Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic instability plays important roles in carcinogenesis. In two cell lines which we established from mammary carcinomas induced in lacI-transgenic rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), spontaneous point mutation rates (MRs) of the endogenous hypoxanthine-guanine phosphoribosyltransferase (hprt) gene and lacI transgene were found to be increased. The two rat mammary carcinoma cell lines lacked microsatellite instability (MSI), and nuclear extracts from them were proficient in G/T mismatch binding. The increase of spontaneous point MRs was considered to be due to a mechanism(s) different from mismatch repair insufficiency, and this type of genetic instability was termed as single nucleotide instability (SNI). SNI in the rat mammary carcinoma cell lines was characterized by the elevation of A:T to C:G transversions of the hprt and lacI genes, which were rarely observed in normal mammary epithelial cells. The elevation of A:T to C:G transversions was also present in the lacI gene of the primary carcinomas of the two cell lines, which suggested that the molecular abnormality present in the cell lines was already present in their primary carcinomas. Mth1 mutation, which is known to cause elevation of A:T to C:G transversions, was analyzed in the 2 cell lines and in 11 primary PhIP-induced mammary carcinomas, but no mutations were observed. Finally, spontaneous point MRs of the hprt gene were measured in six human breast cancer cell lines, and increase was found in five of them. These human breast cancer cell lines were proficient in G/T mismatch binding, and were reported to lack MSI. SNI was suggested to play a wide involvement in human and rat mammary carcinogenesis.
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PMID:Single nucleotide instability: a wide involvement in human and rat mammary carcinogenesis? 1235 Nov 49

The global cellular response to UV-induced DNA damage has been analyzed in the p53-proficient human lymphoblastoid strain TK6 versus two isogenic derivatives wherein p53 activity was abrogated by diverse experimental approaches: (i) NH32, carrying a homozygous genetic knockout of p53; and (ii) TK6-5E, expressing the human papillomavirus E6 oncoprotein which binds and functionally inactivates p53 protein. Although widely employed as such, the extent to which intracellular E6 expression faithfully models the p53 deficient state still remains uncertain. Following irradiation with UV (either monochromatic 254 nm UV or broad-spectrum simulated sunlight), relative to wild-type TK6, p53-null NH32 exhibited virtually identical clonogenic survival and kinetics of G1-S progression but was nonetheless profoundly resistant to apoptosis. In addition, there were significant qualitative and quantitative differences between NH32 and TK6 with respect to UV mutagenesis at the endogenous hypoxanthine phosphoribosyltransferase (hprt) locus. However, important disparities were observed between genetically p53-deficient NH32 and E6-expressing TK6-5E regarding the manner in which they responded to UV-induced genotoxic stress in relation to wild-type TK6. Indeed, although NH32 and TK6-5E behaved similarly with respect to UV mutagenesis at the hprt locus, there were significant differences between these strains in clonogenic survival, apoptosis, and G1-S progression. Using a well-defined isogenic system, our data clearly reveal the influence of p53 inactivation on the global response of human cells to UV-induced DNA damage, and highlight an important caveat in the field of p53 biology by directly demonstrating that this influence varies substantially depending upon whether p53 function is abrogated genetically, or through E6 oncoprotein expression.
Carcinogenesis 2002 Oct
PMID:Modulation of the DNA damage response in UV-exposed human lymphoblastoid cells through genetic-versus functional-inactivation of the p53 tumor suppressor. 1237 71

