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)

The mutagenic potentials of the human bladder carcinogen 4-amino-biphenyl (ABP) and three of its proximate carcinogenic metabolites, N-hydroxy-4-aminobiphenyl (N-OH-ABP), N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) and N-acetoxy-4-acetylaminobiphenyl (N-OAc-AABP) were tested on a prime human target cell type for carcinogenesis, human uroepithelial cells (HUC). SV-HUC (PC), a near diploid, clonally derived, nontumorigenic SV40-immortalized human uroepithelial cell line that is transformable to tumorigenicity after exposure to ABP and its metabolites, was used for quantitative mutation assays. The end point used was the induction of mutations in the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus, selected using 6-thioguanine resistance (TGr). A single, 24-h exposure of SV-HUC to ABP, N-OH-ABP, N-OH-AABP, or N-OAc-AABP caused a statistically significant, dose-dependent increase in mutation frequency resulting in a 2-30-fold increase in the number of TGr mutants in carcinogen-exposed groups compared to untreated controls. These chemicals were similarly mutagenic towards MC-T11, an SV-HUC-derived low grade tumor cell line that was also shown to be responsive to transformation (in a separate study) by ABP, N-OH-ABP, or N-OH-AABP as judged by the generation of higher grade tumors. In contrast, the mutagenic potencies of ABP and N-OH-ABP were lower when tested on a subclone of SV-HUC (BC) that is refractory to transformation by these chemicals. Thus, these data support a model of transformation in which ABP as well as its metabolites contribute to tumorigenic transformation and neoplastic progression of HUC by inducing mutations in susceptible target cell genes.
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PMID:Induction of thioguanine-resistant mutations in human uroepithelial cells by 4-aminobiphenyl and its N-hydroxy derivatives. 131 36

The isolation of deoxyguanosine-resistant 10T1/2 mouse cell lines following stepwise selection in the presence of increasing concentrations of drug led to the identification of a highly metastatic line, as measured by the ability to form secondary tumors in syngenic mice after intravenous injection. This metastatic deoxyguanosine-resistant mutant was determined to be deficient in hypoxanthine-guanine phosphoribosyltransferase activity, accounting for the resistance to deoxyguanosine. Lectin-binding studies determined that the metastatic potential of high- and low-metastatic revertant clones of this deoxyguanosine-resistant mutant was negatively correlated to soybean agglutinin binding, but not to concanavalin A or wheat germ agglutinin binding. Examination of labelled cell-surface glycoproteins led to the identification of two glycoproteins, gp80 and gp48, which were present on the low-metastatic wild-type cell line but absent from the highly metastatic drug-resistant cells. Our studies suggest that these cell-surface glycoprotein alterations play a role in determining the malignant properties of the cells, and indicate that metastatic variants with the properties described in this report would be useful biological tools for investigations into the roles played by specific cell-surface structures in mechanisms of tumor progression.
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PMID:Characterization of deoxyguanosine-resistant hypoxanthine-guanine phosphoribosyltransferase(-)metastatic variants altered in soybean-agglutinin-binding properties and cell-surface glycoproteins. 206 50

Mutatect MN-11 is a tumor line that can be grown subcutaneously in syngeneic C57BL/6 mice. The frequency of spontaneously arising mutants at the hypoxanthine phosphoribosyltransferase (Hprt) locus was observed to be elevated as a result of in vivo growth. The objective of the present study was to identify factors in the tumor microenvironment that might explain this increase in mutant frequency (MF). When tumors were examined histologically, neutrophils were found to be the predominant infiltrating cell type. Quantitative estimates of the number of neutrophils and MF of tumors in different animals revealed a statistically significant correlation (r = 0.63, P < 0.0001). Immunohistochemical analysis for inducible nitric oxide synthase (iNOS) demonstrated its presence, mainly in neutrophils. Biochemical analysis of tumor homogenates for nitric oxide synthase (NOS) activity indicated a statistically significant correlation with MF (r = 0.77, P < 0.0001). Nitrotyrosine was detected throughout the tumor immunohistochemically; both cytoplasmic and nuclear staining was seen. To increase the number of infiltrating neutrophils, tumors were injected with chemoattractant interleukin-8 and prostaglandin E2. This produced a statistically significant increase in neutrophil content (P = 0.005) and MF (P = 0.0002). As in control MN-11 tumors, neutrophil content and MF were strongly correlated (r = 0.63, P = 0. 003). Because neutrophils are a potential source of genotoxic reactive oxygen and/or nitrogen species, our results support the notion that these tumor-infiltrating cells may be mutagenic and contribute to the burden of genetic abnormalities associated with tumor progression.
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PMID:Neutrophils, nitric oxide synthase, and mutations in the mutatect murine tumor model. 1066 80

Genetic or epigenetic inactivation of one of the DNA mismatch repair (MMR) genes in tumor precursor cells causes a profound mutator phenotype, known as the microsatellite mutator phenotype (MMP). This mutator phenotype induces mutations not only in cancer genes that drive tumorigenesis but also in other DNA repair genes. The functional significance of these successive DNA repair gene mutations, however, has not been substantiated. Here we show that the concomitant inactivation of two DNA MMR genes (hMLH1 and hMSH6) increases the mutator phenotype. We isolated cell clones of the SW48 MMP-positive cell line with either active or inactive hMSH6. All of these clones lacked expression of hMLH1 because of promoter hypermethylation. Compared with inactivation of hMLH1 alone, the additional inactivation of hMSH6 produced a higher mutation rate and a different spectrum of mutations in the endogenous hprt gene. These results confirm our model that the mutator phenotype can increase during tumorigenesis by the consecutive inactivation of different members of the DNA MMR system. Thus, a stronger mutator phenotype accelerates the accumulation of mutations in target cancer genes, which, in turn, speeds up tumor progression. The results of this study also have significant impact on our understanding of the mechanism of DNA MMR.
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PMID:Functional significance of concomitant inactivation of hMLH1 and hMSH6 in tumor cells of the microsatellite mutator phenotype. 1174 74