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)

Activating mutations in the region of the beta-catenin gene corresponding to the NH2-terminal phosphorylation sites of glycogen synthetase kinase 3beta have been causally implicated in carcinogenesis. In this study, the beta-catenin exon 3 was examined in hepatic lesions induced by diethylnitrosamine in B6C3F1 mice. PCR and DNA sequencing detected seven beta-catenin mutations in 13 samples dissected from hepatocellular carcinoma tissues, but none in 14 hepatic adenomas. All of the mutations were found in codon 41 encoding a threonine residue, one of the possible glycogen synthetase kinase-3beta phosphorylation sites. Although beta-catenin protein was immunohistochemically stained mainly on the cell membrane in preneoplastic hepatocytic foci and most adenomas, as observed in normal hepatocytes, it was detected in the cytoplasm and nuclei in addition to the cell membrane, indicating stabilization of the protein in HCCs. This shift in staining was observed not only in tumors with mutations, but also in examples lacking exon 3 mutations. Our data demonstrate that beta-catenin alterations may be important for malignant progression during multistep hepatic carcinogenesis in mice.
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PMID:Beta-catenin mutations are frequent in hepatocellular carcinomas but absent in adenomas induced by diethylnitrosamine in B6C3F1 mice. 1021 86

Mutations in the adenomatous polyposis coli gene or activating mutations in the beta-catenin gene itself are thought to be responsible for the excessive beta-catenin signaling involved in intestinal carcinogenesis. We generated transgenic mice that expressed large amounts of a NH2-terminally truncated mutant beta-catenin (deltaN131beta-catenin) in the intestine. These mice had multifocal dysplastic lesions in the small intestine, reminiscent of the early lesions observed in the mouse models of familial adenomatous polyposis. The number of apoptotic cells in the villi of these transgenic mice was 3-4-fold higher than in nontransgenic mice. Expression of the truncated beta-catenin mutant in the kidney led to the development of severe polycystic kidney disease. Our findings support the concept that deregulation of the beta-catenin signaling pathway is the major oncogenic consequence of adenomatous polyposis coli mutations in intestinal neoplasia.
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PMID:Intestinal dysplasia and adenoma in transgenic mice after overexpression of an activated beta-catenin. 1046 73

ras gene mutation, which perpetually turns on the growth signal transduction pathway, occurs frequently in many cancer types. The mouse epidermal JB6 cell line has been transfected with a mutant H-ras gene to mimic carcinogenesis in vitro. These transformed cells (30.7b Ras 12) are able to grow in soft agar, exhibiting anchorage independence and high endogenous activator protein 1 (AP-1) activity, which can be detected by a stable AP-1 luciferase reporter. The present study investigated the ability of different pure green and black tea polyphenols to inhibit this ras signaling pathway. The major green tea polyphenols (catechins), (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin, (-)-epicatechin-3-gallate, (-)-epicatechin, and their epimers, and black tea polyphenols, theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate, and theaflavin-3,3'-digallate (TFdiG), were compared with respect to their ability to inhibit the growth of 30.7b Ras 12 cells and AP-1 activity. All of the tea polyphenols except (-)-epicatechin showed strong inhibition of cell growth and AP-1 activity. Among the catechins, both the galloyl structure on the B ring and the gallate moiety contributed to the growth inhibition and AP-1 activity; the galloyl structure appeared to have a stronger effect on the inhibitory action than the gallate moiety. The epimers of the catechins showed similar inhibitory effects on AP-1 activity. The addition of catalase to the incubation of the cells with EGCG or TFdiG did not prevent the inhibitory effect on AP-1 activity, suggesting that H2O2 does not play a significant role in the inhibition by tea polyphenols. Both EGCG and TFdiG inhibited the phosphorylation of p44/42 (extracellular signal-regulated kinase 1 and 2) and c-jun without affecting the levels of phosphorylated-c-jun-NH2-terminal kinase. TFdiG inhibited the phosphorylation of p38, but EGCG did not. EGCG lowered the level of c-jun, whereas TFdiG decreased the level of fra-1. These results suggest that tea polyphenols inhibited AP-1 activity and the mitogen-activated protein kinase pathway, which contributed to the growth inhibition; however, different mechanisms may be involved in the inhibition by catechins and theaflavins.
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PMID:Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure-activity relationship and mechanisms involved. 1049 15

Environmental factors influence carcinogenesis by interfering with a variety of cellular targets. Carcinogenic nickel compounds, although generally inactive in most gene mutation assays, induce chromosomal damage in heterochromatic regions and cause silencing of reporter genes when they are located near telomere or heterochromatin in either yeast or mammalian cells. We studied the effects of nickel on the lysine acetylation status of the NH2-terminal region of histone H4. At nontoxic levels, nickel decreased the levels of histone H4 acetylation in vivo in both yeast and mammalian cells, affecting only lysine 12 in mammalian cells and all of the four lysine residues in yeast. In yeast, lysine 12 and 16 were more greatly affected than lysine 5 and 8. Interestingly, a histidine Ni2+ anchoring site is found at position 18 from the NH2-terminal tail of H4. Nickel was also found to inhibit the acetylation of H4 in vitro using purified recombinant histone acetyltransferase. To our knowledge, this is the first agent shown to decrease histone H4 acetylation at nontoxic levels.
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PMID:Nickel compounds are novel inhibitors of histone H4 acetylation. 1066 66

The tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and N'-nitrosoanatabine (NAT) are found in substantial quantities in unburned tobacco. Although this has been documented in many previous studies, no data are available on the enantiomeric composition of these nitrosamines, which both have a chiral center at their 2'-positions. We used chiral stationary phase gas chromatography with nitrosamine-selective detection to determine the enantiomeric composition of NNN and NAT in moist snuff, chewing tobacco, and cigarette tobacco. (S)-NNN comprised 75.0 +/- 8.83% (SD) (n = 12) of total NNN while (S)-NAT comprised 82.6 +/- 1.44% (n = 12) of total NAT. Levels of the (S)-enantiomers of NNN and NAT were generally similar to those of the corresponding secondary amines, nornicotine and anatabine, suggesting a precursor to product relationship. Nitrosation of (S)-nicotine at pH 7.0 produced >99% (S)-NNN. These results suggest that nornicotine is a significant precursor of NNN in tobacco. The results of this study provide new insights into the structures and precursors of tobacco-specific nitrosamines in tobacco products.
Carcinogenesis 2000 Apr
PMID:Enantiomeric composition of N'-nitrosonornicotine and N'-nitrosoanatabine in tobacco. 1075 25

Methyl methanesulfonate (MMS), a direct-acting alkylating agent, is a strong brain carcinogen but a poor hepatocarcinogen in rats. To elucidate the mechanism(s) leading to tissue-specific carcinogenesis in response to MMS, we compared the activation of the stress-activated protein kinases (SAPKs), the c-Jun NH2-terminal kinase (JNK) and p38, in the liver and brain of rats after i.p. injection of MMS. p38 was activated in both the liver and brain, but JNK was activated only in the liver in a dose- and time-dependent manner. The activation of JNK was preceded by the activation of SAPK or extracellular signal-regulated protein kinase kinase 1/mitogen-activated protein kinase kinase 4 in the liver, but no activation of SAPK or extracellular signal-regulated protein kinase kinase 1/mitogen-activated protein kinase kinase 4 was observed in the brain. The activation of JNK in the liver was accompanied by increased phosphorylation of activating transcription factor 2 and followed by an increase in the phosphorylation and level of c-Jun protein, in contrast to no such changes in the brain. To study the physiological consequences of these differential molecular events in the liver and brain, we examined MMS-induced apoptosis, a process shown to involve stress kinase activation. A significant increase in apoptotic cell death was detected in the liver but not in the brain after a MMS injection, which correlated with the patterns of JNK activation in the liver. Taken together, our results demonstrate that a tissue-specific signaling pathway(s) leading to distinct physiological responses in the liver and brain of rats exposed to MMS exists, suggesting a possible explanation for tissue-specific carcinogenic effects exerted by MMS in vivo.
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PMID:Differential activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinases by methyl methanesulfonate in the liver and brain of rats: implication for organ-specific carcinogenesis. 1101 30

Inositol hexaphosphate (InsP6) has an effective anticancer action in many experimental models in vivo and in vitro. Ultraviolet B (UVB) radiation is believed to be responsible for many of the carcinogenic effects related to sun exposure, and alteration in UVB-induced signal transduction is associated with UVB-induced carcinogenesis. Here we report the effects of InsP6 on UVB-induced signal transduction. InsP6 strongly blocked UVB-induced activator protein-1 (AP-1) and NF-kappaB transcriptional activities in a dose-dependent manner. InsP6 also suppressed UVB-induced AP-1 and nuclear factor kappaB (NF-kappaB) DNA binding activities and inhibited UVB-induced phosphorylation of extracellular signal-regulated protein kinases (Erks) and c-Jun NH2-terminal kinases (JNKs). Phosphorylation of p38 kinases was not affected. InsP6 also blocked UVB-induced phosphorylation of IkappaB-alpha, which is known to result in the inhibition of NF-kappaB transcriptional activity. InsP6 does not block UVB-induced phosphotidylinositol-3' (PI-3) kinase activity, suggesting that the inhibition of UVB-induced AP-1 and NF-kappaB activities by InsP6 is not mediated through PI-3 kinase. Because AP-1 and NF-kappaB are important nuclear transcription factors that are related to tumor promotion, our work suggests that InsP6 prevents UVB-induced carcinogenesis by inhibiting AP-1 and NF-kappaB transcription activities.
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PMID:Inositol hexaphosphate inhibits ultraviolet B-induced signal transduction. 1147 22

