UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The toxicity of Ni(II), Co(II) and Cu(II) in animals, and that of Cd(II) in cultured cells, has been associated with generation of the promutagenic lesion 8-oxo-7,8-dihydroguanine (8-oxoguanine) in DNA, among other effects. One possible source of this base may be 8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-triphosphate (8-oxo-dGTP), a product of oxidative damage to the nucleotide pool, from which it is incorporated into DNA. To promote such incorporation, the metals would have to inhibit specific cellular 8-oxo-dGTPases that eliminate 8-oxo-dGTP from the nucleotide pool. The present study was designed to test such inhibition in vitro on 8-oxo-dGTPases from two different species, the human MTH1 protein and Escherichia coli MutT protein. In the presence of Mg(II), the natural activator of 8-oxo-dGTPases, all four metals were found to inhibit both enzymes. For MTH1, the IC50 values (+/- SE; n = 3-4) were 17 +/- 2 microM for Cu(II), 30 +/- 8 microM for Cd(II), 376 +/- 71 microM for Co(II) and 801 +/- 97 microM for Ni(II). For MutT, they were 60 +/- 6 microM for Cd(II), 102 +/- 8 microM for Cu(II), 1461 +/- 96 microM for Ni(II) and 8788 +/- 1003 microM for Co(II). Thus, Cu(II) and Cd(II) emerged as much stronger inhibitors than Ni(II) and Co(II), and MTH1 appeared to be generally more sensitive to metal inhibition than MutT. Interestingly, in the absence of Mg(II), the activity of the enzymes could be restored by Co(II) to 73% of that with Mg(II) alone for MutT, and 34% for MTH1, the other metals being much less or non-effective. The difference in sensitivity to metal inhibition between the two enzymes may reflect the differences in the amino acid ligands, especially the cysteine ligand, outside their evolutionarily conserved Mg(II)-binding active sites, which might indicate predominantly non-competitive or uncompetitive mechanism of the inhibition. The overall results suggest that inhibition of 8-oxo-dGTPases may be involved in the mechanisms of induction of the 8-oxoguanine lesion in DNA by the metal ions studied, especially the non-redox-active Cd(II) cation.
Carcinogenesis 1997 Sep
PMID:Sensitivity of Escherichia coli (MutT) and human (MTH1) 8-oxo-dGTPases to in vitro inhibition by the carcinogenic metals, nickel(II), copper(II), cobalt(II) and cadmium(II). 932 76

8-oxo-deoxyguanosine triphosphate (8-oxo-dGTP) is a major oxidation product in the nucleotide pool of the cell and is a potent mutagen, because it can be incorporated into DNA with equal frequency opposite either template C or A. The human MTH1 gene (hMTH1) is a homologue of the E. coli mutator gene mutT, which encodes 8-oxo-dGTPase. hMTH1 protein reduces spontaneous mutations by removing 8-oxo-dGTP from the triphosphate pool. To determine whether this gene is associated with carcinogenesis of human ovarian cancer, the present study examined, for the first time, the hMTH1 sequence in 49 ovarian cancers and 9 ovarian cancer cell lines by means of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and sequencing analyses. A Gright curved arrow A transition at codon 83 was detected in one patient and one cell line (3.4%), followed by an amino acid change (valineright curved arrow methionine) which was known to cause the protein to be less active in vitro. This one base substitution was found in normal and corresponding tumor DNA, and its allele type was heterozygous. The same change has been detected in HNPCC (hereditary non-polyposis colorectal cancer) and gastric cancer patients, and thus it may not represent a mutation specific for ovarian cancer. A silent Tright curved arrow C transition at codon 119 was detected in 12 patients and 2 cell lines (24.1%). No specific mutations in hMTH1 were found in either ovarian cancer patients or cell lines. Thus, it appears that hMTH1 is not directly associated with ovarian cancer.
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PMID:Mutation analysis of the hMTH1 gene in sporadic human ovarian cancer. 1093 85

