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:2.4.2.7 (adenine phosphoribosyltransferase)
692 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well established that exposure to solar UVB (290-320 nm) gives rise to mutations in oncogenes and tumor suppressor genes that initiate the molecular cascade toward skin cancer. Although UVA (320-400 nm) has also been implicated in multistage photocarcinogenesis, its potential contribution to sunlight mutagenesis remains poorly characterized. We have determined the DNA sequence specificity of mutations induced by UVB (lambda > 290 nm), and by UVA (lambda > 350 nm), at the adenine phosphoribosyltransferase locus of Chinese hamster ovary cells. This has been compared to results previously obtained for stimulated sunlight (lambda > or = 310 nm) and 254-nm UVC in the same gene. We demonstrate that T-->G transversions, a generally rare class of mutation, are induced at high frequency (up to 50%) in UVA-exposed cells. Furthermore, this event comprises a substantial proportion of the simulated sunlight-induced mutant collection (25%) but is significantly less frequent (P < 0.05) in cells irradiated with either UVB (9%) or UVC (5%). We conclude that the mutagenic specificity of broad-spectrum solar light in rodent cells is not determined entirely by the UVB component and that UVA also plays an important role.
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PMID:A role for ultraviolet A in solar mutagenesis. 789 70

To investigate the role of nucleotide excision repair (NER) in the cellular processing of carcinogenic DNA photoproducts induced by defined, environmentally relevant portions of the solar wavelength spectrum, we have determined the mutagenic specificity of simulated sunlight (310-1100 nm), UVA (350-400 nm), and UVB (290-320 nm), as well as of the "nonsolar" model mutagen 254-nm UVC, at the adenine phosphoribosyltransferase (aprt) locus in NER-deficient (ERCC1) Chinese hamster ovary (CHO) cells. The frequency distributions of mutational classes induced by UVB and by simulated sunlight in repair-deficient CHO cells were virtually identical, each showing a marked increase in tandem CC-->TT transitions relative to NER-proficient cells. A striking increase in CC-->TT events was also previously documented for mutated p53 tumor-suppressor genes from nonmelanoma tumors of NER-deficient, skin cancer-prone xeroderma pigmentosum patients, compared to normal individuals. The data therefore indicate that the aprt gene in NER-deficient cultured rodent cells irradiated with artificial solar light generates the same distinctive "fingerprint" for sunlight mutagenesis as the p53 locus in NER-deficient humans exposed to natural sunlight in vivo. Moreover, in strong contrast to the situation for repair-component CHO cells, where a significant role for UVA was previously noted, the mutagenic specificity of simulated sunlight in NER-deficient CHO cells and of natural sunlight in humans afflicted with xeroderma pigmentosum can be entirely accounted for by the UVB portion of the solar wavelength spectrum.
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PMID:Mutagenic specificity of solar UV light in nucleotide excision repair-deficient rodent cells. 855 99

We determined the nature of mutations occurring at the autosomal APRT locus in mismatch-repair-proficient and -deficient colorectal carcinoma cell lines. The analysis of mutations that result in APRT deficiency in a mismatch-repair-deficient strain of DLD-1 heterozygous for this locus enabled us to measure the rate of loss of the wild-type gene through deletion, recombination, or gene conversion as well as the rate of point mutation. The overall rate of mutation at the APRT locus in DLD-1 was elevated 100-fold compared with the mismatch-repair-proficient colorectal carcinoma cell line SW620. Loss of heterozygosity (LOH) at APRT accounted for only 4 to 9% of mutant strains derived from DLD-1, indicating a rate for these types of events of 4 x 10(-7) to 9 x 10(-7). In SW620 the rate of LOH at APRT was about 10-fold higher. LOH was not found at polymorphic markers within the same chromosome subband as APRT, indicating that only a limited portion of the chromosome was affected by these alterations. Chromosome painting of SWS620 mutants revealed that the loss of APRT occurred together with a substantial portion of the long arm of chromosome 16. Differences in the nature of base substitutions at APRT (e.g., the proportion of mutations resulting from transitions or transversions) in these tumor cell lines were also detected. There was also an important similarity---the presence of a mutant APRT gene with multiple base substitutions that may be the result of some sort of error-prone DNA synthesis.
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PMID:Loss of heterozygosity and base substitution at the APRT locus in mismatch-repair-proficient and -deficient colorectal carcinoma cell lines. 888 80

