Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.44 (AGT)
 770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alkylation lesions in DNA and RNA result from endogenous compounds, environmental agents and alkylating drugs. Simple methylating agents, e.g. methylnitrosourea, tobacco-specific nitrosamines and drugs like temozolomide or streptozotocin, form adducts at N- and O-atoms in DNA bases. These lesions are mainly repaired by direct base repair, base excision repair, and to some extent by nucleotide excision repair (NER). The identified carcinogenicity of O(6)-methylguanine (O(6)-meG) is largely caused by its miscoding properties. Mutations from this lesion are prevented by O(6)-alkylG-DNA alkyltransferase (MGMT or AGT) that repairs the base in one step. However, the genotoxicity and cytotoxicity of O(6)-meG is mainly due to recognition of O(6)-meG/T (or C) mispairs by the mismatch repair system (MMR) and induction of futile repair cycles, eventually resulting in cytotoxic double-strand breaks. Therefore, inactivation of the MMR system in an AGT-defective background causes resistance to the killing effects of O(6)-alkylating agents, but not to the mutagenic effect. Bifunctional alkylating agents, such as chlorambucil or carmustine (BCNU), are commonly used anti-cancer drugs. DNA lesions caused by these agents are complex and require complex repair mechanisms. Thus, primary chloroethyl adducts at O(6)-G are repaired by AGT, while the secondary highly cytotoxic interstrand cross-links (ICLs) require nucleotide excision repair factors (e.g. XPF-ERCC1) for incision and homologous recombination to complete repair. Recently, Escherichia coli protein AlkB and human homologues were shown to be oxidative demethylases that repair cytotoxic 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) residues. Numerous AlkB homologues are found in viruses, bacteria and eukaryotes, including eight human homologues (hABH1-8). These have distinct locations in subcellular compartments and their functions are only starting to become understood. Surprisingly, AlkB and hABH3 also repair RNA. An evaluation of the biological effects of environmental mutagens, as well as understanding the mechanism of action and resistance to alkylating drugs require a detailed understanding of DNA repair processes.
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PMID:Alkylation damage in DNA and RNA--repair mechanisms and medical significance. 1538 96

The population of Linxian in north central China is at high risk for gastric cardia adenocarcinoma (GCC) and esophageal squamous cell carcinoma (ESCC), and chronic inflammation may contribute to this risk. Interleukin-8 (IL8), a potent chemoattractant, has three well-characterized single nucleotide polymorphisms (SNP), one (-251) of which alters transcriptional activity. Four well-described SNPs in the two IL8 receptors, IL8RA and IL8RB, have been associated with inflammation. We conducted a case-cohort study in the Nutrition Intervention Trials (Linxian, China) to assess the association between these SNPs and incident GCC (n = 90) and ESCC (n = 131). IL8, IL8RA, and IL8RB SNPs were analyzed using a multiplex assay system, haplotypes were constructed, and risks were estimated using Cox proportional hazards models. The homozygous variants of IL8 -251 and +396 were associated with 2-fold increased relative risks for GCC, but the highest risk observed was for the AGT/AGC haplotype of IL8 -251/+396/+781 (relative risk, 4.14; 95% confidence interval, 1.31-13.1). Variation within IL8 was not associated with ESCC. Few subjects had variation at the IL8RA SNP and no significant associations were observed for IL8RB SNPs or haplotypes with either GCC or ESCC. We conclude that variation in IL8 seems to increase the risk for GCC but not ESCC in this high-risk population. These variants could confer an altered IL8 expression pattern or interact with environmental factors to increase the risk for inflammation and GCC.
Cancer Epidemiol Biomarkers Prev 2004 Dec
PMID:Variants of the IL8 and IL8RB genes and risk for gastric cardia adenocarcinoma and esophageal squamous cell carcinoma. 1559 88

ABSTRACTS: BACKGROUND: The carcinogenesis of colorectal cancer has been accepted by a model for a cascade of genetic alterations, named the adenoma-carcinoma sequence. In order to elucidate the carcinogenesis of the colorectal cancer more clearly, the genetic abnormalies of the non-neoplastic mucosal epithelium of the colon and rectum should be investigated. It has been speculated that colonic Paneth cell metaplasia (PaM) is one of the pre-neoplastic mucosa of colonic cancer. Therefore, we studied the propria mucosa of the right colon with PaM from the standpoints of the frequency of the K-ras codon 12 mutations (K-ras), which is initial genetic abnormality in colorectal cancer, and the loss of heterozygosity of microsatellite markers (LOH-MS), which has a relationship to development of colorectal cancer. METHODS: Fifty-two regions with PaM histopathologically from 12 surgically resected right colon specimens were studied. DNA extraction of the colonic mucosa with PaM was obtained using a microdissection method, and the frequency of the K-ras of PaM was investigated by enriched polymerase chain reaction-enzyme linked mini-sequence assay, and the frequency of the LOH-MS (D2S123, D17S250 and D5S346) of PaM was examined by high resolution fluorescenced labeled PCR primers. RESULTS: K-ras mutation was detected in fifteen regions among 52 PaM (28.9%). All mutations were a single mutation and GGT changed to AGT in eleven and GAT in four. LOH-MS were detected in twenty-one regions among 52 PaM (40.4%) (D2S123: 35.4%, 17/48 regions, D17S250: 13.7%, 7/51 regions, and D5S346: 0%, 0/52 regions). No K-ras mutations and LOH-MS were detected in the controls (Colorectal mucosa with no PaM). CONCLUSIONS: Colonic mucosa with Paneth cell metaplasia may be one of the pre-neoplastic mucosa in the development of the colonic epithelial neoplasia.
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PMID:Colonic Paneth cell metaplasia is pre-neoplastic condition of colonic cancer or not? 1570 98