Oxidative DNA damage is thought to contribute to carcinogenesis, ageing, and neurological degeneration. Further, the cumulative risk of cancer increases dramatically with age in humans. In general terms, cancer can be regarded as a degenerative disease of ageing. There is evidence for the accumulation of oxidative DNA damage with age based on studies mainly measuring an increase in 8-oxoguanine. 8-Oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is formed in the nucleotide pool of a cell during normal cellular metabolism. When 8-oxoguanine is incorporated into DNA causes mutation. Organisms possess 8-oxo-dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP. To analyze the function of MTH1 with 8-oxo-dGTPase activity in vivo, we generated a mouse line carrying a mutant MTH1 allele created by targeted gene disruption. MTH1 homozygous mutant mice were found to have a physically normal appearance, but seemed to have lost 8-oxo-dGTPase activity in liver extracts. When we examined the susceptibility of the mutant mice to spontaneous tumorigenesis, no significant difference was observed in survival rate of MTH1+/+ and MTH1-/- mice. However, pathological examination revealed a statistically significant difference in the incidence of tumors. More tumors were formed in lungs, livers, and stomachs of MTH1-/- mice than in those of the wild type mice. These studies with MTH1-null mutant mice provided an important insight into the role of this nucleotide sanitization enzyme in terms of the spontaneous tumorigenesis as well as mutagenesis caused by the oxygen-induced DNA damage.
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PMID:Analysis of MTH1 gene function in mice with targeted mutagenesis. 1137 88

MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP to monophosphates, and thus avoids errors caused by their misincorporation during DNA replication or transcription, which may result in carcinogenesis or neurodegeneration. This substrate specificity for oxidized purine nucleoside triphosphates was investigated by mutation analyses based on the sequence comparison with the Escherichia coli homolog, MutT, which hydrolyzes only 8-oxo-dGTP and 8-oxo-rGTP but not oxidized forms of dATP or ATP. Neither a replacement of the phosphohydrolase module of MTH1 with that of MutT nor deletions of the C-terminal region of MTH1, which is unique for MTH1, altered the substrate specificity of MTH1. In contrast, the substitution of residues at position Trp-117 and Asp-119 of MTH1, which showed apparent chemical shift perturbations with 8-oxo-dGDP in NMR analyses but are not conserved in MutT, affected the substrate specificity. Trp-117 is essential for MTH1 to recognize both 8-oxo-dGTP and 2-hydroxy-dATP, whereas Asp-119 is only essential for recognizing 2-hydroxy-dATP, thus suggesting that origins of the substrate-binding pockets for MTH1 and MutT are different.
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PMID:A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1. 1175 18

Oxidative damage of nucleotides within DNA or precursor pools caused by oxygen radicals is thought to play an important role in spontaneous mutagenesis, as well as carcinogenesis and aging. In particular, 8-oxodGTP and 2-OHdATP are potent mutagenic substrate for DNA synthesis. Mammalian MTH1 catalyzes hydrolysis of these mutagenic substrates, suggesting that it functions to prevent mutagenesis caused by these oxidized nucleotides. We have established MTH1(-/-) mice lacking the 8-oxodGTPase activity, which were shown to be susceptible to lung, liver and stomach cancers. To examine in vivo mutation events due to the MTH1-deficiency, a reporter gene, rpsL of Escherichia coli, was introduced into MTH1(-/-) mice. Interestingly, the net frequency of rpsL(-) forward mutants showed no apparent increase in MTH1(-/-) mice as compared to MTH1(+/+) mice. However, we found differences between these two genotypes in the class- and site-distributions of the rpsL(-) mutations recovered from the mice. Unlike MutT-deficient E. coli showing 1000-fold higher frequency of A:T-->C:G transversion than the wild type cells, an increase in frequency of A:T-->C:G transversion was not evident in MTH1 nullizygous mice. Nevertheless, the frequency of single-base frameshifts at mononucleotide runs was 5.7-fold higher in spleens of MTH1(-/-) mice than in those of wild type mice. Since the elevated incidence of single-base frameshifts at mononucleotide runs is a hallmark of the defect in MSH2-dependent mismatch repair system, this weak site-specific mutator effect of MTH1(-/-) mice could be attributed to a partial sequestration of the mismatch repair function that may act to correct mispairs with the oxidized nucleotides. Consistent with this hypothesis, a significant increase in the frequency of G:C-->T:A transversions was observed with MTH1(-/-) MSH2(-/-) mice over MSH2(-/-) mice alone. These results suggest a possible involvement of multiple anti-mutagenic pathways, including the MTH1 protein and other repair system(s), in mutagenesis caused by the oxidized nucleotides.
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PMID:Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. 1253 Oct 17

