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)

As the pathogenesis of pituitary adenomas remains unclear, the tumor clonal composition of these common neoplasms was studied. Clonality was determined in female patients by analysis of restriction fragment length polymorphisms of the X-chromosome genes hypoxanthine phosphoribosyl transferase and phosphoglycerate kinase in conjunction with their respective methylation patterns. Peripheral lymphocyte DNA was screened from 62 female patients undergoing transsphenoidal surgery for pituitary adenoma. Eleven patients were heterozygous for the BglI site on PGK, 4 for the BamHI site on HPRT, and 1 patient for both sites. Of these 16 patients, 3 had acromegaly, 4 had Cushing's disease, 7 had hyperprolactinemia, and 2 were clinically nonfunctional. After surgery, morphological study, including immunohistochemistry and electron microscopy of the pathological specimens, allowed a direct comparison between clonality and tumor cell type. Control fresh normal pituitary tissue was found to be polyclonal. The following tumors were monoclonal: all 3 somatotroph adenomas, 4 of 4 lactotroph tumors, 3 of 4 corticotroph cell adenomas, a gonadotroph adenoma, and a nonsecretory adenoma. A mixed plurihormonal adenoma was polyclonal, as were 2 tumors consisting of adenomatous lactotrophs interspersed with nontumorous adenohypophyseal pituitary tissue and one corticotroph adenoma mixed with normal pituitary tissue. Functional pituitary adenomas derived from somatotrophs, corticotrophs, or lactotrophs and nonsecretory tumors are monoclonal in nature, suggesting that somatic cell mutations precede clonal expansion of these cells and play a major role in pituitary tumorigenesis.
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PMID:Clonal origin of pituitary adenomas. 197 59

Previous work based on the relative tissue content of glucose-6-phosphate dehydrogenase isoenzymes suggested that parathyroid adenomas, like primary hyperplasia, may be multicellular (not clonal) in origin. We have reexamined this issue by using two independent molecular genetic methods. We report tumor-cell-specific restriction-fragment-length alterations involving the parathyroid hormone gene from two human parathyroid adenomas. These abnormal restriction fragments indicate that in each case a clonal proliferation of cells was present and also suggest that DNA alterations involving the parathyroid hormone locus may be important in the tumorigenesis or clonal evolution of some parathyroid adenomas. In addition, we used a restriction-fragment-length polymorphism in an X-linked gene (hypoxanthine phosphoribosyltransferase) to examine the clonality of eight parathyroid adenomas in women. Of these eight adenomas, six had the DNA hybridization pattern of monoclonality, and two had an equivocal pattern. None of five hyperplastic parathyroid glands had a monoclonal pattern. We conclude that some (and perhaps many) single parathyroid adenomas are monoclonal neoplasms. Our observations suggest that there is a fundamental biologic difference between parathyroid adenomas and primary hyperplasia--a difference that could prove useful in distinguishing these entities clinically.
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PMID:Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. 334 17

Loss of heterozygosity (LOH) plays an important role in the expression of recessive mutations in mammalian cells. To gain insight into the rate and mechanisms of LOH the autosomal HLA-A gene was used as a model system. Spontaneous HLA-A2 mutants originated with a rate of respectively 4.1 x 10(-6) and 6.9 x 10(-6) per cell per generation in TK6 and WI-L2-NS, two isogenic lymphoblastoid cell lines which differ in TP53 status. The rate of loss of HLA-A2 is 10-50 times higher compared to the mutation rate of the X-linked HPRT gene. The homozygous TP53 mutation in WI-L2-NS had no effect on the rate of HLA-A2 loss or the spectrum of these mutations. Microsatellite analysis of most of the HLA-A2 mutants (84%) showed LOH for multiple markers on chromosome arm 6p telomeric of a recombination breakpoint, LOH for all 6p markers, or LOH for markers on both the 6p- and 6q-arms. Cytogenetic analysis showed that these mechanisms gave mutant cells which harbored two intact chromosomes 6 and which were indistinguishable from non-mutant cells. Therefore, loss of HLA-A2 is mainly caused by somatic recombination (33-50%) or chromosome loss with duplication of the remaining chromosome (34-40%). These findings correspond to the mechanisms behind loss of the wild-type RBI allele in retinoblastoma and suggest that both somatic recombination and chromosome loss followed by duplication contribute to tumorigenesis.
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PMID:Chromosome loss with concomitant duplication and recombination both contribute most to loss of heterozygosity in vitro. 944 39