We have shown that phenolic antioxidant tocopherols are oxidized to nonarylating alpha-tocopheryl quinone (alpha-TQ) and arylating gamma- and delta-TQ electrophiles. The arylating quinones stimulate apoptosis and are highly cytotoxic in mammalian cells. Some xenobiotic phenolic antioxidants are mutagens, and it has been suggested that their arylating quinone metabolites are the active agents in mutagenesis related to carcinogenesis. We found that neither alpha- nor gamma-TQ was directly genotoxic in supercoiled-to-nicked circular DNA conversions, but these agents interacted with the cytomegalovirus reporter-driven plasmid and enhanced luciferase transfection, with gamma-TQ > alpha-TQ. The Ames test, using gamma-TQ and a number of Salmonella strains, showed no evidence of bacterial mutagenesis. gamma-TQ was highly cytotoxic and alpha-TQ slightly cytotoxic in eukaryocyte AS52 cells. A guanosine phosphoribosyltransferase gene assay showed that gamma-TQ was highly mutagenic and alpha-TQ slightly mutagenic in AS52 cells. A review of the literature identified associations where a decrease in dietary gamma-tocopherol (gamma-T) diminishes and an increase in dietary gamma-T and its quinone enhances carcinogenicity. Humans and other omnivores selectively accumulate alpha-tocopherol, even though gamma-T is their principal dietary tocopherol. We suggest that this selectivity confers an evolutionary advantage by limiting tissue gamma-T, a putative precursor of the mutagen gamma-TQ.
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PMID:Mutagenicity of tocopheryl quinones: evolutionary advantage of selective accumulation of dietary alpha-tocopherol. 1246 42

Nickel compounds are known to be carcinogenic to humans and show genotoxicity, including the ability to induce chromosome aberrations and neoplastic transformation in vitro. The mutagenicity of nickel compounds is, however, equivocal and the mechanisms of carcinogenesis are still not clear. In this study, the possibility that nickel compounds induce genetic or chromosomal instability was examined, because recent studies in cancer research show that these conditions are critically involved in carcinogenesis. V79 Chinese hamster cells were treated with 320 microM nickel sulfate for 24 h at low cell density (100 cells/100 mm diameter dish) and clones derived from single cells surviving Ni treatment were isolated. When cells grew up to 23-25 population doublings post-treatment, mutation frequency at the HPRT locus and the chromosome aberration frequency of each clone were examined. Five out of 37 clones (13.5%) derived from Ni-treated cells showed a remarkably increased frequency of HPRT mutations (>or=1 x 10(-4)), while only one out of 37 control clones (2.7%) showed this high mutation rate. In addition, 17 out of 37 clones (45.9%) from Ni-treated cells showed structural chromosomal aberrations in 10% or more of cells (up to 45.5%), while only three out of 31 control clones (9.7%) showed this high aberration rate. Out of 37 clones derived from Ni-treated cells, eight (21.6%) and 11 (29.7%) clones showed an increased frequency (>or=5%) of aneuploid and polyploid cells, respectively, while only a few control clones showed such an increase in aneuploid and polyploid cells. These results indicate that nickel sulfate can induce genetic and chromosomal instability in V79 cells.
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PMID:Induction of genetic instability and chromosomal instability by nickel sulfate in V79 Chinese hamster cells. 1262 Oct 68

Epidemiological studies have demonstrated protective effects of vegetables and fruit on risk of cancer, but underlying mechanisms remain unclear. Intervention studies have in some cases contradicted previous epidemiological evidence, e.g. for beta-carotene supplementation and lung cancer, emphasizing the need for mechanistic data. We assessed in vivo mutagenic effects of several dietary items using the HPRT (hypoxanthine-guanine phosphoribosyl transferase) gene assay with T-lymphocytes from 312 individuals (158 lung cancer cases, 154 population controls), who provided information on diet and smoking habits. HPRT mutant frequency (MF) was significantly decreased in relation to intake of vegetables, citrus fruits and berries, respectively, as well as calculated vitamin C intake from diet. There was a significant U-shaped association with dietary carotenoid intake, with lowest MF near population average carotenoid intakes and higher mutation frequencies both at low and high intakes, and a similar borderline significant association was observed for beta-carotene. Our study is consistent with known diet-cancer associations and provides novel human in vivo mechanistic support for a cancer-protective effect of vegetables and fruit by modulation of somatic mutagenesis. Our results also provide support for the increase in lung cancer risk observed particularly in smokers in studies of beta-carotene supplementation.
Carcinogenesis 2003 Apr
PMID:Dietary fruit and vegetables protect against somatic mutation in vivo, but low or high intake of carotenoids does not. 1272 97

