Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with ataxia-telangiectasia (A-T) and cancer are exposed to additional toxicity due to their underlying inability to repair chemotherapy-induced DNA damage. The authors report the development of osteosarcoma as a second neoplasia in a child with A-T who was treated, without being irradiated, for non-Hodgkin's lymphoma as a primary malignancy. This is the first report of osteosarcoma associated with A-T. The authors postulate that the mechanisms of carcinogenesis are common and independent of the different histopathology categories of these two neoplasias, and the underlying "canvas" of the A-T mutated gene was further triggered by chemotherapy, leading to the development of a second malignancy.
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PMID:Osteosarcoma as a second tumor after treatment for primary non-Hodgkin's lymphoma in a child with ataxia-telangiectasia: presentation of a case and review of possible pathogenetic mechanisms. 1521 20

Array-based comparative genomic hybridization (aCGH) allows the identification of DNA sequence copy number changes at high resolution by co-hybridizing differentially labelled test and control DNAs to a micro-array of genomic clones. The present study has analysed a series of 23 formalin-fixed, paraffin wax-embedded tissue samples of Barrett's adenocarcinoma (BCA, n = 18) and non-neoplastic squamous oesophageal (n = 2) and gastric cardia mucosa (n = 3) by aCGH. The micro-arrays used contained 287 genomic targets covering oncogenes, tumour suppressor genes, and DNA sequences localized within chromosomal regions previously reported to be altered in BCA. DNA sequence copy number changes for a panel of approximately 50 genes were identified, most of which have not been previously described in BCA. DNA sequence copy number gains (mean 41 +/- 25/BCA) were more frequent than DNA sequence copy number losses (mean 20 +/- 15/BCA). The highest frequencies for DNA sequence copy number gains were detected for SNRPN (61%); GNLY (44%); NME1 (44%); DDX15, ABCB1 (MDR), ATM, LAMA3, MYBL2, ZNF217, and TNFRSF6B (39% each); and MSH2, TERC, SERPINE1, AFM137XA11, IGF1R, and PTPN1 (33% each). DNA sequence copy number losses were identified for PDGFB (44%); D17S125 (39%); AKT3 (28%); and RASSFI, FHIT, CDKN2A (p16), and SAS (CDK4) (28% each). In all non-neoplastic tissue samples of squamous oesophageal and gastric cardia mucosa, the measured mean ratios were 1.00 (squamous oesophageal mucosa) or 1.01 (gastric mucosa), indicating that no DNA sequence copy number chances were present. For validation, the DNA sequence copy number changes of selected clones (SNRPN, CMYC, HER2, ZNF217) detected by aCGH were confirmed by fluorescence in situ hybridization (FISH). These data show the sensitivity of aCGH for the identification of DNA sequence copy number changes at high resolution in BCA. The newly identified genes may include so far unknown biomarkers in BCA and are therefore a starting point for further studies elucidating their possible role in Barrett's carcinogenesis.
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PMID:Array-based comparative genomic hybridization for the detection of DNA sequence copy number changes in Barrett's adenocarcinoma. 1522 37

Ataxia telangiectasia (AT) is a hereditary human disorder resulting in a wide variety of clinical manifestations, including progressive neurodegeneration, immunodeficiency, and high incidence of lymphoid tumors. Cells from patients with AT show genetic instability, hypersensitivity to radiation, and a continuous state of oxidative stress. Oxidative stress and genetic instability, including DNA deletions, are involved in carcinogenesis. We examined the effect of dietary supplementation with the thiol-containing antioxidant N-acetyl-l-cysteine (NAC) on levels of oxidative DNA damage and the frequency of DNA deletions in Atm-deficient (AT-mutated) mice. We confirmed that Atm-deficient mice display an increased frequency of DNA deletions (Bishop et al., Cancer Res 2000;60:395). Furthermore, we found that Atm-deficient mice have significantly increased levels of 8-OH deoxyguanosine, an indication of oxidative DNA damage. Dietary supplementation with NAC significantly reduced 8-OH deoxyguanosine level and the frequency of DNA deletions in Atm-deficient mice. These levels were similar to the levels in wild-type mice. Our findings demonstrate that NAC counteracts genetic instability and suggest that genetic instability may be a consequence of oxidative stress in Atm-deficient mice.
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PMID:Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice. 1528 18