Current models suggest that genomic instability is crucial in the accumulation of the multiple alterations required for tumorigenesis. However, the nature of the initial damage responsible for the origin of genomic instability remains poorly understood. In this investigation we demonstrate that the nucleotide analog 2,6-diaminopurine (DAP) can be used to induce highly focused damage to the large blocks of paracentromeric heterochromatin on chromosomes 1, 9 and 16. A large fraction of cells exposed to DAP exhibit undercondensation of alpha and classical heterochromatin which persists into metaphase. Subsequent chromosome breakage was observed for one of the target chromosomes by preferential exclusion of chromosome 16 fragments into micronuclei (P < 0.0001). The specificity of DAP-induced chromosomal breakage enabled us to utilize it as a reagent to demonstrate that paracentromeric heterochromatin is a sensitive target for the induction of persistent genomic instability. We observed a 100-fold increase in mutagenesis affecting a chromosome 16 marker (APRT) compared with marker loci on chromosomes 17 (TK) or X (HPRT). We previously reported that APRT- mutants were recovered at a high rate upon selection in DAP in a process involving recombinationally mediated loss of heterozygosity that extends from the telomere to the boundary region of the paracentromeric heterochromatin. Karyotypic analysis of DAP-resistant APRT- mutant clones demonstrated extensive genomic instability, particularly evidence of multiple and sequential events affecting chromosome 16. These data suggest that the heterochromatic breakage observed cytogenetically immediately following DAP exposure is also responsible for the initiation of persistent genomic instability.
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PMID:Targeted breakage of paracentromeric heterochromatin induces chromosomal instability. 980 Jan 88

Genetic events leading to the loss of heterozygosity (LOH) have been shown to play a crucial role in the development of cancer. However, LOH events do not occur only in genetically unstable cancer cells but also have been detected in normal somatic cells of mouse and man. Mice, in which one of the alleles for adenine phosphoribosyltransferase (Aprt) has been disrupted by gene targeting, were used to investigate the potency of carcinogens to induce LOH in vivo. After 7,12-dimethyl-1,2-benz[a]anthracene (DMBA) exposure, a 3-fold stronger mutagenic response was detected at the autosomal Aprt gene than at the X chromosomal hypoxantine-guanine phosphoribosyltransferase (Hprt) gene in splenic T-lymphocytes. Allele-specific PCR analysis showed that the normal, nontargeted Aprt allele was lost in 70% of the DMBA-induced Aprt mutants. Fluorescence in situ hybridization analysis demonstrated that the targeted allele had become duplicated in almost all DMBA-induced mutants that displayed LOH at Aprt. These results indicate that the main mechanisms by which DMBA caused LOH were mitotic recombination or chromosome loss and duplication but not deletion. However, after treatment with the alkylating agent N-ethyl-N-nitrosourea, Aprt had a similar mutagenic response to Hprt while the majority (90%) of N-ethyl-N-nitrosourea-induced Aprt mutants had retained both alleles. Unexpectedly, irradiation with x-rays, which induce primarily large deletions, resulted in a significant increase of the mutant frequency at Hprt but not at Aprt. This in vivo study clearly indicates that, in normal somatic cells, carcinogen exposure can result in the induction of LOH events that are compatible with cell survival and may represent an initiating event in tumorigenesis.
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PMID:Carcinogen-induced loss of heterozygosity at the Aprt locus in somatic cells of the mouse. 981 74

