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)

We previously found two new mutagens, compounds I and II, in bacteriological-grade beef extract by monitoring the mutagenicity to a new Salmonella strain, YG1024; compound I was identified as 2-amino-4-hydroxymethyl-3,8-dimethylimidazo[4,5-f]quinoxaline (4-CH2OH-8-MeIQx). In the present study, we isolated compound II from the beef extract, which accounted for 2% of the total mutagenicity of materials adsorbed on blue cotton. Further, we found that a large quantity of compound II was produced by heating a mixture of creatine, threonine and glucose (1:1:0.5) at 200 degrees C for 5 h, the level being 860-fold of that in the beef extract. The structure of this compound was determined to be 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx) by X-ray crystallography. The amount of 7,9-DiMeIgQx in bacteriological-grade beef extract was estimated to be 53 ng/g. This compound induced 13 800 and 670 revertants of S. typhimurium YG1024 and TA98 respectively, per micrograms in the presence of S9 mix.
Carcinogenesis 1994 Jun
PMID:Structural determination of a new mutagenic heterocyclic amine, 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx), present in beef extract. 802 Jan 48

Mixtures of creatinine, glucose and threonine with the addition of a small amount, 250 microCi, of [U-14C]glucose, [1-14C]glucose or [6-14C]glucose were heated at 180 degrees C for 30 min in an aqueous model system. The mixtures were purified and analysed using HPLC, scintillation and Ames tests. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx) were detected as the main radioactive mutagens. The amount of MeIQx and 4,8-DiMeIQx produced from threonine was estimated at 18 and 60 nmol/mmol glucose respectively. Radioactive carbon atoms originating from glucose were also shown to be incorporated into 2-amino-3-methylimidazo[4,5-f]quinoxaline (IQx). The specific activity was calculated to be 0.6, 0.3 and 0.1-0.3 mCi/mmol for MeIQx, 4,8-DiMeIQx and IQx respectively for all three labelled forms of glucose. By the incorporation of carbon atoms originating from glucose into the imidazoquinoxaline mutagens it was clearly demonstrated that glucose is a precursor in the formation of these food mutagens.
Carcinogenesis 1993 Oct
PMID:Incorporation of carbon atoms from glucose into the food mutagens MeIQx and 4,8-DiMeIQx using 14C-labelled glucose in a model system. 822 49

The adenomatous polyposis coli (APC) gene, responsible for familial adenomatous polyposis, is also associated with development of sporadic tumors in digestive system as colon, stomach, or pancreas. In order to investigate whether or not APC mutations occur as an early genetic event during gastric carcinogenesis, we examined somatic mutations of APC in flat adenomas of the stomach. DNAs isolated from flat adenomas were examined by means of an RNase protection analysis coupled with polymerase chain reaction (PCR) followed by DNA sequencing of the PCR products. By screening a mutation cluster region (MCR: codons between 1286 and 1513) of APC in which two-thirds of somatic mutations were detected in colorectal tumors, somatic mutations were found in four of ten flat adenomas: three of which caused truncation of the gene product due to a nonsense mutation or 4-bp deletion; one other was a point mutation that altered amino acid from alanine to threonine. Our results imply that APC plays a crucial role in an early step of gastric carcinogenesis, as was observed in colorectal carcinogenesis.
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PMID:Somatic mutations of the APC gene in precancerous lesion of the stomach. 824 71

By monitoring the mutagenicity to a new Salmonella tester strain, YG1024, which has a much higher level of O-acetyltransferase activity than S.typhimurium TA98, we found two new mutagenic compounds in bacteriological-grade beef extract. One of them (compound I), which had a similar UV spectrum to that of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), was isolated and shown to account for approximately 2% of the total mutagenicity of the materials adsorbed to blue cotton, and its concentration was estimated to be 6.0 ng/g beef extract. This amount of compound in beef extract was insufficient to allow measurements of various spectra, but its level was increased approximately 9-fold by heating beef extract with creatine and threonine at 200 degrees C for 5 h. From UV and mass spectra of the compound obtained from beef extract heated with creatine plus threonine, it was deduced to be a hydroxymethyl derivative of aminodimethylimidazo-quinoxaline. Compound I was isolated from the urine of rats given 4,8-DiMeIQx and identified as 2-amino-4-hydroxymethyl-3,8-dimethylimidazo[4,5-f]quinoxaline (4-CH2OH-8-MeIQx) by 1H-NMR analysis. 4-CH2OH-8-MeIQx induced 326,000 revertants of YG1024 and 99,000 revertants of TA98 per micrograms in the presence of S9 mix.
Carcinogenesis 1994 Jan
PMID:Isolation and identification of a new mutagen, 2-amino-4-hydroxy-methyl-3,8-dimethylimidazo[4,5-f]quinoxaline (4-CH2OH-8-MeIQx), from beef extract. 829 43

