Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 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 constructed Chinese hamster V79-derived cell lines (V79-rSULT1B1-A and -B) that express rat sulfotransferase 1B1 (rSULT1B1). Sulfotransferase activity towards 1-naphthol was 1020 +/- 220 pmol/min/mg cytosolic protein in V79-rSULT1B1-A cells and 57 +/- 9 pmol/ min/mg in V79-rSULT1B1-B cells. These activities were similar over 100 population doublings and at varying cell densities. Immunostaining indicated a cytoplasmatic localization of rSULT1B1. Expression usually was homogeneous within colonies but showed some variation between colonies. The level of rSULT1B1 protein in V79-rSULT1B1-B cells was similar to that in rat liver but higher than in colon mucosa. The cytotoxicity of the benzylic alcohols 4H-cyclopenta[def]chrysen-4-ol and 6-hydroxymethylbenzo-[a]pyrene was enhanced >100-fold in V79-rSULT1B1-A cells compared with SULT-deficient cells (V79p). Likewise, these compounds showed mutagenic effects (at the hprt locus) in V79-rSULT1B1-A cells starting at a concentration of 0.02 and 0.01 micro M, respectively, but were inactive in V79p cells even at a concentration of 1 micro M. The cell line with the lower expression level, V79-rSULT1B1-B, showed only marginal toxification of the compounds investigated, indicating an important role of the expression level in the test system. A thoroughly characterized mammalian cell system, including positive controls, is now available for studying rSULT1B1-mediated bioactivation of promutagens and protoxicants.
Carcinogenesis 2002 Nov
PMID:Stable expression of rat sulfotransferase 1B1 in V79 cells: activation of benzylic alcohols to mutagens. 1241 36

Lead, a possible human carcinogen, affects signal transduction pathways in many aspects, yet exhibits low mutagenicity in human cells. In this study, we explore whether signaling pathways including the four MAPKs and AKT affect DNA repair and mutagenicity in the exposure of mammalian cells to lead acetate [Pb(II)]. Pb(II) increased the phosphorylated ERK1/2 and phosphorylated AKT but not the phosphorylated ERK5, phosphorylated p38 and JNK activity in human non-small cell lung adenocarcinoma CL3 cells. The duration of ERK1/2 activation was much longer than AKT activation and these two signals were independently activated by Pb(II) in CL3 cells. Intriguingly, a MKK1/2 inhibitor PD98059 (25-50 micro M) markedly suppressed ERK1/2 activation and greatly promoted the hprt mutation frequency and cytotoxicity in Pb(II)-treated CL3 cells. Conversely, inhibition of the AKT signal by wortmannin did not exhibit such effects. Inhibition of the persistently activated ERK1/2 in Pb(II)-treated diploid human fibroblasts by PD98059 also markedly increased the mutagenicity and cytotoxicity. The Pb(II)-induced mutagenicity and cytotoxicity were significantly higher in nucleotide excision repair (NER)-deficient UVL-10 rodent cells than their counterpart AT3-2 cells; also, ERK1/2 activation by Pb(II) was observed in AT3-2 but not UVL-10 cells. Furthermore, cellular NER synthesis was enhanced by Pb(II) exposure, which was markedly suppressed by PD98059. Activation of ERK1/2 by expressing a constitutively active form of MKK1 in CL3 cells also elevated cellular NER synthesis. Together, these results indicate that persistent activation of ERK1/2 signaling by Pb(II) enhances cellular NER synthesis, thereby conferring anti-cytotoxicity and anti-mutagenicity.
Carcinogenesis 2003 Jan
PMID:Persistent activation of ERK1/2 by lead acetate increases nucleotide excision repair synthesis and confers anti-cytotoxicity and anti-mutagenicity. 1253 49