We examined human papillomavirus (HPV) typing and the status of ATM, chk2, CDC25C, cdc2 and cyclinB1 in cervical intraepithelial neoplasia (CIN) and invasive cancer (IC). A total of 93 samples [normal: 10; CIN: 34 (CINI:9, CINII:12, CINIII:13); IC: 49 (stage I:10, stage II:21, stage III:15, stage IV:3)] were included in this study. HPV status was evaluated by the PCR non-radioactive HPV detection system. We analyzed ATM, chk2, CDC25C, cdc2 and cyclinB1 protein expression by immunohistochemistry. HPV DNA was detected in 73.5% of 34 CINs and 89.8% of 49 ICs. Detection of HPV subtypes 16 and 18 was more frequent in ICs (46.9%) than in CINs (23.5%) (p=0.0387). Abnormal expression of ATM, chk2, CDC25C, cdc2 and cyclinB1 were 2.9%, 32.4%, 2.9% 20.6% and 0% in CINs and 8.2%, 30.6%, 10.2%, 46.9% and 12.2% in ICs. The alteration of cdc2 was higher in ICs than in CINs (p=0.0198). Altered expression of cdc2 was higher in HPV16 and 18 cases (69.6%) than in other cases (26.9%) (p=0.0042). However, the relationship between HPV typing and ATM, chk2, CDC25C and cyclinB1 expression was not significant. Cdc2 is implicated in cervical carcinogenesis and may be related to p53 inactivation by HPV.
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PMID:Relationship between HPV typing and the status of G2 cell cycle regulators in cervical neoplasia. 1528 42

Gene promoter hypermethylation is increasingly recognized to play an important role in cancer development through silencing of gene transcription. This study determined the methylation profiles of primary colorectal cancers and adenomas to elucidate the role of epigenetic changes in different stages of colorectal carcinogenesis. We examined the methylation profiles of 47 sporadic colorectal cancers, 36 colonic adenomas from patients without cancer and 34 colonic biopsies from patients without colonic lesions. Paired adjacent dysplasia tissues obtained from 17 cancer patients were also examined. Promoter hypermethylation in 10 tumor-related genes (APC, ATM, GSTP1, HLTF, MGMT, hMLH1, p14, p15, SOCS-1 and TIMP-3) were studied by methylation-specific PCR. Promoter hypermethylation was frequently detected in more than 40% of colonic cancers and adenomas in APC, ATM, HLTF, MGMT and hMLH1 genes (p < 0.0001 vs. normal). While low level of methylation was detected in p14, p15 and TIMP-3, there was no methylation detected in GSTP1 and SOCS-1. The frequencies of methylation were comparable between tumors and adenomas, and advanced and nonadvanced adenoma. In contrast, K-ras mutation was only detected in advanced adenomas and cancers. Concurrent methylation in >/= 3 genes was found in 66.7% adenomas and 68.1% cancers but not in normal colonic tissues. Methylation was associated with reduced protein expressions in colorectal adenomas and cancers. Moreover, methylation in ATM was more common in older cancer patients (p = 0.002), but there was no significant association between promoter hypermethylation and other clinicopathologic characteristics of cancer. Our study demonstrated the early and specific involvement of promoter hypermethylation in the colorectal adenoma-carcinoma sequence.
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PMID:Promoter hypermethylation of tumor-related genes in the progression of colorectal neoplasia. 1538 72

