[Pierisin, an apoptosis-inducing protein from cabbage butterfly].
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ADP Ribose Transferases↗
Biomedical subjects
T Sugimura
Publications and source records attributed to T Sugimura.
Inhibitory effect of a prostaglandin E receptor subtype EP(1) selective antagonist, ONO-8713, on development of azoxymethane-induced aberrant crypt foci in mice.
We previously reported that prostaglandin E(2) contributes to colon carcinogenesis through its binding to the prostaglandin E receptor subtype EP(1) using a genetic approach in EP(1)-knockout mice and a pharmacological approach with the EP(1) selective antagonist, ONO-8711. In the present study, we examined the effects of another more selective EP(1) receptor antagonist, ONO-8713, on development of azoxymethane (AOM)-induced aberrant crypt foci (ACFs) in male C57BL/6J mice treated i.p. with 10mg/kg body weight AOM once a week for 3weeks. Administration of ONO-8713 at doses of 250, 500 and 1000ppm in diet during and post-AOM treatment for 5weeks resulted in a dose-dependent reduction of ACF formation, being 15, 30 and 36% inhibition of the control value, respectively. The level of inhibition was similar to that with ONO-8711. Moreover, ONO-8713 suppressed the development of ACF when administered at post-AOM, as in the case of ONO-8711. The data confirm EP(1) receptor involvement in colon carcinogenesis.
Animals↗
Chromosomal mapping of genes controlling development, histological grade, depth of invasion, and size of rat stomach carcinomas.
Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are widely used as a model of differentiated-type human stomach cancers. ACI/N (ACT) rats are susceptible and BUF/Nac (BUF) rats are resistant to MNNG-induced stomach carcinogenesis, and the presence of an autosomal gene with a dominant BUF allele has been suggested. In this study, we performed a carcinogenicity test by giving MNNG in drinking water to 117 male ACI x (ACIxBUF)F1 backcross rats. Each of 100 effective rats was diagnosed for its "carcinoma development" and when it was bearing stomach carcinoma(s), for histological grade, depth of invasion, and size and number of tumors. Carcinoma development was diagnosed based both on the age of the rat and on the presence of stomach carcinoma(s). Linkage analysis was performed with the genotypes of 161 loci, covering 1637 cM of the rat genome. Contrary to our original expectations, the most influential gene was the one on chromosome (chr.) 15, Gastric cancer susceptibility gene 1 (Gcs1), which confers susceptibility to stomach carcinogenesis (LOD, 3.8) with a dominant BUF allele by promoting conversion from adenomas to carcinomas. Two resistance genes on chr. 4 and chr. 3, Gastric cancer resistance gene 1 (Gcr1) and Gcr2, were shown to confer dominant resistance (LOD, 2.7 and 2.6, respectively). Gcs1, Gcr1, and Gcr2 exerted additive effects on the development of stomach carcinomas. A gene on chr. 16, Gcr3, was indicated to reduce the depth of invasion (LOD, 2.2) and sizes of tumors (LOD, 1.9). No linkage was obtained using the number of tumors. These findings show that the coordinate effect of a susceptibility gene, Gcs1, and two resistance genes, Gcr1 and Gcr2, is responsible for the development of MNNG-induced stomach carcinomas and that Gcr3 is responsible for the growth of a stomach carcinoma, reflected in the depth of invasion and in the tumor size.
Animals↗
How we should deal with unavoidable exposure of man to environmental mutagens: cooked food mutagen discovery, facts and lessons for cancer prevention.
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Amines↗
Suppression of azoxymethane-induced colonic aberrant crypt foci by a nitric oxide synthase inhibitor.
Nitric oxide synthase (NOS), an important bioregulator of a variety of biological processes, is overexpressed in colonic tumors of humans and rodents. In this study, effects of L-N(G)-nitroarginine methyl ester (L-NAME), a NOS inhibitor, on development of aberrant crypt foci (ACF) induced by azoxymethane (AOM) in F344 male rats were investigated. Six-week-old male F344 rats were fed diets containing 0 or 100 ppm L-NAME, and given s.c. injections of AOM at 15 mg/kg body wt, once a week for 2 weeks. At 17 weeks of age, all animals were sacrificed and their colons were evaluated for numbers of ACF. Feeding of 100 ppm L-NAME inhibited the development of ACF in different sizes by 24-39%, those containing four or more crypts being most markedly affected. Assessment of silver-stained nucleolar organizer regions protein (AgNORs)/nucleus further revealed a 44% reduction by administration of L-NAME. These results suggest that the NOS inhibitor, L-NAME, may be an effective chemopreventive agent against colon carcinogenesis due to depression of cell proliferation.