Recently, many potent inhibitors of protein serine/threonine phosphatases (PPs) have been found. Some of them have proven to be tumor promoters in mouse skin two-step carcinogenesis and rat liver medium-term tests. Among these inhibitors, okadaic acid (OA) selectively inhibits PP2A, and its use has therefore been proposed to facilitate analysis of biological roles of this phosphatase. OA shows bimodal effects on in vitro transformation and, in addition to such epigenetic changes, also induces marked genetic changes. OA treatment for more than 1 week flattened NIH 3T3 transformants irreversibly, with loss of the transfected genes. It is also known to induce diphtheria toxin-resistant mutations in Chinese hamster lung cells and sister chromatid exchanges (SCEs) in Chinese hamster ovary cells and human lymphocytes. To analyze roles of protein phosphatases in gene stability, we isolated OA-resistant mutants. They were proven to have a mutation in the PP2A alpha catalytic subunit, in which cysteine 269 had been substituted for glycine; and it was demonstrated that this region interacts with OA. The recombinant mutant protein was 4 approximately 9-fold more resistant to OA than the wild type. Although the OA resistant mutants of CHO cells expressed high levels of P-glycoprotein, inhibition of PP2A itself was suggested to lead to SCE induction. However, the number of molecular species of PP which are known to be sensitive to OA continues to increase, and we have isolated cDNA for a novel type of OA sensitive PP. Our studies indicate that the fact that the roles of PP2A cannot be elucidated using only OA is of crucial importance.
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PMID:Protein serine/threonine phosphatases as binding proteins for okadaic acid. 853 25

This is the first report on estrogen-dependent growth of human-derived colon carcinoma cells. Under selected conditions, growth of subconfluent Caco-2 cells is triggered by estradiol. Cell growth is estradiol concentration dependent, with maximal effect occurring at about 0.4 nM. Growth is prevented by two different antiestrogens: the partial agonist, OH-Tamoxifen, and the pore antagonist, ICI 182,780. The growth effect is specific for estradiol since other hormonal steroids tested do not affect cell growth. The amount of estradiol receptor in subconfluent Caco-2 cells, detected by blot with monoclonal antibodies directed against the receptor as well as estradiol binding assays, is similar to that of the classical estradiol-responsive, human mammary cancer-derived MCF-7 cells. Estradiol treatment of subconfluent Caco-2 cells rapidly and reversibly stimulates four important intermediates in a signal transduction pathway that is known to trigger cell proliferation: two members of the large family of c-src-related tyrosine kinases, c-src and c-yes, and two serine/threonine kinases, the mitogen-activated protein (MAP) kinases, erk-1 and erk-2. Tyrosine kinases activated by estradiol are up-stream MAP kinases and Caco-2 cell proliferation. In fact, genistein, a specific tyrosine kinase inhibitor, abolishes the estradiol stimulatory effect on both erk-2 activity and cell proliferation. Our findings show that in subconfluent Caco-2 cells, the estradiol-receptor complex activates the c-src, c-yes/MAP kinase pathway and activates growth. This could have important implications for the understanding of human intestinal carcinogenesis.
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PMID:Estradiol activation of human colon carcinoma-derived Caco-2 cell growth. 881 50