Lung cancer is a leading cause of cancer mortality with an inter-individual difference in susceptibility to the disease. The inheritance of low-efficiency genotypes involved in DNA repair and replication may contribute to the difference in susceptibility. We investigated 44 single nucleotide polymorphisms (SNPs) in 20 DNA repair genes including nucleotide excision repair (NER) genes XPA, ERCC1, ERCC2/XPD, ERCC4/XPF and ERCC5/XPG; base excision repair (BER) genes APE1/APEX, OGG1, MPG, XRCC1, PCNA, POLB, POLiota, LIG3 and EXO1; double-strand break repair (DSB-R) genes XRCC2, XRCC3, XRCC9, NBS1 and ATR; and direct damage reversal (DR) gene MGMT/AGT. The study included 343 non-small cell lung cancer (NSCLC) cases and 413 controls from Norwegian general population. Our results indicate that SNPs in the NER genes ERCC1 (Asn118Asn, 15310G>C, 8902G>T), XPA (-4G>A), ERCC2/XPD (Lys751Gln) and ERCC5/XPD (His46His); the BER genes APE1/APEX (Ile64Val), OGG1 (Ser326Cys), PCNA (1876A>G) and XRCC1 (Arg194Trp, Arg280His, Arg399Gln); and the DSB-R genes ATR (Thr211Met), NBS1 (Glu185Gln), XRCC2 (Arg188His) and XRCC9 (Thr297Ile) modulate NSCLC risk. The level of polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adducts in normal lung tissue from 211 patients was analysed. The variant alleles of XRCC1(Arg280His), XRCC1 (Arg399Gln), ERCC1(G8092T), ERCC5(His46His) and MGMT/AGT(Lys178Arg) were more frequent in patients with PAH-DNA adduct levels lower than the mean whereas the XRCC1(Arg194Trp) variant was more frequent in cases with higher adduct levels than the mean.
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PMID:Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. 1619 37

O6-methylguanine DNA methyltransferase/O6-alkylguanine DNA alkyltransferase (MGMT/AGT) removes alkyl adducts from the O6-position of guanine in DNA. Expression of MGMT in human cancers has been associated with resistance to therapies using alkylating agents. MGMT promoter methylation regulates its expression and response to alkylating agents. A combination of O6-benzylguanine-based inhibitors of MGMT with alkylating agents improved the efficacy. However, this is associated with enhanced cytotoxicity and the induction of GC to AT transition mutations presumably also in progenitor/stem cells. A few recent studies have described analogs of O6-benzylguanine targeting defined pathways of cancer cells that can be used to improve the selectivity of O6-benzylguanine-based inhibitors for cancer cells. Therefore, MGMT inhibitor targeting represents a reliable strategy for improving cancer therapy with alkylating agents.
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PMID:S-alkylthiolation of O6-methylguanine-DNA-methyltransferase (MGMT) to sensitize cancer cells to anticancer therapy. 1729 93

We performed this study to investigate the aberrant methylation profile of the cancer-related genes in Korean non-small cell lung cancer (NSCLC) that previously exhibited high frequencies of methylation in Western populations. The aberrant promoter methylation of eight genes (GSTP1, p16, FHIT, APC, RASSF1A, hMLH1, hMSH2, AGT) was determined by MSP in 99 surgically resected NSCLCs and their corresponding nonmalignant lung tissues. Methylation in the tumor samples was detected at 15% for GSTP1, 22% for p16, 34% for FHIT1, 48% for APC, 40% for RASSF1A, 18% for hMLH1, 8% for hMSH2 and 21% for AGT, whereas it occurred at lower frequencies in the corresponding nonmalignant lung tissues, particularly in the p16 (1%) and RASSF1A (1%) genes. These results suggest that the methylation profiles of NSCLCs in a Korean population are similar to those in Western populations.
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PMID:Aberrant DNA methylation profiles of non-small cell lung cancers in a Korean population. 1753 92