Animals↗
Construction of a high-throughput rat genetic mapping system with 466 arbitrarily primed-representational difference analysis markers.
Linkage mapping of quantitative trait loci (QTLs) requires genetic markers that can be efficiently genotyped for a large number of individuals. To isolate genetic markers suitable for this purpose, we previously established the arbitrarily primed RDA (AP-RDA) method. Dot-blotting AP-PCR products (AP-amplicons) onto filters at a high density and hybridization of the filters with the AP-RDA markers made it possible to genotype a large number of individuals simultaneously for multiple loci. In this study, by using 25 primers or primer combinations, we isolated a total of 419 AP-RDA markers by subtracting the AP-amplicon of BUF rats from that of ACI rats, and vice versa. By combining 47 previously isolated markers, a rat genetic map was drawn with 466 AP-RDA markers. Between two given strains of rats other than ACI and BUF, the average informativeness of the markers was 38%. As for the intercross of ACI and BUF rats, 12 selected primers served to genotype 259 loci. In addition, the amounts and quality of genomic DNA to be used for AP-PCR were examined to guarantee reliable genotyping. Now, initial genome scanning of the rat for linkage analysis can be performed efficiently using this mapping system with AP-RDA markers.
Animals↗
Genetic and epigenetic alterations in carcinogenesis.
Precise and deliberate observations on tumors stand true for decades, and then meet mechanistic explanations. The presence of genetic alterations in tumors is now widely accepted, and explains the irreversible nature of tumors. However, observations on tissue differentiation indicated that it shares something in common with carcinogenesis, that is, "epigenetic" changes. Now, DNA methylation in CpG sites is known to be precisely regulated in tissue differentiation, and is supposed to be playing key roles. Many tumor suppressor genes are known to be inactivated by the hypermethylation of their promoter regions. DNA methylation is connected to histone deacetylation and chromatin structure, and regulatory enzymes of DNA methylation are being cloned. Dedifferentiation, dis(dys)differentiation and convergence of cancer cells were studied phenotypically and biochemically, and are now explained from molecular aspects of disturbances in tissue-specific transcription factors. Spontaneous regression of malignant tumors enchanted researchers, and it is now noticed that genes inactivated by hypermethylation are frequently involved in tumors that relatively often undergo spontaneous regression. Carcinogenic mechanisms of some carcinogens seem to involve modifications of epigenetic switch, and some dietary factors also have the possibility to modify the switches. Based on the growing understanding of the roles of DNA methylation, several new methodologies were developed to make a genome-wide search for changes in DNA methylation. Now, a wave of new findings is in sight.
DNA Methylation↗
The response of Parp knockout mice against DNA damaging agents.
Gene-disruption studies involving poly(ADP-ribose) polymerase (Parp) have identified the various roles of Parp in cellular responses to DNA damage. The partial rescue of V[D]J recombination process in SCID/Parp(-/-) double mutant mice indicates the participation of Parp in the repair of DNA strand break. Parp(-/-) mice are more sensitive to the lethal effects of alkylating agents. Parp is also thought to be involved in base-excision repair after DNA damage caused by alkylating agents. On the other hand, resistance of Parp(-/-) mice to DNA damage induced by reactive oxygen species implicates the contribution of Parp to cell death through NAD depletion. Parp(-/-) mice with two different genetic backgrounds also show enhanced sensitivity to the lethal effects of gamma-irradiation. Parp(-/-) mice show more severe villous atrophy of the small intestine compared to the wild-type counterpart in a genetic background of 129Sv/C57BL6. Other forms of enhanced tissue damage have been identified in Parp(-/-) mice with a genetic background of 129Sv/ICR. For example, Parp(-/-) mice exhibit extensive hemorrhage in the glandular stomach and other tissues, such as the testes, after gamma-irradiation. Severe myelosuppression is also observed in both Parp(+/+) and Parp(-/-) mice, but Parp(+/+) mice show extensive extramedullary hematopoiesis in the spleen during the recovery phase of post-irradiation, whereas the spleen of Parp(-/-) mice exhibits severe atrophy with no extramedullary hematopoiesis. The absence of extramedullary hematopoiesis in the spleen is probably the underlying mechanism of hemorrhagic tendency in various tissues of Parp(-/-) mice. These findings suggest that loss of Parp activity could contribute to post-irradiation tissue hemorrhage.