We describe an in vivo mutagenesis model that utilizes reverse mutation and forward mutation at the endogenous Aprt locus. Reverse mutation provides an in situ method for detecting environments or agents that cause point mutations. Forward mutation detects large chromosomal events, including mitotic recombination, chromosome loss, and large multilocus deletion, all of which can lead to loss of heterozygosity. Detection of reverse mutation in vivo is based on the differential capacity of Aprt and Aprt cells to sequester radiolabeled adenine by catalyzing its conversion to adenosine monophosphate with subsequent incorporation into nucleic acids. Cells lacking APRT activity cannot accumulate exogenously administered, tagged adenine, whereas Aprt+ cells can and will thereby become marked. Thus, genetically modified mice with mutant but revertible Aprt alleles should be a useful vehicle for in situ detection of mutagenic activity in the whole animal. the feasibility of this model has been illustrated, first, by showing that APRT-deficient mice are viable and, second, by demonstrating that the minority of Aprt+ cells within a chimeric tumor growing in an Aprt+ mouse can be selectively labeled following IP injection of [14C]-adenine and can be identified by autoradiography. Forward mutation, detected by growth in selective medium of primary cells derived from Aprt+/- heterozygous mice, provides on independent estimate of in vivo mutation frequency. The frequency with which Aprt colonies arise provides a measure of the frequency of Aprt(-)-negative cells in the tissue at that point in time. Culture of skin fibroblasts in 2,6-diaminopurine (DAP) produced Aprt+ colonies with a frequency of about 10(-4). This frequency is similar to that found for human T lymphocytes from individuals heterozygous at the Aprt locus. In both cases, the majority of mutagenic events involved allele loss. Polymerase chain reaction with linked polymorphic microsatellites on mouse chromosome 8 demonstrated that allele loss was mediated mostly by mitotic recombination, as was the case for human T lymphocytes. The high frequency of mitotic recombination and allele loss at a neutral locus has significant implications for the process of tumorigenesis and argues that spontaneous or induced mitotic recombination may play a causal role in the progression to cancer.
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PMID:APRT: a versatile in vivo resident reporter of local mutation and loss of heterozygosity. 899 Oct 80

We have used the adenine phosphoribosyltransferase gene (APRT; 16q24) to investigate the mechanisms of loss of heterozygosity (LOH) in normal human somatic cells in vivo. APRT-deficient (APRT-/-, APRT-/0) T lymphocytes from the peripheral blood of four obligate APRT heterozygotes (APRT+/-) with characterized germ-line mutations were selected in medium containing 100 microM 2,6-diaminopurine. A total of 80 2,6-diaminopurine-resistant T-cell clones from 2 of the heterozygotes were analyzed for this study. The presence or absence of LOH of proximal linked microsatellite repeat markers was used to divide the clones into two groups: (a) those in which LOH was likely due to localized changes in APRT (e.g., point mutations); and (b) those with LOH at additional loci. A total of 61 clones (76%) exhibited LOH of linked microsatellite repeat markers at different locations on 16q, which extended from the smallest measured region (<5.5 cM) to the entire 16q arm. The remaining 19 clones (24%) had point mutations in APRT or other relatively minor alterations. Ten clones with LOH encompassing different regions of 16q were examined by conventional cytogenetics and by fluorescence in situ hybridization using an APRT cosmid probe. All clones exhibited a normal diploid karyotype, and nine exhibited two copies of APRT. The one clone that was hemizygous for APRT had the smallest observed region of LOH in clones from that individual. These results indicate that mitotic recombination and, to a much lesser extent, deletion may be the primary mechanisms for the relatively high frequency of in vivo LOH observed in normal human T cells. Because LOH leads to the expression of recessive tumor suppressor genes in many cancers, these data have significant implications for the role of LOH in the early stages of tumor development, especially in breast cancer.
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PMID:High frequency in vivo loss of heterozygosity is primarily a consequence of mitotic recombination. 906 91

Loss of heterozygosity (LOH) is an important event in tumor formation. We have used polymorphic microsatellite repeat markers to identify and characterize LOH in spontaneous mutants of a human cell line, MR12-1, that is heterozygous for the adenine phosphoribosyltransferase gene (APRT+/-) located on chromosome 16q24.3. Initially, clones without extensive LOH (which are likely derived as a consequence of intragenic point mutations) and clones with multilocus LOH (which are likely due to major chromosome alterations) were identified. Clones with major regions of LOH were further characterized by assaying additional informative microsatellite markers. Analysis of 20 spontaneously-arising, independent APRT-/- clones from MR12-1 demonstrated that nine of the mutants retained both copies of APRT and 11 had undergone multilocus genetic alterations. The nature of LOH in four of the latter clones has been examined in detail by karyotype and fluorescence in situ hybridization analysis (Shao et al., 1996). These data demonstrate that LOH of chromosome 16 may be due to mitotic recombination, interstitial or partial deletion, or to more complex mechanisms. LOH in these clones may be a consequence of events similar to those observed in many tumors.
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PMID:Loss of heterozygosity analysis in a human fibrosarcoma cell line. 918 27

