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

In human lung cancers, alterations of both a dominant oncogene (ras) and a tumor suppressor gene (p53) have been identified. Polymerase chain reaction (PCR) analysis of mRNA was used to amplify the c-Ki-ras-2 and p53 genes from Syrian golden hamsters. The PCR products were confirmed by predicted-size analysis, probing with nonradioactive (biotin-labeled) oligonucleotides, and direct sequencing. Lung tumors were produced in hamsters by repeated injections of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Of six tumors examined, three (50%) had mutations in codon 12 of Ki-ras. Examination of the conserved regions of p53 revealed no mutations. We conclude that NNK-induced carcinogenesis in the hamster results in characteristic alterations of Ki-ras but may not necessarily involve the p53 gene.
 ...
PMID:Mutational analysis of a dominant oncogene (c-Ki-ras-2) and a tumor suppressor gene (p53) in hamster lung tumorigenesis. 144 20

Alterations in the p53 tumor suppressor gene and Epstein-Barr virus status were investigated in 15 nasopharyngeal carcinoma (NPC) biopsies, 4 xenografts, and 2 cell lines from the Cantonese region of southern China. One other established NPC cell line obtained from a northern Chinese patient was also studied. Restriction fragment length polymorphism analysis revealed a loss of heterozygosity for chromosome 17p, where the p53 gene resides, in only one of 15 NPC biopsies. Polymerase chain reaction-single-stranded conformational polymorphism analysis and direct sequencing failed to detect sequence alterations in exons 5 through 8 of the p53 gene in the 15 tumors and in the 4 NPC xenografts, all of which tested positive for Epstein-Barr virus. In contrast, the 3 NPC cell lines were all negative for Epstein-Barr virus and contained G----C transversions in the p53 gene, with cell lines CNE-1 and CNE-2 harboring identical AGA (arginine) to ACA (threonine) changes at codon 280. These results suggest that p53 inactivation is not a necessary component of nasopharyngeal carcinogenesis in Cantonese but may be important in the establishment of cell lines derived from these tumors.
 ...
PMID:Absence of p53 gene mutations in primary nasopharyngeal carcinomas. 151 42

A significant role for mouse chromosome 7 abnormalities during chemically induced skin carcinogenesis has been advanced based on previous cytogenetic and molecular studies. To determine the frequency of allelic losses at different loci of chromosome 7 in skin tumors induced in the outbred SENCAR mouse stock by a two-stage initiation-promotion protocol, we compared the constitutional and tumor genotypes of premalignant papillomas and squamous cell carcinomas for loss of heterozygosity at different informative loci. In a previous study, these tumors had been analyzed for their allelic composition at the Harvey ras-1 (Ha-ras-1) locus and it was found that 39% of squamous cell carcinomas had lost the normal Ha-ras-1 allele exhibiting 3 or 2 copies of the mutated counterpart or gene amplification. In the present study, by combining Southern blot and polymerase chain reaction fragment length polymorphism analyses, we detected complete loss of heterozygosity at the beta-globin (Hbb) locus, distal to Ha-ras-1, in 15 of 20 (75%) skin carcinomas. In addition, 5 of 5 informative cases attained homozygosity at the int-2 locus, 27 centimorgans distal to Hbb. Polymerase chain reaction analysis of DNA extracted from papillomas devoid of stromal contamination by fluorescence-activated sorting of single cell dispersions immunolabeled with anti-keratin 13 antibody revealed loss of heterozygosity at the Hbb locus, demonstrating that this event occurs during premalignant stages of tumor development. Interestingly, loss of heterozygosity was only detected in late-stage lesions exhibiting a high degree of dysplasia and areas of microinvasion. Analysis of allelic ratios by densitometric scanning of tumors that had become homozygous at Hbb but retained heterozygosis at Ha-ras-1 indicated mitotic recombination as the mechanism underlying loss of heterozygosity on mouse chromosome 7 during chemically induced skin carcinogenesis. These findings are consistent with the presence of a putative tumor suppressor gene linked to the Hbb locus in the 7F1-ter region of mouse chromosome 7, the functional inactivation of which may constitute a critical event in skin tumor progression, possibly during the malignant conversion stage.
 ...
PMID:Overlapping loss of heterozygosity by mitotic recombination on mouse chromosome 7F1-ter in skin carcinogenesis. 190 26