For the simultaneous assessment of in vitro carcinogenicity and mutagenicity of phytoestrogens, the abilities of 5 phytoestrogens, daidzein, genistein, biochanin A, prunetin, and coumestrol, to induce cell transformation and genetic effects were examined using the Syrian hamster embryo (SHE) cell model. Cellular growth was inhibited by all phytoestrogens in a concentration-related manner. The growth inhibitory effect of the compounds was ranked: genistein, prunetin > coumestrol > biochanin A > daidzein, which did not correspond to their apoptosis-inducing abilities. Morphological transformation in SHE cells was elicited by all phytoestrogens, except, prunetin. The transforming activities were ranked as follows: genistein > coumestrol > daidzein > biochanin A. Somatic mutations in SHE cells at the Na(+)/K(+) ATPase and hprt loci were induced only by genistein, coumestrol, or daidzein. Chromosome aberrations were induced by genistein or coumestrol, and aneuploidy in the near diploid range was occurred by genistein or biochanin A. Genistein, biochanin A or daidzein induced DNA adduct formation in SHE cells with the abilities: genistein > biochanin A > daidzein. Prunetin was negative for any of these genetic endpoints. Our results provide evidence that genistein, coumestrol, daidzein and biochanin A induce cell transformation in SHE cells and that the transforming activities of these phytoestrogens correspond to at least 2 of the mutagenic effects by each phytoestrogen, i.e., gene mutations, chromosome aberrations, aneuploidy or DNA adduct formation, suggesting the possible involvement of mutagenicity in the initiation of phytoestrogen-induced carcinogenesis.
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PMID:Cell-transforming activity and mutagenicity of 5 phytoestrogens in cultured mammalian cells. 1270 63

In the budding yeast Saccharomyces cerevisiae, DNA polymerase zeta (pol zeta) is responsible for the great majority of mutations generated during error-prone translesion replication of DNA that contains UV-induced lesions. The catalytic subunit of pol zeta is encoded by the Rev3 gene. The orthologue of Rev3 has been cloned from higher eukaryotic cells, including human, but its role in mutagenesis and carcinogenesis remains obscure. Investigation into the cellular function of pol zeta has been hindered by the fact that Rev3 knockout mice do not survive beyond midgestation, and embryonic stem cells used to derive these mice are not genetically stable. We have generated a transgenic mouse that expresses antisense RNA transcripts to mRev3 endogeneous RNA. These mice are viable, have greatly reduced levels of Rev3 transcript, and have reduced levels of B cells and impaired development of high-affinity memory B cells. Here, we report that exposure of fibroblasts derived from these mice to UV resulted in a 4-5-fold reduction in mutant frequency at the hprt locus at every dose examined, and the mutation spectrum was highly aberrant compared with the control cells. In the control cells, 80% of the mutations were transitions and approximately 75% of these arose from photoproducts in the putative leading strand template. Strikingly, in transgenic cells, most of the mutations were transversions and there was a complete loss of strand bias. This mutation spectrum is highly aberrant and is similar to that induced by UV in human xeroderma pigmentosum variant cells, which lack polymerase eta. These data indicate that most UV-induced mutations are dependent on DNA pol zeta, a function that has been conserved from yeast to higher eukaryotic cells. However, in mammalian cells, other DNA polymerase(s) may accomplish error-prone translesion replication and are responsible for residual UV mutagenesis observed in the absence of pol zeta. Further, these data support a central role for DNA polymerase eta in the error-free bypass of UV photoproducts. The antisense Rev3 mice should be a useful model to study mutagenic lesion bypass by pol zeta in mammalian cells and to investigate the role this polymerase plays in carcinogenesis.
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PMID:Decreased frequency and highly aberrant spectrum of ultraviolet-induced mutations in the hprt gene of mouse fibroblasts expressing antisense RNA to DNA polymerase zeta. 1451 46