Recently, we have shown a hypermutable response to the food-associated heterocyclic amine 2-amino-1-methyl-6-phenylimidazo-[4,5-b]-pyridine (PhIP) in human cells defective in mismatch repair (MMR). These findings suggest that exogenous compounds such as PhIP may play an important role in the generation of tumors in MMR-defective individuals. The specificity of mutations induced by PhIP exposure at the endogenous HPRT locus was determined in cell lines defective in MMR to better understand the mutagenic effects of PhIP in MMR-defective individuals and to gain insight into the molecular mechanism of carcinogenesis induced by PhIP. Eighty-six induced HPRT mutants from two different cell lines were isolated and sequenced after exposure to 10 microM PhIP. Nineteen (22%) of these mutants contained G:C to T:A transversion mutations, consistent with the promutagenic adduct of PhIP at the C8 position of guanine miscoding with adenine. This level of PhIP-induced G:C to T:A transversions was approximately 4.5-fold higher than spontaneous G:C to T:A frequencies. Additionally, a hotspot for mutation was observed in a run of six guanines in HPRT exon 3, where a total of 23 (27%) of all PhIP-induced mutations occurred. These mutations consisted of transversions, transitions, and frameshift mutations. The increase in mutant frequency at this run of guanines corresponded to a 24-fold elevation above the spontaneous frequency in one cell line and a 3.3-fold increase in the other. These data suggest that PhIP may increase the risk of human carcinogenesis mediated by MMR by increasing mutations at runs of guanine residues. PhIP may thereby promote tumorigenesis by mutating growth-regulating genes that contain runs of guanines in their coding sequences, such as BAX, the insulin-like growth factor II receptor IGFIIR, and even the mismatch repair gene hMSH6.
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PMID:Specificity of mutations induced by the food-associated heterocyclic amine 2-amino-1-methyl-6-phenylimidazo-[4,5-b]-pyridine in colon cancer cell lines defective in mismatch repair. 1098 7

Cockayne syndrome (CS) patients are deficient in the transcription coupled repair (TCR) subpathway of nucleotide excision repair (NER) but in contrast to xeroderma pigmentosum patients, who have a defect in the global genome repair subpathway of NER, CS patients do not have an elevated cancer incidence. To determine to what extent a TCR deficiency affects carcinogen-induced mutagenesis and carcinogenesis, CS group B correcting gene (CSB)-deficient mice were treated with the genotoxic carcinogen benzo(a)pyrene (B[a]P) at an oral dose of 13 mg/kg body weight, three times a week. At different time points, mutant frequencies at the inactive lacZ gene (in spleen, liver, and lung) as well as at the active hypoxanthine phosphoribosyltransferase (Hprt) gene (in spleen) were determined to compare mutagenesis at inactive versus active genes. B[a]P treatment gave rise to increased mutant frequencies at lacZ in all of the organs tested without a significant difference between CSB-/- and wild-type mice, whereas B[a]P-induced Hprt mutant frequencies in splenic T-lymphocytes were significantly more enhanced in CSB-/- mice than in control mice. The sequence data obtained from Hprt mutants indicate that B[a]P adducts at guanine residues were preferentially removed from the transcribed strand of the Hprt gene in control mice but not in CSB-/- mice. On oral treatment with B[a]P, the tumor incidence increased in both wild-type and CSB-deficient animals. However, no differences in tumor rate were observed between TCR-deficient CSB-/- mice and wild-type mice, which is in line with the normal cancer susceptibility of CS patients. The mutagenic response at lacZ, in contrast to Hprt, correlated well with the cancer incidence in CSB-/- mice after B[a]P treatment, which suggests that mutations in the bulk of the DNA (inactive genes) are a better predictive marker for carcinogen-induced tumorigenesis than mutations in genes that are actively transcribed. Thus, the global genome repair pathway of NER appears to play an important role in the prevention of cancer.
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PMID:The relationship between benzo[a]pyrene-induced mutagenesis and carcinogenesis in repair-deficient Cockayne syndrome group B mice. 1105 60