Alkylating Agents↗
Isolation and identification of a new 2-phenylbenzotriazole-type mutagen (PBTA-3) in the Nikko river in Aichi, Japan.
We have previously determined the chemical structures of two 2-phenylbenzotriazole mutagens (PBTA-1 and PBTA-2) in blue cotton-adsorbed material from the Nishitakase River in Kyoto, Japan. In the present study, further analysis of mutagenic substances in the Nikko River, which flows through Aichi Prefecture in Japan, allowed the isolation of a new mutagen. Material (2.2 g) adsorbed on blue cotton (3 kg) at a site below the sewage plant on the Nikko River was purified by various column chromatographies, and a mutagen (120 microg) accounting for 11% of the total mutagenicity was isolated. On the basis of data from UV, mass, and (1)H NMR spectra of the mutagen, the compound was deduced to be a PBTA-1 analogue. As with PBTA-1, the mutagen was able to be synthesized from the azo dye 2-[(2-bromo-4, 6-dinitrophenyl)azo]-4-methoxy-5-[(2-hydroxyethyl)amino]acetanilide by reduction and chlorination. Since all spectra of the mutagen isolated from the river water were the same as those of the synthesized form, the structure was concluded to be 2-[2-(acetylamino)-4-[(2-hydroxyethyl)amino]-5-methoxyphenyl]-5-amino -7-bromo-4-chloro-2H-benzotriazole (PBTA-3). PBTA-3 is a potent mutagen, inducing 81 000 and 3 000 000 revertants per microgram of Salmonella typhimurium TA 98 and YG1024 respectively, in the presence of an S9 mix. In addition to its detection in the water of the Nikko River, PBTA-3 was detected in water samples from three other rivers flowing through regions where dyeing industries have been developed. Like PBTA-1 and PBTA-2, PBTA-3 might have also been produced from azo dyes during industrial processes in dyeing factories and/or through treatment at sewage plants.
Chromatography, High Pressure Liquid↗
Purification and cloning of pierisin-2, an apoptosis-inducing protein from the cabbage butterfly, Pieris brassicae.
The cabbage butterfly Pieris rapae contains a strong apoptosis-inducing substance, pierisin, against human cancer cell lines, which is thought to act via ADP-ribosylation. Here we report the purification and cloning of an apoptosis-inducing substance, designated as pierisin-2, from another cabbage butterfly, Pieris brassicae. Pierisin-2 was purified from pupae by sequential chromatography and its cytotoxic and apoptosis-inducing activities to various cancer cells were similar to those of pierisin, designated as pierisin-1, from P. rapae. cDNA cloning of pierisin-2 was performed on the basis of the partial amino-acid sequence. The nucleotide sequence indicated that the cDNA encodes an 850-amino-acid protein with a calculated molecular mass of 97 986. The deduced amino-acid sequence of pierisin-2 was 91% identical with that of pierisin-1. In vitro expressed protein in the reticulocyte lysate exhibited apoptosis-inducing activities against human gastric carcinoma TMK-1 and cervical carcinoma HeLa cells, similar to the purified native pierisin-2 from the pupae. Pierisin-2 shows regional sequence similarities with certain ADP-ribosylating toxins such as the A-subunit of cholera toxin. The results from site-directed mutagenesis at Glu165, a conserved residue among ADP-ribosylating enzymes necessary for NAD binding, and from experiments with ADP-ribosylating enzyme inhibitors suggested that pierisin-2 could be considered as an ADP-ribosylating toxin like pierisin-1.
ADP Ribose Transferases↗
Detection of thioredoxin in gastric cancer: association with histological type.
Thioredoxin (TRX) is a redox-active protein with multiple intra- and extracellular functions. This protein exists ubiquitously in all life forms, from primitive living cells, such as Escherichia coli and yeast, to higher mammals. Recently, augmentation of the expression and transcription level of TRX has been reported in tumors of various organs. In this study, we examined the expression of TRX in gastric cancer with respect to its histological type and depth of invasion. The association with cell proliferation was also studied. Results of histochemical analysis of surgical specimens as well as cytochemical analysis and Northern blot analysis of gastric cancer cell lines indicated that TRX is predominantly expressed in undifferentiated type gastric cancer rather than in the differentiated type. Neither the depth of tumor invasion nor cell proliferation significantly determined the staining intensity for TRX.