A hemopoietic multistep tumor model, in which IL-3 dependent PB-3c mast cells, following expression of v-H-ras progress in vivo to IL-3 producing autocrine tumors has previously been established. Central for this oncogenic progression is a recessive step, which is reversible by cell fusion and leads to stabilization of IL-3 mRNA with concomitant activation of the autocrine loop. Comparing the IL-3 dependent PB-3c and the IL-3 autocrine V2D1 tumor cells with differential display PCR revealed 12 differentially expressed genes of which eight were upregulated and four downregulated in the tumor. They included four proteases (mouse mast cell protease 2, granzyme B, pepsinogen F and serine protease 1) and two metabolic enzymes (adenine phosphoribosyltransferase and fructose1,6-bisphosphatase). For validation, expression of the identified genes was tested in independent PB-3c precursor clones and their tumor derivatives. Expression of an endogenous retroviral IAP element and three unknown transcripts were consistently upregulated in all tumor lines. In somatic cell hybrids, two of these unknown cDNAs showed a dominant and one a recessive expression pattern. One transcript, expressed in the precursor but downregulated in the tumor cells, was cloned and identified as the murine calcium channel mtrp6.
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PMID:Search for oncogenic regulators in an autocrine tumor model using differential display PCR: identification of novel candidate genes including the calcium channel mtrp6. 1005 Aug 85

Heritable gene silencing is an important mechanism of tumor suppressor gene inactivation in a variety of human cancers. In the present study, we show that methylation-associated silencing of the autosomal adenine phosphoribosyltransferase (Aprt) locus occurs in primary mouse kidney cells. Aprt-deficient cells were isolated from mice that were heterozygous for Aprt, i.e., they contained one wild-type Aprt allele and one targeted allele bearing an insertion of the bacterial neo gene. Although silencing of the wild-type allele alone was sufficient for the cells to become completely Aprt-deficient, biallelic methylation of the promoter region was found to occur. Moreover, despite the absence of selective pressure against the targeted allele, phenotypic silencing of the inserted neo gene accompanied silencing of the wild-type Aprt allele. A potential role for allelic homology in these events is discussed.
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PMID:Biallelic methylation and silencing of mouse Aprt in normal kidney cells. 1091 47

Pluripotent embryonic stem (ES) cells have been used to produce genetically modified mice as experimental models of human genetic diseases. Increasingly, human ES cells are being considered for their potential in the treatment of injury and disease. Here we have shown that mutation in murine ES cells, heterozygous at the selectable Aprt locus, differs from that in embryonic somatic cells. The mutation frequency in ES cells is significantly lower than that in mouse embryonic fibroblasts, which is similar to that in adult cells in vivo. The distribution of spontaneous mutagenic events is remarkably different between the two cell types. Although loss of the functional allele is the predominant mutation type in both cases, representing about 80% of all events, mitotic recombination accounted for all loss of heterozygosity events detected in somatic cells. In contrast, mitotic recombination in ES cells appeared to be suppressed and chromosome loss/reduplication, leading to uniparental disomy (UPD), represented more than half of the loss of heterozygosity events. Extended culture of ES cells led to accumulation of cells with adenine phosphoribosyltransferase deficiency and UPD. Because UPD leads to reduction to homozygosity at multiple recessive disease loci, including tumor suppressor loci, in the affected chromosome, the increased risk of tumor formation after stem cell therapy should be viewed with concern.
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PMID:Embryonic stem cells and somatic cells differ in mutation frequency and type. 1189 38

Mice null for the Pms2 mismatch repair (MMR) gene exhibit a predisposition to lymphoma, microsatellite repeat instability, and failure of spermatogenesis. To study the role of Pms2 in the maintenance of in vivo genomic integrity in somatic cells, we characterized Aprt mutations in T cells and fibroblasts of 129 x C3H Pms2-/-Aprt+/- mice. The spontaneous frequency of DAP-resistant T lymphocytes, as a consequence of APRT-deficiency, was increased threefold. Point mutation, which accounted for less than 20% of the DAP(r) mutant clones in Pms2+/+ mice, was predominant in the mutant T cell clones from Pms2-/- mice. These point mutations were predominantly TA to CG transitions. Fibroblasts of Pms2-/- mice exhibited only a modest increase in the frequency of clones with point mutations, such that mitotic recombination was still the primary cause of APRT deficiency. Thus, the mutator phenotype as a consequence of PMS2 deficiency is tissue-dependent, which may be related to the tissue-specific tumor proneness of Pms2-/- mice.
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PMID:Loss of heterozygosity and point mutation at Aprt locus in T cells and fibroblasts of Pms2-/- mice. 1197 43


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