In response to ionizing radiation and other agents that damage DNA, the p53 tumor suppressor protein activates multiple cellular processes including cell cycle checkpoints and programmed cell death. Although loss of p53 function is associated with radiation-induced genetic instability in cell lines, it is not clear if this relationship exists in vivo. To study the role of p53 in maintenance of genetic stability in normal tissues following irradiation, we have measured mutant frequencies at the adenine phosphoribosyltransferase (Aprt) and hypothanine-guanine phosphoribosyltransferase (Hprt) loci and examined mechanisms of loss of heterozygosity (LOH) in normal T cells of p53-deficient, Aprt heterozygous mice that were subjected to whole-body irradiation with a single dose of 4Gy X-rays. The radiation-induced mutant frequency at both the Aprt and Hprt loci was elevated in cells from mice with different p53 genotypes. The radiation-induced elevation of p53-/- mice was significantly greater than that of p53+/- or p53+/+ mice and was caused by several different kinds of mutational events at the both chromosomal and intragenic levels. Most significantly, interstitial deletion, which occurs rarely in unirradiated mice, became the most common mechanism leading to LOH in irradiated p53 null mice. These observations support the idea that absence or reduction of p53 expression enhances radiation-induced tumorigenesis by increasing genetic instability at various loci, such as those for tumor suppressor genes.
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PMID:Radiation-induced genetic instability in vivo depends on p53 status. 1199 74

BLM, the gene mutated in Bloom syndrome (BS), encodes an ATP-dependent RecQ DNA helicase that is involved in the resolution of Holliday junctions, in the suppression of crossovers and in the management of damaged replication forks. Cells from BS patients have a characteristically high level of sister chromatid exchanges (SCEs), and increased chromosomal aberrations. Fibroblasts and lymphocytes of BS patients also exhibit increased mutation frequency at the X-linked reporter gene HPRT, suggesting that BLM also plays a role in preventing small scale genomic rearrangements. However, the nature of such small scale alterations has not been well characterized. Here we report the characterization of Hprt mutations in vivo in Blm hypomorphic mice, Blm(tm1Ches)/Blm(tm3Brd). We found that the frequency of Hprt mutants was increased about 6-fold in the Blm(tm1Ches)/Blm(tm3Brd) mice when compared to Blm(tm3Brd) heterozygous mice or wildtype mice. Molecular characterization of Hprt gene in the mutant clones indicates that many of the mutations were caused by deletions that range from several base pairs to several thousand base pairs. While deletions in BLM-proficient somatic cells are often shown to be mediated by direct repeats, all three deletion junctions in Hprt of Blm(tm1Ches)/Blm(tm3Brd) mice were flanked by inverted repeats, suggesting that secondary structures formed during DNA replication, when resolved improperly, may lead to deletions. In addition, single base pair substitution and insertion/deletion were also detected in the mutant clones. Taken together, our results indicated that BLM function is important in preventing small scale genetic alterations. Thus, both large scale and small scale genetic alterations are elevated when BLM is reduced, which may contribute to loss of function of tumor suppressor genes and subsequent tumorigenesis.
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PMID:Small scale genetic alterations contribute to increased mutability at the X-linked Hprt locus in vivo in Blm hypomorphic mice. 2029 87

RHOXF1 has been shown to be expressed in embryonic stem cells, adult germline stem cells and some cancer lines. It has been proposed as a candidate gene to encode transcription factors regulating downstream genes in the human testis with antiapoptotic effects. Its expression in cancer cell lines has implied a similar role in the process of tumorigenesis. The human breast cancer cell lines MDA-MB-231 and MCF-7 were cultured in DMEM medium and transfected with a pGFP-V-RS plasmid bearing an RHOXF1 specific shRNA. Quantitative real- time RT-PCR was performed for RHOXF1, CASP8, BCL2 and HPRT genes. Decreased RHOXF1 expression was confirmed in cells after transfection. shRNA knock down of RHOXF1 resulted in significantly decreased BCL2 expression in both cell lines but no change in CASP8 expression. shRNA targeting RHOXF1 was shown to specifically mediate RHOXF1 gene silencing, so RHOXF1 can mediate transcriptional activation of the BCL2 in cancers and may render tumor cells resistant to apoptotic cell death induced by anticancer therapy. shRNA mediated knock down of RHOXF1 can be effective in induction of apoptotic pathway in cancer cells via BCL2 downregulation, so it can have potential therapeutic utility for human breast cancer.
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PMID:shRNA mediated RHOXF1 silencing influences expression of BCL2 but not CASP8 in MCF-7 and MDA-MB-231 cell lines. 2331 70


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