Adenocarcinoma↗
Nutrition and dietary carcinogens.
Three major factors for human carcinogenesis are (i) cigarette smoking, (ii) infection and inflammation and (iii) nutrition and dietary factors. Nutrition and dietary factors include two categories, namely genotoxic agents and constituents including tumor promotion-associated phenomena. This article first describes the genotoxic agents as microcomponents. These are mutagens/carcinogens in cooked food, fungal products, plant and mushroom substance, and nitrite-related materials, polycyclic aromatic hydrocarbons and oxidative agents. Emphasis has been given to heterocyclic amines (HCAs) to which humans are continuously exposed in an ordinary lifestyle. HCAs in food are mainly produced from creatin(in)e, sugar and from amino acids in meat (upon heating). They are imidazoquinoline and imidazoquinoxaline derivatives and phenylimidazopyridine. HCAs are pluripotent in producing cancers in various organs including breast, colon and prostate. Discussion is also given to plant flavonoids which are mutagenic but not carcinogenic. As a macrocomponent, overintake of total calories, fat and sodium chloride is discussed from the viewpoint of the increase of genetic alterations in tissues and of tumor promotion-associated issues. Studies of nutrition and dietary condition will eventually lead us to cancer prevention, namely delay of onset of cancer to the late phase of human life, which is called 'natural-end cancer' (Tenju-gann).
Amines↗
Inhibitory effects of Bifidobacterium-fermented soy milk on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced rat mammary carcinogenesis, with a partial contribution of its component isoflavones.
High consumption of soybean and soybean-related products is hypothesized to contribute to protection against breast cancer. Soybean is a rich source of genistein, a putative cancer chemopreventive agent. Fermented soy milk (FSM), which is made of soy milk fermented with the Bifidobacterium breve strain Yakult, contains larger amounts of the isoflavone aglycones genistein and daidzein than unfermented soy milk. In the present study, we examined the effects of FSM and its component isoflavone mixture (genistein:daidzein 4:1) on 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP)-induced mammary carcinogenesis in rats. Starting at 7 weeks of age, female Sprague-Dawley rats were given PhIP at a dose of 85 mg/kg body wt by intragastric administration four times a week for 2 weeks. They were fed control high fat basal diet or experimental high fat diet containing 10% FSM or 0.02 or 0.04% isoflavone mixture during and after carcinogen exposure. The incidences (percentage of rats with tumors) of mammary gland tumors were 71% in the control diet group, 51% in the FSM group and 68 and 61% in the groups treated with isoflavone mixture at 0.02 and 0.04%, respectively. Mammary tumor multiplicities (number of tumors per rat) were 1.2 +/- 0.2 for 10% FSM, 2.2 +/- 0.4 for 0.02% isoflavone mixture and 1.5 +/- 0.3 for 0.04% isoflavone mixture, being clearly smaller than the control diet value (2.6 +/- 0.5). Furthermore, feeding of FSM and the isoflavone mixture at both doses reduced the sizes of mammary tumors. Since the amounts of isoflavones in 10% FSM are approximately equivalent to those in the 0.02% isoflavone mixture, the chemopreventive activity of FSM could be partly attributable to the presence of isoflavones such as genistein and daidzein.
Animals↗
Suppression of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells by chemopreventive agents with a resorcin-type structure.
Cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells. It has been reported that inhibition of COX-2 enzyme activity is shown to prevent colon carcinogenesis. Thus, suppression of COX-2 expression may also be an effective chemopreventive strategy. In the present study, we constructed a beta-galactosidase reporter gene system in human colon cancer DLD-1 cells, and measured COX-2 promoter-dependent transcriptional activity in the cells. Interferon gamma suppressed this COX-2 promoter activity, while 12-O-tetradecanoylphorbol-13-acetate and transforming growth factor alpha (TGFalpha) exerted enhancing effects. We then tested the influence of 14 candidate cancer chemopreventive compounds on COX-2 promoter activity. Chemopreventive agents such as quercetin, kaempferol, genistein, resveratrol and resorcinol, all having a common resorcin moiety, were found to effectively suppress the COX-2 promoter activity with and without TGFalpha-stimulation in DLD-1 cells. Since all these compounds have a resorcin moiety as a common structure, a resorcin-type structure may play an active role in the inhibition of COX-2 expression in colon cancer cells.