In yeast, mutations induced by UV radiation are dependent on the function of the Rev1 gene product, a Y-family DNA polymerase that assists in translesion replication with potentially mutagenic consequences. Human REV1 has been cloned, but its role in mutagenesis and carcinogenesis remains obscure. To examine the role of REV1 in UV mutagenesis in human cells and to evaluate its potential as a therapeutic target to prevent such mutations, we developed a ribozyme that cleaves human REV1 mRNA in vitro. Stable expression of the ribozyme in human cells reduced the target REV1 mRNA up to 90%. We examined the cytotoxic and mutagenic response to UV of seven independent clones that had reduced levels of endogenous REV1 mRNA. In each case, the clonogenic survival after UV was not different from that of the parental cell strains. In contrast, the UV-induced mutant frequencies at the endogenous HPRT locus were reduced up to 75% in cells with reduced levels of REV1 mRNA. The data support the idea that targeting the mutagenic translesion DNA replication pathway can greatly reduce the frequency of induced mutations.
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PMID:Ribozyme-mediated REV1 inhibition reduces the frequency of UV-induced mutations in the human HPRT gene. 1293 Sep 47

An early step in the carcinogenesis of hereditary non-polyposis colorectal cancer (HNPCC) and some sporadic colorectal cancers (CRCs) is the acquisition of a 'mutator phenotype' resulting from defects in DNA mismatch repair (MMR) genes, which normally maintain genomic stability. This mutator phenotype causes an approximately 100-1000-fold increase in base substitutions and small insertion/deletion mutations thereby driving carcinogenesis. It also causes genome-wide microsatellite instability (MSI) due to the inability to repair mutations within these small, hard to replicate, repetitive DNA elements. In contrast, less is known about the role of mutator phenotypes in microsatellite stable (MSS) CRC. In this report, we have measured the mutation rates in 11 MSS CRC cell lines to obtain an estimate of the prevalence of mutator phenotypes in MSS carcinogenesis. Of the 11 cell lines, three of them (27%) possess spontaneous hypoxanthine phosphoribosyltransferase mutation rates approximately 10-100-fold above background. When challenged with alkylating and oxidising agents, the degree of survival and apoptotic responses are different, indicating that these cell lines may represent more than one mutator phenotype. These data demonstrate that a significant portion of MSS CRC cell lines has increased mutation rates and that this may play a role in MSS CRC carcinogenesis.
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PMID:A subgroup of microsatellite stable colorectal cancers has elevated mutation rates and different responses to alkylating and oxidising agents. 1508 1

Long-term exposure to synthetic and endogenous estrogens has been associated with the development of cancer in several tissues. One potential mechanism of estrogen carcinogenesis involves catechol formation and these catechols are further oxidized to electrophilic/redox active o-quinones, which have the potential to both initiate and promote the carcinogenic process. Previously we showed that 4-hydroxyequilenin (4-OHEN) autoxidized to an o-quinone and caused a variety of damage to DNA. Since these deleterious effects could contribute to gene mutations, we investigated the Chinese hamster V79 cells to ascertain the relative ability of estradiol, 4-hydroxyestradiol, 17beta-hydroxyequilenin, 4,17beta-hydroxyequilenin, estrone, 4-hydroxyestrone, equilenin, and 4-hydroxyequilenin to induce the mutation of the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene. All the 4-hydroxylated catechols induced significantly more colony formations in V79 cells as compared to the parent phenols at 100nM, suggesting that the catechol estrogen metabolites are more mutagenic towards the hprt gene than estrogens. Since 4-OHEN induced the highest mutation frequency, we examined a biomarker for transformation potential of this compound in MCF-10A cells using an anchorage-independent growth assay. Although 4-OHEN induced anchorage-independent growth of these cells, the isolated clones were not able to grow as tumors in vivo when injected into nude mice. These cells were assayed for genetic changes using cDNA microarrays. Real time RT-PCR confirmation of some of the differentially expressed genes showed down-regulation of metallothionein 2A, p53, BRCA1, and c-myc. Moreover, we showed the involvement of other genes important in cell transformation and oxidative stress, strengthening the hypothesis that this mechanism plays a considerable role in 4-OHEN-induced anchorage-independent growth.
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PMID:Equine estrogen metabolite 4-hydroxyequilenin induces anchorage-independent growth of human mammary epithelial MCF-10A cells: differential gene expression. 1513 45