To gain insight into the mechanisms by which carcinogens induce mutations in human cells, we have been comparing the frequency and spectrum of mutations induced when a shuttle vector, pS189, carrying covalently bound residues of structurally related carcinogens, replicates in human 293 cells. In the present study, we investigated the mutagenic effects of N-hydroxy-1-amino-6-nitropyrene, a partially reduced derivative of 1,6-dinitropyrene (1,6-DNP). The results were compared with what was found previously in the same assay with N-hydroxy-1-aminopyrene, the partially reduced derivative of 1-nitropyrene. The shuttle vector plasmids were exposed to tritiated 1-nitro-6-nitrosopyrene for 1 h in the presence of ascorbic acid, which served as a reducing agent to generate N-hydroxy-1-amino-6-nitropyrene. 32P-Postlabeling showed that only a single adduct was formed, i.e. N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene. There was a linear increase in the number of adducts per plasmid as a function of applied concentration and also in the frequency of supF mutants as a function of adducts per plasmid, reaching 58.8 x 10(-4) above a background of 0.8 x 10(-4). When the frequency of mutants induced when plasmids carrying residues of 1,6-DNP replicated in the human cells was compared with that induced by 1-NP residues, the former was 1.8 times more mutagenic than the latter. Both carcinogens induced mainly base substitutions, primarily G.C----T.A transversions; but 1,6-DNP adducts produced a significant fraction of -1 frameshifts, with most of these located in a unique run of five Gs in the gene. Polymerase termination reactions indicated that 1,6-DNP adducts were formed at every guanine, but not elsewhere in the gene. The 'hot spots' for adduct formation were not perfectly correlated with 'hot spots' for mutation induction. This indicates that the ultimate biological effect of the chemical depends not only on the number of adducts originally formed, but also on such processes as cellular DNA repair, which may remove such adducts from the plasmids before DNA replication occurs, as well as on the structure of the neighboring bases at the site of the adduct.
Carcinogenesis 1991 Jan
PMID:Kinds of mutations found when a shuttle vector containing adducts of 1,6-dinitropyrene replicates in human cells. 198 71

The catalytic activity of the nuclear enzyme poly(ADP-ribose) polymerase (NAD+ ADP-ribosyl transferase, EC 2,4,2,30) is totally dependent upon the presence of DNA strand breaks. Having isolated a full-length cDNA for the polymerase, we have now evaluated the effect of endogenously and exogenously induced DNA strand breaks on the transcriptional control of this enzyme. During retinoic acid or dimethyl-sulfoxide-induced differentiation of HL-60 human leukemia cells, which may involve DNA breaks as well as other changes in chromatin, mRNA levels for the polymerase increased very early and remained high for up to 48 h after which it decreased to pre-induced levels. Polymerase transcript levels did not change, however, during the induction of DNA strand breaks by dimethylsulfate, a variety of other alkylating agents, X-irradiation, or UV-irradiation in several mammalian cell lines. It appears that in sharp contrast to the catalytic requirement of the polymerase, the induction of transcription of the polymerase gene may not be a strand-break-dependent process. The noninducibility of the polymerase gene following DNA damage suggested that there may be adequate levels of the polymerase in the cells to cope with DNA damage. To test this hypothesis we examined the efficacy of DNA repair in Cos cells engineered to overexpress the polymerase. Although there was a slight augmentation of the repair rate, this increase was apparent only after very high levels of DNA damage and only at early repair times. After a longer repair period, the extent of repair in control cell was similar to that in the cell overexpressing the polymerase. We thus conclude that the basal levels of the polymerase are adequate for significant amounts of DNA damage.
Carcinogenesis 1990 Jan
PMID:Expression of the poly(ADP-ribose) polymerase gene following natural and induced DNA strand breakage and effect of hyperexpression on DNA repair. 210 80

High mol. wt genomic DNA was prepared from normal hamster pancreas and the solid and ascites variants of two different hamster transplantable carcinomas, one induced by N-nitrosobis(2-oxopropyl)amine and the other spontaneously occurring. This DNA was transfected into NIH/3T3 cells and resulted in cells that were capable of forming tumors when injected into nude mice. Analysis of the nude mouse tumors by Southern blotting revealed the presence of a band specific for hamster K-ras. Polymerase chain reaction (PCR)-mediated amplification of the K-ras codon 12-13 region of genomic DNA prepared from the transplantable tumors produced a 117 bp fragment which was analyzed by both allele-specific oligonucleotide hybridization and direct DNA sequencing. Oligonucleotide hybridization with probes specific for changes in the first or second position of codons 12 or 13 detected a G to A transversion in the second position of codon 12 in the chemically induced transplantable tumor, and a G to A change in the second position of codon 13 in the spontaneously occurring transplantable carcinomas. The result obtained for the chemically induced tumor was confirmed by direct dideoxy sequencing of the PCR-amplified product. These findings are the first to show a specific oncogene activation in an experimental pancreatic tumor model and also parallel the results recently reported for K-ras mutations in human pancreatic carcinoma.
Carcinogenesis 1990 Nov
PMID:Activation of K-ras in transplantable pancreatic ductal adenocarcinomas of Syrian golden hamsters. 217 98

Activation of c-Ki-ras by point mutation within exon 1 was studied in 33 specimens of dysplastic gastrointestinal lesions or of cancers presumed to arise from dysplasia. Samples were obtained from patients with underlying ulcerative colitis or Barrett's esophagus, two diseases associated with dysplasia and increased rates of colonic or esophageal adenocarcinoma, respectively. Genomic DNA was amplified using primers bounding this exon in the polymerase chain reaction. Polymerase chain reaction products were analyzed by direct dideoxy sequencing. Three point mutations in codon 13 of c-Ki-ras were found, all in colonic specimens (two high-grade dysplasias and one adenocarcinoma arising in ulcerative colitis). No point mutations were observed in the second exon of c-Ki-ras or in and around codons 12, 13, and 61 of c-N-ras and C-Ha-ras in a partial sampling of the specimens. These data indicate that ras family protooncogene activation is an uncommon event at this level of malignant progression in these disease states. Carcinogenesis in ulcerative colitis and Barrett's esophagus may proceed via different pathways than in sporadic colon cancer, perhaps involving loss or inactivation of suppressor genes.
 ...
PMID:Activation of c-Ki-ras in human gastrointestinal dysplasias determined by direct sequencing of polymerase chain reaction products. 218 99