Adenocarcinoma↗
Hypomethylation of LINE1 retrotransposon in human hepatocellular carcinomas, but not in surrounding liver cirrhosis.
BACKGROUND: Cytosine methylation of LINE1 (L1) elements, some of which are capable of retrotransposition in human cells, is known to play important roles in transcriptional repression of these retrotransposons. We have previously identified consistent hypomethylation of L1 elements in mouse liver tumors by a genome-wide search technique for aberrant methylations. In this study, we analyzed the methylation status of the L1 elements in human hepatocellular carcinomas (HCCs). METHODS: Nine pairs of an HCC and its surrounding tissue were obtained from clinical cases. Genomic DNA was digested with HpaII, a methylation-sensitive restriction enzyme, and hybridized with a probe derived from the promoter region of the L1 elements. RESULTS: Hypomethylation of the L1 elements was detected in eight of the nine HCCs, but never in the surrounding liver tissues, whether or not liver cirrhosis was present. CONCLUSION: Specific occurrence of the hypomethylation of the L1 elements in the HCCs indicated its diagnostic value for malignancy. The hypomethylation could also lead to increased incidence of retrotransposition and resultant genomic instability in HCCs.
Aged↗
Report of the Thirteenth International Symposium of the Foundation for Promotion of Cancer Research: cancer screening-past, present and future.
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Japan↗
Responses to umami substances in taste bud cells innervated by the chorda tympani and glossopharyngeal nerves.
The chorda tympani (CT) and glossopharyngeal (GL) nerves of several mammalian species respond differently to umami substances (US) such as monosodium glutamate (MSG), disodium 5'-inosinate (IMP) and disodium 5'-guanylate (GMP). In mice and rhesus monkeys, responses to US are greater in the GL than the CT nerve, with the GL nerve containing larger numbers of MSG-sensitive fibers. Gurmarin, a sweet response inhibitor, suppresses the mouse CT responses to the mixture of MSG and IMP to approximately 65% of control levels but not to the metabotropic and ionotropic glutamate agonists 2-amino-4-phophonobutyrate and N-methyl-D-aspartate. Gurmarin does not inhibit any taste responses in the GL. In mice, CT responses to MSG may be masked by their greater sensitivity to sodium ions. Calcium imaging studies demonstrate that some mouse taste cells isolated from the fungiform papilla innervated by the CT respond selectively (as indicated by a rise in intracellular Ca(2+) concentrations) to MSG and/or IMP or GMP. These MSG responses are not suppressed notably by reducing the Ca(2+) concentration of the stimulus solution, suggesting that the observed Ca(2+) release is from intracellular stores. Measurements of second messengers in the mouse fungiform papilla have revealed consistently that MSG elicits increases in both inositol 1,4,5-trisphosphate and adenosine 3', 5'-cyclic monophosphate levels. Together, these results suggest that US may stimulate two different transduction mechanisms in the fungiform papilla. They also suggest that gurmarin-insensitive components of receptors for US, including metabotropic and ionotropic glutamate receptors, may be commonly involved in transduction for umami taste in taste cells on both anterior and posterior parts of the tongue.
Animals↗
Expression and processing of the canine calicivirus capsid precursor.
The ORF2 product of canine calicivirus (CaCV) was identified and its processing in mammalian cells was analysed. Immunoblot analysis revealed the presence of the 75 kDa capsid precursor in addition to a 57 kDa capsid protein and a 22 kDa N-terminal polypeptide in CaCV-infected cells treated at an elevated temperature. When the CaCV ORF2 was expressed in a transient mammalian expression system, only the 75 kDa precursor was detected in immunoblot analysis, suggesting that no post-translational processing occurred in this system. However, the precursor was processed to a 57 kDa protein and a 22 kDa polypeptide by the proteinase of feline calicivirus (FCV) when this was co-expressed with ORF2. Processing was blocked by site-directed mutagenesis of the putative cleavage site in the capsid precursor. The results indicate that the proteinase of FCV can cleave the capsid precursor of CaCV to produce the mature capsid protein and that CaCV may have a similar proteinase.
Animals↗