Recent observations raise possibility for constitutively active, mutated JAK2 to modulate expression of RAS genes in CMPD. We analyzed the expression of AGT, renin, AT2R1 and ACE genes in normal and bone marrows of PV and ET patients with the respect to the presence of V617F JAK2 mutation. PV and ET had different expression patterns of major RAS components compared to normal BM which was primarily associated with the JAK2V617F mutation and less with PV or ET disease phenotype. However, AT2R1 was exclusively markedly upregulated only in PV, while ET showed moderate expression irrespective of the JAK2 mutational status.
Cancer Biol Ther 2007 Sep
PMID:Bone marrow renin-angiotensin system expression in polycythemia vera and essential thrombocythemia depends on JAK2 mutational status. 1787 18

Angiotensinogen, a member of the serpin family, is involved in the suppression of tumor growth and metastasis. To investigate whether human angiotensinogen protects against tumor progression in vivo, we established an original bitransgenic model in which transgenic mice expressing human angiotensinogen (Hu-AGT-TG mice) were crossed with a transgenic mouse model of hepatocellular carcinoma (HCC-TG mice). Bitransgenic mice overexpressing human angiotensinogen (HCC/Hu-AGT-TG) had a significantly longer survival time than the HCC-TG mice and a reduction of both tumor growth and blood flow velocities in the liver. This antitumor effect of angiotensinogen is related to a reduced angiogenesis, impaired expression of endothelial arterial markers (active Notch4, Delta-like 4 ligand, and ephrin B2) with a decrease of arterial vessel density in HCC/Hu-AGT-TG mice liver. Overexpression of human angiotensinogen decreases angiogenesis, and prevents tumor sinusoids from remodeling and arterialization, thus delaying tumor progression in vivo.
Cancer Res 2009 Apr 01
PMID:Angiotensinogen delays angiogenesis and tumor growth of hepatocarcinoma in transgenic mice. 1931 81

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. The majority of cases occur in south-east Asia and sub-Saharan Africa where the major risk factors are chronic infection with hepatitis B and C viruses (HBV and HCV) as well as dietary exposure to aflatoxins. Aflatoxin B1, the most commonly occurring and potent of the aflatoxins is associated with a specific AGG to AGT transversion mutation at codon 249 of the p53 gene in human HCC, providing mechanistic support to a causal link between exposure and disease. Prospective epidemiological studies have shown a more than multiplicative interaction between HBV and aflatoxins in terms of HCC risk. However, the biology underlying this statistical interaction is not fully understood. There are a number of potential mechanisms including, among others: the fixation of AFB1-induced mutations in the presence of liver regeneration and hyperplasia induced by chronic HBV infection; the predisposition of HBV-infected hepatocytes to aflatoxin-induced DNA damage; an increase in susceptibility to chronic HBV infection in aflatoxin-exposed individuals; and oxidative stress exacerbated by co-exposure to aflatoxins and chronic hepatitis infection. Priorities for prevention are global HBV vaccination, primary and secondary prevention strategies against aflatoxin and the avoidance of transmission of HCV through good hygiene practices.
Cancer Lett 2009 Dec 01
PMID:A model of interaction: aflatoxins and hepatitis viruses in liver cancer aetiology and prevention. 1934 1

Patients with biliary tract carcinoma have a poor prognosis. Early detection efforts are urgently needed to ameliorate the dismal prognosis for these patients. Mutations of the KRAS2 gene are one of the most common genetic aberrations in this cancer. In this study, we used LigAmp, an ultrasensitive technology for detecting point mutations, to analyze KRAS2 mutations in patients with a variety of neoplastic and non-neoplastic pancreatobiliary diseases. DNA was isolated from 64 samples, including 44 bile samples and 20 serum samples. Oligonucleotides specific for KRAS2 G35A (GAT, G12D), G35T (GTT, G12V), and G34A (AGT, G12S) mutations were used. KRAS2 mutations were detected in 14 of 16 (87.5%) neoplastic bile samples and in 9 of 28 (32.1%) non-neoplastic bile samples. However, the mutation levels were significantly lower in the non-neoplastic bile (median = 0.4%) compared with those in the neoplastic bile (median = 5.1%). KRAS2 mutations were also detected in 9 of 11 (81.8%) serum samples from patients with biliary tract carcinoma, which was further confirmed by cloning BstN1-refractory PCR products and DNA sequencing. However, KRAS2 mutations were not present in the sera from eight patients with benign pancreatobiliary diseases. These data demonstrate that KRAS2 mutations are detectable in both bile and serum using LigAmp. This technology has the potential for early biliary tract carcinoma detection and possibly for residual disease monitoring post-therapy.
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PMID:Ultrasensitive detection of KRAS2 mutations in bile and serum from patients with biliary tract carcinoma using LigAmp technology. 1981 96


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