Mitogen-activated protein kinases (MAPKs) play a critical role in the regulation of cell proliferation, differentiation and apoptosis. We evaluated MAPKs, extracellular signal-regulated kinases (ERKs), c-Jun NH2-terminal kinases (JNKs) and p38 MAPKs in the kidney of young and old rats in response to a direct-acting alkylating agent, methyl methanesulfonate (MMS). It is shown that the basal activity of ERKs was strongly down-regulated in the kidney of old rats compared to their young counterparts without a significant difference in the basal expression of ERKs. Upon treatment with MMS, ERKs were deactivated about 5-fold (P<0.05) in the kidney of young rats, whereas they were activated about 4-fold (P<0.01) in old rats. Strikingly, expression of JNKs was not detected in old animals, whereas it was clearly present and strongly activated after MMS treatment in the kidney of young animals. The basal activity of p38 significantly increased in the kidney of old rats as compared to young animals, whereas no difference in the basal expression of p38 was detected. After treatment with MMS, p38 was activated in the kidney of both young and old rats, where activation was dramatically stronger than in young animals. Taken together, these results demonstrate age-specific MAPKs signaling pathways in the rat kidney. The implications in age-related changes in susceptibility of the kidney to MMS-induced carcinogenesis are discussed.
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PMID:Differential activation of mitogen-activated protein kinases by methyl methanesulfonate in the kidney of young and old rats. 1152 3

Amine conjugates of activated aflatoxin (AF) B(1) are formed in various systems, e.g., buffer amines and with protein lysine groups. Structures have been published in the literature, but the evidence is indirect in that (i) halogenated AFB(1) was usually used as the precursor and (ii) the assignment of the structure of the five-membered ring formed by cyclization is based on NMR chemical shifts. To better define these adducts and distinguish among several possibilities, we synthesized AFB(1) dialdehyde and reacted this with the surrogate methylamine at neutral pH, to simplify the system. The isolated product had the expected molecular ion (mass spectrometry) and showed pH-dependent UV spectra similar to those published for a lysine conjugate. Nuclear Overhauser enhanced spectroscopy (two-dimensional NMR, 800 MHz) of the sample (2H(2)O) showed proximity of the N-CH(3) protons only with a singlet at delta 4.10, assigned to the methylene of the added five-membered ring, but not to a delta 6.53 singlet assigned as the vinylic proton of that ring. All protons in the coumarin-furanone portion of the system were correlated to each other but not to those in the added five-membered ring. These experiments establish the structure as 2,3-dihydro-2-oxo-4-(1,2,3,4-tetrahydro-7-hydroxy-9-methoxy-3,4-dioxocyclopenta[c][1]benzopyran-6-yl)-1H-pyrrole-1-methane. The similarity of the reaction to that occurring in the reaction of AFB(1) dialdehyde with lysine and the agreement of the UV spectra suggest that this structure is applicable for the lysine analogue. The NMR results support the possible structure B of Sabbioni et al. [Sabbioni, G., Skipper, P. L., Buchi, G., and Tannenbaum, S. R. (1987) Carcinogenesis 8, 819-824] and the proposed structure 8 of Sabbioni [Sabbioni, G. (1990) Chem.-Biol. Interact. 75, 1-15] but not alternative proposals. Kinetic and mechanistic considerations of the reaction of lysine with AFB(1) dialdehyde are presented in the previous article in this issue [Guengerich, F. P., Arneson, K. O., Williams, K. M., Deng, Z., and Harris, T. M. (2002) Chem. Res. Toxicol. 15, 780-793].
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PMID:Structure of the aflatoxin B(1) dialdehyde adduct formed from reaction with methylamine. 1206 46

Rhein (4,5-Dihydroxyanthraquinone-2-carboxylic acid), a constituent enriched in the rhizome of rhubarb (R. palmatum L. or R. tanguticum Maxim), is a traditional Chinese herb used as a laxative and stomachic drug. In the present study, we investigated the anti-carcinogenesis of rhein by using mouse epidermal cell JB6 line, an in vitro model for elucidating the molecular mechanisms of cancer chemopreventive agents. Rhein is shown to inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation and activator protein-1 (AP-1) activation in a dose-dependent manner. Signal cascade analysis revealed that rhein inhibits the phosphorylation and abundance of c-Jun protein, c-Jun NH2-terminal kinase (JNK) phosphorylation, but does not inhibit the phosphorylation of extracellular signal-regulated protein kinase (ERK) and p38 kinase. Thus, these results provide the first evidence suggesting that rhein inhibits AP-1 activity and cell transformation through the inhibition of a JNK-dependent, ERK- and p38-independent molecular mechanism.
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PMID:Rhein inhibits TPA-induced activator protein-1 activation and cell transformation by blocking the JNK-dependent pathway. 1263 75


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