Arsenic compounds, which are well-documented human carcinogens, are now used in cancer therapy. Knowledge of the mechanism by which arsenic exerts its toxicity may help in designing a more effective regimen for therapy. In this study, we showed that arsenite could induce prominent mitotic arrest in CGL-2 cells and demonstrated the presence of damaged DNA in arsenite-arrested mitotic cells. We then explored why these cells with arsenite-induced DNA damage were arrested at mitosis instead of G2 stage. When synchronized CGL-2 cells were treated with arsenite at stage G1, S or G2, all progressed into, and arrested at, the mitotic stage and contained damaged DNA, as demonstrated by the appearance of the DNA double-strand break marker, phosphorylated histone H2A.X (gamma-H2AX). Since X-irradiation induced G2 arrest in CGL-2 cells, these cells clearly have a functional G2 DNA damage checkpoint. However, treatment of X-irradiated CGL-2 cells with arsenite resulted in a decrease in G2 cells and an increase in mitotic cells, suggesting that arsenite may inhibit activation of the G2 DNA damage checkpoint and thus allow cells with damaged DNA to proceed from G2 into mitosis. Immunoblot analysis confirmed that arsenite treatment reduced the X-irradiation-induced phosphorylation of both ataxia-telangiectasia, mutated at serine 1981 and Cdc25C at serine 216, events which are crucial for G2 checkpoint activation and G2 arrest. Moreover, a higher frequency of apoptotic cells is observed in mitotic CGL-2 cells arrested by arsenite than those arrested by nocodazole or taxol. Our results show that the combined effects of arsenite in inducing DNA damages, inhibiting the activation of G2 checkpoint, and arresting cells with damaged DNA in the mitotic stage may subsequently enhance the induction of apoptosis in arsenite-arrested mitotic CGL-2 cells.
Carcinogenesis 2005 Jan
PMID:Arsenite induces prominent mitotic arrest via inhibition of G2 checkpoint activation in CGL-2 cells. 1547 1

Angiotensin II is a multi-functional bioactive peptide and recent reports have suggested that angiotensin II is a proangiogenic growth factor. A retrospective cohort study revealed that angiotensin converting enzyme inhibitors decreased cancer risk, however, the precise mechanism is unknown. We hypothesized that endogenous angiotensin II plays a crucial role in tumor-associated angiogenesis. Tumors implanted in the subcutaneous tissue of wild-type mice developed intensive angiogenesis with vascular endothelial growth factor (VEGF) induction in tumor stroma. AT1a receptor (AT1a-R), but not AT1b receptor or AT2 receptor was expressed in tumor stroma and systemic administration of an AT1-R antagonist reduced tumor-associated angiogenesis and VEGF expression in tumor stroma. Angiotensin II up-regulates VEGF expression through the pathway including protein kinase C, AP-1 and NF-kappaB in fibroblasts, the major cellular component of tumor stroma. VEGF is a major determinant of tumor-associated angiogenesis in the present model, since angiogenesis was markedly reduced by either a VEGF neutralizing antibody or a VEGF receptor kinase inhibitor. Compared with the wild-type, tumor-associated angiogenesis was reduced in AT1a-R null mice, with reduced expression of VEGF in the stroma, and this reduction in AT1a-R null mice was not inhibited by an AT1-R antagonist. These suggest that host stromal VEGF induction by AT1a-R signaling is a key regulator of tumor-associated angiogenesis and tumor growth. AT1a-R signaling blockade may be a novel and effective therapeutic strategy against cancers.
Carcinogenesis 2005 Feb
PMID:Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth. 1563 93

Loss of function of oncogenes, tumor suppressor genes and DNA damage processing genes has been implicated in the development of many types of cancer, but for the vast majority of cases, there is no link to specific germ line mutations. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair pathways was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced. Because the effect of haploinsufficiency for one protein is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes, critical for pathways that control DNA damage signaling, repair or apoptosis. To address this issue, primary mouse cells, haploinsufficient for one or two proteins, ATM and RAD9, related to the cellular response to DNA damage were examined. The results show that cells having low levels of both ATM and RAD9 proteins are more sensitive to transformation by radiation, have different DNA double-strand break repair dynamics and are less apoptotic when compared with wild-type controls or those cells haploinsufficient for only one of these proteins. Our conclusions are that under stress conditions, the efficiency and capacity for DNA repair mediated by the ATM/RAD9 cell signaling network depend on the abundance of both proteins and that, in general, DNA repair network efficiencies are genotype-dependent and can vary within a specific range.
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PMID:Combined haploinsufficiency for ATM and RAD9 as a factor in cell transformation, apoptosis, and DNA lesion repair dynamics. 1570 93