2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) and some metabolites were investigated for mutagenicity in mammalian cell lines and bacterial strains engineered for the expression of human enzymes. MeAalphaC induced gene mutations (studied at the hprt locus) in Chinese hamster V79-derived cells co-expressing cytochrome (CYP) 1A2 and sulphotransferase (SULT) 1A1 even at a concentration of 30 nM, but was inactive in cells co-expressing CYP1A2 and N-acetyltransferase (NAT) 1 or 2. MeAalphaC, tested in the presence of rat liver post-mitochondrial fraction, showed strongly enhanced mutagenicity in a Salmonella typhimurium strain expressing human SULT1A1 compared with the control (recipient) strain TA1538/1,8-DNP (deficient in endogenous acetyltransferase). Mutagenicity was also enhanced, although to a lesser extent, when NAT2 was expressed in the latter strain. The metabolite, 2-hydroxylamino-3-methyl-9H-pyrido[2,3-b]indole (N-OH-MeAalphaC) was a direct mutagen to strains TA1538 and TA1538/ 1,8-DNP. This mutagenicity was strongly enhanced in corresponding strains expressing SULT1A1. A moderate enhancement was observed when SULT1A2, SULT1B1, SULT1C2 or NAT2 were expressed in strain TA1538. The remaining enzymes studied (SULT1A3, 1C1, 1E1, 2A1, 2B1a, 2B1b, 4A1 and NAT1) did not indicate any activation of N-OH-MeAalphaC. Preliminary mutagenicity experiments in SULT-expressing S.typhimurium strains were conducted with other hydroxylated metabolites of MeAalphaC. The phenols, 6- and 7-hydroxy-MeAalphaC, were inactive under the conditions studied. The benzylic alcohol, 2-amino-3-hydroxymethyl-9H-pyrido[2,3-b]indole, was mutagenic in a strain expressing SULT1A1, but its activity was much weaker than that of N-OH-MeAalphaC. Thus, N-hydroxylation (e.g. mediated by CYP1A2) and sulpho conjugation (primarily mediated by SULT1A1) was the dominating activation pathway of MeAalphaC in model systems engineered for human enzymes. Some other SULT forms as well as NAT2 were also capable of activating N-OH-MeAalphaC, although with much lower efficiency than SULT1A1. Another minor activation pathway involved benzylic hydroxylation followed by sulpho conjugation by SULT1A1.
Carcinogenesis 2004 May
PMID:Bioactivation of the heterocyclic aromatic amine 2-amino-3-methyl-9H-pyrido [2,3-b]indole (MeAalphaC) in recombinant test systems expressing human xenobiotic-metabolizing enzymes. 1472 82

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

Ground glass hepatocytes (GGHs) are the historic hallmarks for the hepatocytes in the late and non-replicative stages of hepatitis B virus (HBV) infection. We have identified type I and type II GGHs that contain two mutant types of large HBV surface antigens (HBsAg) with deletions over the pre-S1 and pre-S2 regions, respectively. These pre-S mutant HBVsAg accumulate in endoplasmic reticulum (ER), resulting in strong ER stress. Type II GGHs often appear in hepatic nodules in the late phases of HBV infection and proliferate in clusters, suggesting that these mutant pre-S1/S2 HBsAg may be involved in HBV-related hepatocarcinogenesis, associated with ER stress. In this study, we investigated the potential genomic instability imposed by pre-S mutant HBsAg. Based on the analysis of comet assays, we found that the pre-S1 and pre-S2 mutant HBsAg caused oxidative stress and DNA damage. The DNA repair gene ogg1 was greatly induced by over-expression of pre-S mutant HBsAg. Induction of the DNA repair gene ogg1 was also detected in the pre-S2 HBsAg transgenic mice, as well as the type II GGHs from patients with hepatocellular carcinoma, strongly suggesting that the pre-S mutant HBsAg contributes to the oxidative DNA damage to hepatocytes. In addition, the mutation rates in the X-linked hprt gene were enhanced in mouse hepatoma ML1-4a cells, which constitutively expressed the pre-S1/S2 HBsAg. These results indicate that pre-S1/S2 mutant HBsAg, which make up GGHs, induce oxidative DNA damage and mutations in hepatocytes in the late stages of HBV infection.
Carcinogenesis 2004 Oct
PMID:Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. 1518 Sep 47


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