In mammalian cells, more than one genome in a single cell has to be maintained throughout the entire life of the cell, namely, one in the nucleus and the other in the mitochondria. The genomes and their precursor nucleotides are highly exposed to reactive oxygen species, which are inevitably generated as a result of the respiratory function in mitochondria. To counteract such oxidative damage in nucleic acids, cells are equipped with several defense mechanisms. Modified nucleotides in the nucleotide pools are hydrolyzed, thus avoiding their incorporation into DNA or RNA. Damaged bases in DNA with relatively small chemical alterations are mainly repaired by the base excision repair (BER) system, which is initiated by the excision of damaged bases by specific DNA glycosylases. MTH1 protein hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, and 2-hydroxy (OH)-dATP to the monophosphates, and MTH1 are located in the cytoplasm, mitochondria, and nucleus. We observed an increased susceptibility to spontaneous carcinogenesis in Mth1-deficient mice and an alteration of MTH1 expression along with the accumulation of 8-oxo-dG in patients with various neurodegenerative diseases. Enzymes for the BER pathway, namely, 8-oxoG DNA glycosylase (OGG1), 2-OH-A/adenine DNA glycosylase (MUTYH), and AP endonuclease (APEX2) are also located both in the mitochondria and in the nuclei, and the expression of mitochondrial OGG1 is altered in patients with various neurodegenerative diseases. We also observed increased susceptibilities to spontaneous carcinogenesis in OGG1 and MUTYH-deficient mice. The increased occurrence of lung tumor in OGG1-deficient mice was completely abolished by the concomitant disruption of the Mth1 gene.
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PMID:Biological significance of the defense mechanisms against oxidative damage in nucleic acids caused by reactive oxygen species: from mitochondria to nuclei. 1512 88

To counteract oxidative damage in nucleic acids, mammalian cells are equipped with several defense mechanisms. We herein review that MTH1, MUTYH and OGG1 play important roles in mammalian cells avoiding an accumulation of oxidative DNA damage, both in the nuclear and mitochondrial genomes, thereby suppressing carcinogenesis and cell death. MTH1 efficiently hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP and 2-hydroxy (OH)-dATP, to the monophosphates, thus avoiding the incorporation of such oxidized nucleotides into the nuclear and mitochondrial genomes. OGG1 excises 8-oxoG in DNA as a DNA glycosylase and thus minimizes the accumulation of 8-oxoG in the cellular genomes. MUTYH excises adenine opposite 8-oxoG, and thus suppresses 8-oxoG-induced mutagenesis. MUTYH also possesses a 2-OH-A DNA glycosylase activity for excising 2-OH-A incorporated into the cellular genomes. Increased susceptibilities to spontaneous carcinogenesis of the liver, lung or intestine were observed in MTH1-, OGG1- and MUTYH-null mice, respectively. The increased occurrence of lung tumors in OGG1-null mice was abolished by the concomitant disruption of the Mth1 gene, indicating that an increased accumulation of 8-oxoG and/or 2-OH-A might cause cell death. Furthermore, these defense mechanisms also likely play an important role in neuroprotection.
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PMID:The defense mechanisms in mammalian cells against oxidative damage in nucleic acids and their involvement in the suppression of mutagenesis and cell death. 1529 49