The tumor suppressor gene p16/MTS1, located on chromosome 9p21, is a cell cycle regulatory gene which is frequently altered in human cancers. The role of this gene in prostate cancer is unknown. To determine the frequency of deletions and point mutations of p16/MTS1 in human prostate cancer, we examined 18 cancer and matched benign and hyperplastic tissue specimens. Deletions of p16/MTS1 were detected by semi-quantitative multiplex polymerase chain reaction in which a portion of exon 2 of the p16/MTS1 gene and a control marker, the glyceraldehyde 3-phosphate dehydrogenase gene, were amplified simultaneously. 'Cold' single-stranded conformational polymorphism (SSCP) analysis was performed to examine exons 1 and 2 of the p16/MTS1 gene for point mutations. Our data indicate no evidence for intragenic homozygous deletion in the prostate tumors. One prostate tumor and matched benign tissue showed mobility shifts. Direct DNA sequencing of the SSCP positive samples showed a G --> A transition in codon 140 which would result in an amino acid change from alanine to threonine. Our results indicate that deletions and point mutations in the p16/MTS1 gene are rare and do not play a major role in human prostate carcinogenesis.
Carcinogenesis 1996 Dec
PMID:Absence of p16/MTS1 gene mutations in human prostate cancer. 900 95

Allelic deletion of multiple regions on the short arm of chromosome 3 (3p) implies the presence of multiple important tumor suppressor genes in human carcinogenesis. The FHIT gene, identified recently in chromosome 3p14.2, shows frequent allelic deletion and aberrant transcripts in gastrointestinal tumors. After determining the intron sequences flanking each of the coding exons of the FHIT gene and designing intron primers to facilitate mutation analysis of genomic DNA samples, we analyzed the complete coding sequences in matched cancer and normal tissues from 40 cases with primary gastric cancer using intron primers, PCR-single-strand conformation polymorphism analysis, and direct sequencing. A somatic missense mutation in exon 6, codon 61, ACG (threonine) --> ATG (methionine) was found in a signet ring cell adenocarcinoma. We also evaluated allelic deletion in these tumors by PCR-based microsatellite analysis; allelic deletion occurred in 42.1% (16 of 38) of evaluable cases. This is the first report of a somatic missense mutation of the FHIT gene in a primary tumor. Presence of a point mutation and frequent allelic deletions are consistent with the hypothesis that FHIT gene alterations are involved in the development of primary gastric cancers.
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PMID:FHIT mutations in human primary gastric cancer. 910 41

Okadaic acid (OA) is an inhibitor of serine/threonine protein phosphatase (PP) and a tumor promoter in mouse skin carcinogenesis. According to Carcinogenesis Division, National Cancer Center Research Institute, OA induces various genetic alterations, such as loss of exogenous genes, sister chromatid exchanges and diphtheria toxin resistant mutants, although there is no evidence showing that it interacts with DNA directly or produces active oxygen under the conditions used. In this study, minisatellite, which is a hotspot of recombination, was investigated regarding the induction of alteration and instability by OA. It was also attempted to elucidate the roles of minisatellite instability in carcinogenesis. NIH3T3 cells were cultured either with or without OA, subcloned and DNA from each clone was subjected to fingerprint analysis using the Pc-1 minisatellite probe. The frequency of minisatellite recombination was 29% in OA-treated cells, as opposed to 3% in nontreated cells. Furthermore, OA-treated cells exhibited tumorigenicity in nude mice. Minisatellite fingerprint analysis of clones obtained from the tumors revealed that those tumors had acquired minisatellite instability. These mechanisms may be involved in tumor promotion by OA.
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PMID:[Minisatellite instability induced by okadaic acid]. 912 47

The frequency and nature of genetic alterations in the p16 tumor suppressor gene in 25 esophageal squamous cell carcinoma specimens from Chinese patients were investigated by PCR-SSCP and DNA sequencing techniques. No gross deletions occurred in either exon 1 and 2 of the gene by PCR amplification. However, genetic changes were observed in three cases. These included a point mutation in codon 12 of exon 1 with a resulting Ala --> Thr amino acid substitution, a point mutation at base 91 in the non-coding region of exon 1, and a 1 base pair insertion in codon 116 of exon 2. The low mutation frequency of 12% is consistent with that of three previous studies involving Japanese and Caucasian patients (8, 16 and 21% frequency: Esteve et al., 1996, Igaki et al., 1995 and Zhou et al., 1994). p16 gene mutations do not appear to play a major role in esophageal carcinogenesis.
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PMID:p16 tumor suppressor gene mutations in Chinese esophageal carcinomas in Hong Kong. 914 25


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