Advanced age is strikingly linked to increased incidence of cancer. To gain insight into the mechanism underlying the association between increased cancer incidence and aging in normal human physiological conditions, we used a case-control design and measured the mRNA expression levels of p53, ATM, hTERT and TRF2, the four major protectors of genomic integrity, in isolated peripheral blood lymphocytes from 202 confirmed bladder cancer (BC) patients and 199 healthy controls. Significant age effects on expression levels were observed. When we divided the study subjects into three age groups (<57, 57-65 and > or = 65), the expressions of p53, ATM and TRF2 significantly decreased with advancing age in cases (P for trend < or = 0.001, 0.01 and 0.01 for p53, ATM and TRF2, respectively). In controls, however, p53 expression significantly increased with advancing age (P for trend = 0.05). Among subjects > or = 65 years of age, the expressions of p53, ATM and TRF2 were significantly lower in cases than in controls (P = 0.003, 0.04 and 0.05 for p53, ATM and TRF2, respectively), suggesting that attenuated genomic maintenance mechanisms lead to increased cancer risk in older individuals. When we dichotomized our study population at the median age of study subjects (61 years old), low p53 expression was associated with a significantly increased BC risk in older people (OR = 2.27, 95% CI = 1.00-5.16). In addition, older subjects without detectable hTERT expression had a significantly reduced BC risk (OR = 0.41, 95% CI = 0.17-0.99). Our study provides the first epidemiologic evidence that the increased genomic instability resulting from the combination of telomere dysfunction, impaired ATM- and p53-mediated DNA damage, and/or telomere dysfunction response pathway contributes to increased cancer incidence in the elderly population.
Carcinogenesis 2005 Oct
PMID:Roles of tumor suppressor and telomere maintenance genes in cancer and aging--an epidemiological study. 1590 4

Resveratrol is one of the most extensively studied cancer chemopreventive agents; however, its mechanisms of action are not completely understood. Here, we observed that resveratrol induces S phase arrest via Tyr15 phosphorylation of Cdc2 in human ovarian carcinoma Ovcar-3 cells. Overexpression of Cdc2AF, a mutant resistant to Thr14 and Tyr15 phosphorylation, ablated resveratrol-induced S phase arrest. Further upstream, we observed that resveratrol causes phosphorylation of cell division cycle 25C (Cdc25C) tyrosine phosphatase via the activation of checkpoint kinases Chk1 and Chk2, which in turn were activated via ATM (ataxia telangiectasia mutated)/ATR (ataxia telangiectasia-Rad3-related) kinase in response to DNA damage, as resveratrol also increased phospho-H2A.X (Ser139), which is known to be phosphorylated by ATM/ATR in response to DNA damage. The involvement of these molecules in resveratrol-induced S phase was also supported by the studies showing that addition of ATM/ATR inhibitor caffeine reverses resveratrol-caused activation of ATM/ATR-Chk1/2 as well as phosphorylation of Cdc25C, Cdc2 and H2A.X, and S phase arrest. In additional studies assessing whether observed effects of resveratrol are specific to Ovcar-3 cells, we observed that it also induces S phase arrest and H2A.X (Ser139) phosphorylation in other ovarian cancer cell lines PA-1 and SKOV-3, albeit at different levels; whereas, resveratrol showed only marginal S phase arrest in normal human foreskin fibroblasts with undetectable level of phospho-H2A.X (Ser139). These findings for the first time identify that resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for DNA damage and S phase arrest selectively in ovarian cancer cells, and provide a rationale for the potential efficacy of ATM/ATR agonists in the prevention and intervention of cancer.
Carcinogenesis 2005 Nov
PMID:Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar-3 cells. 1597 56


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