Mammalian MTH1 proteins, homologs of Escherichia coli MutT, are enzymes decomposing 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) to 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-monophosphate and inorganic pyrophosphate. They play an antimutagenic role by preventing the incorporation of promutagenic 8-oxo-dGTP into DNA. MTH1 gene expression is higher in some physiological types of mammalian cells and in numerous cancer cells, but the mechanism of that upregulation still remains unclear. It has been hypothesized that MTH1 expression might be associated with a proliferation rate of the cells. Therefore, we tested this hypothesis by comparing the functional levels of MTH1 gene expression measured as the 8-oxo-dGTPase activity of its protein products in normal mouse livers and hepatectomized regenerating livers. Although the proliferation rate of the hepatocytes in the regenerating livers was much higher than that in control livers, as confirmed by immunohistochemical assay of proliferating cell nuclear antigen, the 8-oxo-dGTPase activity was not different. In a second approach, we used 57 lines of human cancer cells in which 8-oxo-dGTPase activity was measured and confronted with cell population doubling time. No significant correlations between 8-oxo-dGTPase activity and proliferation rate were observed within groups of six leukemia, eight melanoma, nine lung, seven colon, six central nervous system, six ovarian, eight renal, and seven breast cancer cell lines. Thus, we conclude that the MTH1 expression manifested as the 8-oxo-dGTPase activity of its protein products in mammalian cells is not associated with proliferation rate. Our results will help in further testing of the hypothesis that MTH1 overexpression may be a specific marker of carcinogenesis and/or oxidative stress.
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PMID:Cellular 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase activity of human and mouse MTH1 proteins does not depend on the proliferation rate. 1547 5

Genomes and their precursor nucleotides are highly exposed to reactive oxygen species, which are generated both as byproducts of oxygen respiration or molecular executors in the host defense, and by environmental exposure to ionizing radiation and chemicals. To counteract such oxidative damage in nucleic acids, mammalian cells are equipped with three distinct enzymes. MTH1 protein hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-2'-deoxyguanosine triphosphate and 2-hydroxy-2'-deoxyadenosine triphosphate (2-OH-dATP), to the corresponding monophosphates. We observed increased susceptibility to spontaneous carcinogenesis in MTH1-null mice, which exhibit an increased occurrence of A:T-->C:G and G:C-->T:A transversion mutations. 8-Oxoguanine (8-oxoG) DNA glycosylase, encoded by the OGG1 gene, and adenine DNA glycosylase, encoded by the MUTYH gene, are responsible for the suppression of G:C to T:A transversions caused by the accumulation of 8-oxoG in the genome. Deficiency of these enzymes leads to increased tumorigenesis in the lung and intestinal tract in mice, respectively. MUTYH deficiency may also increase G:C to T:A transversions through the misincorporation of 2-OH-dATP, especially in the intestinal tract, since MUTYH can excise 2-hydroxyadenine opposite guanine in genomic DNA and the repair activity is selectively impaired by a mutation found in patients with autosomal recessive colorectal adenomatous polyposis.
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PMID:Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids. 1660 34

Fifty single-nucleotide polymorphisms (SNPs) associated with amino acid changes in 36 genes involved in diverse DNA repair pathways were assessed for associations with risk for small cell lung carcinoma (SCLC) by a case-control study consisting of 211 SCLC cases and 685 controls. An SNP, Val83Met, in the MTH1 (microtT homolog 1) gene encoding a triphosphatase that hydrolyzes pro-mutagenic oxidized nucleoside triphosphates, such as 8-hydroxy-dGTP and 2-hydroxy-dATP, showed the strongest and a significant association with SCLC risk [odds ratio (OR)=1.6, 95% confidence interval (CI): 1.2-2.2, P=0.004], while three other SNPs in the TP53, BLM and SNM1 genes, respectively, also showed marginal associations (0.05<P<0.1). Another SNP, which causes a nucleotide change in the 5'-UTR of MTH1 transcripts leading to alternative translation initiation, was additionally examined and the SNP also showed a significant association (OR=1.7, 95% CI: 1.2-2.3, P=0.002). The two SNPs in the MTH1 gene were in linkage disequilibrium, and the OR for carrying a copy of the haplotype consisting of both the risky SNP alleles was 2.0 (95% CI: 1.2-3.2, P=0.002). The present results indicate that inter-individual differences in MTH1 activities due to SNPs are involved in susceptibility to SCLC.
Carcinogenesis 2006 Dec
PMID:Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk. 1677 34

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