To study the roles of DNA polymerases alpha and beta during replication and repair of damaged DNA, use was made of the fact that during chronic treatment with carcinogens, replication and repair do not necessarily follow the same time sequence. Early cell damage and restorative hyperplasia cause a transient wave of DNA synthesis, while repair replication might be expected to continue throughout the period of treatment with the carcinogen. N-acetylaminofluorene (AAF) was fed in the diet for periods of up to 35 weeks, and at intervals during the feeding period measurements were made of DNA synthesis in vivo, and of DNA polymerases alpha and beta as assayed in vitro after fractionation. The activity of polymerase alpha increased and decreased with the transient early wave of DNA synthesis. Polymerase beta showed an initial rapid increase in activity which peaked before the increase in DNA synthesis, and then decreased. The decrease in activity may be due to the fact that, although AAF continues to be fed in the diet, the foci and nodules which develop no longer metabolise the carcinogen to a form which damages DNA. Thus replication occurs in the nodules while DNA damage and repair occur in the surrounding non-neoplastic liver. With the rapid growth of nodules there is overall an increase in neoplastic tissue, a relative decrease in nonneoplastic tissue, and thus a relative decrease in DNA damage, repair, and induction of polymerase beta. Histological examination showed that by 35 weeks the conversion to neoplasia was virtually complete. These results support the concept that polymerase alpha functions in de novo replication of DNA, and is induced during cell replication, while polymerase beta functions in repair replication, and increases in activity during chronic damage to DNA. Whether it is induced by treatment with carcinogens depends on the duration of treatment, and on other processes (e.g. metabolism of the carcinogen) which take place during the development of malignancy.
Carcinogenesis 1981
PMID:DNA polymerases in replication and repair of DNA during carcinogenesis induced by feeding N-acetylaminofluorene. 727 90

Polymerase chain reaction (PCR)-based screening methods were used to classify mutations arising in vivo at the hypoxanthine guanine phosphoribosyl-transferase (hprt) locus in small samples of human T-lymphocyte clones (< 5 x 10(4) cells) from 29 bus maintenance workers exposed to diesel exhaust, and 14 control individuals. All subjects were healthy, non-smoking males. Among 462 T-cell mutants studied by multiplex-PCR of genomic DNA, only 12 (2.6%) deletions were found: three total deletions, five partial exon deletions and four mutants with one or two exons deleted. Point mutations were classified in 323 mutants using reverse transcriptase-PCR amplification: 74 (22.9%) of these had splice site mutations and 241 (74.6%) had coding errors. Splice mutation was more frequent among the garage workers (24.8%) as compared to the controls (19.5%), possibly reflecting a polycyclic aromatic hydrocarbon-specific mutation induction in these workers. Our results also show that both gene deletion and splice mutation at the hprt-locus in T-cells of healthy non-smokers could be less frequent than previously reported.
Carcinogenesis 1995 Aug
PMID:Classification of mutations at the human hprt-locus in T-lymphocytes of bus maintenance workers by multiplex-PCR and reverse transcriptase-PCR analysis. 754 76

To elucidate the role of p53 in colon tumorigenesis in mice, we examined allele loss and mutational alteration of the p53 gene in colon tumors induced by 1,2-dimethylhydrazine (DMH) in F1 hybrid mice. Intragenic polymorphism of the p53 gene among parental strains enabled us to assess allele loss of the p53 gene and also to determine parental origin of mutated and/or lost alleles. Allele loss was detected in two of 163 tumors heterozygous for the p53 gene. Polymerase chain reaction-single-strand conformation polymorphism analysis of p53 exons 5-8 revealed 33 mutations in 20 of 182 colon tumors, the incidence being lower than that in human colon cancers. The majority of these mutations were of transition type: G:A transitions at non-CpG sites were most prevalent, while those at CpG sites were less common. Distribution of the mutations along p53 amino acid sequence revealed a difference in the location of 'hot spots' between mice and humans. Incidence of p53 alterations did not differ among alleles of different parental origins, suggesting that genetic changes in DMH-induced mouse colon tumors had occurred independently of parental origin and DMH susceptibility. Detailed analysis of p53 mutations on each allele revealed intratumoral heterogeneity in mouse colon tumors. The low incidence of p53 mutations and rare allele loss suggest that p53 alteration plays only a minor role in colon tumorigenesis in mice.
Carcinogenesis 1995 Nov
PMID:Mutational and LOH analyses of p53 alleles in colon tumors induced by 1,2-dimethylhydrazine in F1 hybrid mice. 758 83


1 2 3 4 5 6 7 8 9 10 Next >>