation of H1 histone by PKC in a concentration dependent manner. While cepharanthine inhibited the association of H1 histone with phospholipid vesicles, autophosphorylation of PKC was not inhibited by this drug. Cepharanthine also inhibited TPA-stimulated phosphorylation of some cytoplasmic proteins of mouse skin epidermis. These results indicated the possibility that anti-tumor promoting action of cepharanthine was the result of inhibition of PKC dependent cytoplasmic protein phosphorylation through the reduction of the interaction of these proteins with the plasma membrane.
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PMID:Inhibition of 12-O-tetradecanoyl phorbol-13-acetate promoted tumorigenesis by cepharanthine, a biscoclaurine alkaloid, in relation to the inhibitory effect on protein kinase C. 198 45

Rat liver nuclei or hepatocytes were incubated with the procarcinogen benzo[a]pyrene (B[a]P) and its ultimate carcinogen, anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE). When nuclei were fractionated by mild micrococcal nuclease digestion into different chromatin regions to determine the distribution of covalent binding to proteins, there was a much higher level of B[a]P bound to proteins of the non-released fraction than to those of released mono- and oligonucleosomes. When non-released material was further fractionated with 2 M NaCl, the highest level of B[a]P binding was found in the proteins of the salt-insoluble fraction. Electrophoretic analysis of [3H]B[a]P-modified nuclear proteins revealed radioactive species migrating in the regions of histones H1 and H3, high mobility group (HMG) proteins 1 and 2, and various high mol. wt non-histone proteins. The non-released fraction contained prominent B[a]P-modified species migrating in the position of the lamins, major components of the nuclear matrix. To confirm B[a]P modification of nuclear matrix proteins, following exposure to B[a]P or BPDE, nuclei were fractionated by a different procedure into an active chromatin fraction, a bulk chromatin fraction, a high-salt-extracted chromatin fraction and a nuclear matrix fraction. Proteins of the nuclear matrix bound consistently more B[a]P metabolites than those of bulk chromatin. This was true following exposure to B[a]P or both low and high concentrations of BPDE, in contrast to previous data on damage to nuclear matrix DNA. Proteins of active chromatin bound more carcinogen than bulk chromatin proteins at low concentrations of BPDE, but less than bulk chromatin at higher concentrations, in parallel with previous data on DNA damage in active chromatin. The potential significance of B[a]P binding to nuclear matrix proteins is discussed.
Carcinogenesis 1991 Mar
PMID:Preferential binding of the carcinogen benzo[a]pyrene to proteins of the nuclear matrix. 200 93

The analysis has been made of the literary and the author's own experimental evidences on the antigenic diversion of tumor cells resulting from the expression of hetero-organic antigens, which is one of the most characteristic manifestations of disturbance of cytodifferentiation in carcinogenesis. Studies of hepatocellular tumors and liver of rats subject to single hepatocarcinogen injections being exemplified, the author considers some cases of detection of hetero-organic antigens of kidney origin in the cytosol, on the outer cell membranes and within the chromosomal non-histone proteins (NHP). Under discussion is the interrelation between the expression of hetero-organic antigens, attributed to the same tissue type in different cell structures, and a possible role of NHP as factors directing the disdifferentiation of neoplastically transformed cells.
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PMID:[The antigenic divergence of tumor cells due to the expression of hetero-organic antigens as a manifestation of disordered differentiation in carcinogenesis]. 227 13

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

CCl4 has been reported to be a liver carcinogen for several mice strains, for Syrian Golden hamsters, but not for Sprague-Dawley rats. CCl4 is an experimental carcinogen for which no convincing evidence of mutagenicity is available despite the fact that CCl4 reactive metabolites bind covalently to liver DNA. Here we describe studies on the relationship between the intensities of the covalent binding (CB) of CCl4 reactive metabolites to liver DNA and nuclear proteins either in vivo or in vitro after activation to reactive metabolites by nuclear preparations, considering the known susceptibility of the C3H mice, Syrian Golden hamsters and Sprague-Dawley rats to CCl4. There was no correlation between the intensity of CCl4 carcinogenic effects on the liver and CB of CCl4 reactive metabolites to total DNA either in vitro or in vivo. A good correlation between carcinogenicity and CB to total nuclear proteins (in vivo or in vitro was found. Nuclear protein fractionation studies revealed CB of CCl4 reactive metabolites to both histone and non-histone proteins when nuclear preparations activated CCl4 either in the presence or absence of NADPH. Acidic and residual nuclear proteins were the favorite targets of the interaction with CCl4 reactive metabolites. A good correlation between CB to these nuclear protein fractions and CCl4 carcinogenicity in the three species was found.
Carcinogenesis 1989 Feb
PMID:Species differences in the interaction between CCl4 reactive metabolites and liver DNA or nuclear protein fractions. 264 84


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