Environmental tobacco smoke (ETS), or second-hand smoke, is a widespread contaminant of indoor air in environments where smoking is not prohibited. It is a significant source of exposure to a large number of substances known to be hazardous to human health. Numerous expert panels have concluded that there is sufficient evidence to classify involuntary smoking (or passive smoking) as carcinogenic to humans. According to the recent evaluation by the International Agency for Research on Cancer, involuntary smoking causes lung cancer in never-smokers with an excess risk in the order of 20% for women and 30% for men. The present paper reviews studies on genotoxicity and related endpoints carried out on ETS since the mid-1980s. The evidence from in vitro studies demonstrates induction of DNA strand breaks, formation of DNA adducts, mutagenicity in bacterial assays and cytogenetic effects. In vivo experiments in rodents have shown that exposure to tobacco smoke, whole-body exposure to mainstream smoke (MS), sidestream smoke (SS), or their mixture, causes DNA single strand breaks, aromatic adducts and oxidative damage to DNA, chromosome aberrations and micronuclei. Genotoxicity of transplacental exposure to ETS has also been reported. Review of human biomarker studies conducted among non-smokers with involuntary exposure to tobacco smoke indicates presence of DNA adducts, urinary metabolites of carcinogens, urinary mutagenicity, SCEs and hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene mutations (in newborns exposed through involuntary smoking of the mother). Studies on human lung cancer from smokers and never-smokers involuntarily exposed to tobacco smoke suggest occurrence of similar kinds of genetic alterations in both groups. In conclusion, these overwhelming data are compatible with the current knowledge on the mechanisms of carcinogenesis of tobacco-related cancers, occurring not only in smokers but with a high biological plausibility also in involuntary smokers.
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PMID:Genotoxicity of environmental tobacco smoke: a review. 1557 89

This report reviews the literature on the genotoxicity of mainstream tobacco smoke and cigarette smoke condensate (CSC) published since 1985. CSC is genotoxic in nearly all systems in which it has been tested, with the base/neutral fractions being the most mutagenic. In rodents, cigarette smoke induces sister chromatid exchanges (SCEs) and micronuclei in bone marrow and lung cells. In humans, newborns of smoking mothers have elevated frequencies of HPRT mutants, translocations, and DNA strand breaks. Sperm of smokers have elevated frequencies of aneuploidy, DNA adducts, strand breaks, and oxidative damage. Smoking also produces mutagenic cervical mucus, micronuclei in cervical epithelial cells, and genotoxic amniotic fluid. These data suggest that tobacco smoke may be a human germ-cell mutagen. Tobacco smoke produces mutagenic urine, and it is a human somatic-cell mutagen, producing HPRT mutations, SCEs, microsatellite instability, and DNA damage in a variety of tissues. Of the 11 organ sites at which smoking causes cancer in humans, smoking-associated genotoxic effects have been found in all eight that have been examined thus far: oral/nasal, esophagus, pharynx/larynx, lung, pancreas, myeoloid organs, bladder/ureter, uterine cervix. Lung tumors of smokers contain a high frequency and unique spectrum of TP53 and KRAS mutations, reflective of the PAH (and possibly other) compounds in the smoke. Further studies are needed to clarify the modulation of the genotoxicity of tobacco smoke by various genetic polymorphisms. These data support a model of tobacco smoke carcinogenesis in which the components of tobacco smoke induce mutations that accumulate in a field of tissue that, through selection, drive the carcinogenic process. Most of the data reviewed here are from studies of human smokers. Thus, their relevance to humans cannot be denied, and their explanatory powers not easily dismissed. Tobacco smoke is now the most extreme example of a systemic human mutagen.
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PMID:Genotoxicity of tobacco smoke and tobacco smoke condensate: a review. 1557 90


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