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PubMed1996

Identification and characterization of a new gene physically linked to the ATM gene.

Ataxia telangiectasia (AT) is an autosomal recessive disease of unknown etiology associated with cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, and hypersensitivity to ionizing radiation. Although AT has been divided into four complementation groups by its radioresistant-DNA synthesis phenotype, the ATM gene has been isolated as the candidate gene responsible for all AT groups. We identified a new gene, designated NPAT, from the major AT locus on human chromosome 11q22-q23. The gene encoded a 1421-amino-acid protein containing nuclear localization signals and phosphorylation target sites by cyclin-dependent protein kinases associated with E2F. The messenger RNA of NPAT was detected in all human tissues examined, and its genomic sequence was strongly conserved through eukaryotes, suggesting that the NPAT gene may be essential for cell maintenance and may be a member of the housekeeping genes. Analysis of the genomic region of NPAT surprisingly revealed that the gene existed only 0.5 kb apart from the 5' end of the ATM transcript with opposite transcriptional direction. It may be possible to propose the idea that the promoter region could be shared by both housekeeping genes and that each gene could influence the expression of the other.

Amino Acid Sequence↗
PubMed2006

ATM-dependent DNA damage surveillance in T-cell development and leukemogenesis: the DSB connection.

The immune system is capable of recognizing and eliminating an enormous array of pathogens due to the extremely diverse antigen receptor repertoire of T and B lymphocytes. However, the development of lymphocytes bearing receptors with unique specificities requires the generation of programmed double strand breaks (DSBs) coupled with bursts of proliferation, rendering lymphocytes susceptible to mutations contributing to oncogenic transformation. Consequently, mechanisms responsible for monitoring global genomic integrity must be activated during lymphocyte development to limit the oncogenic potential of antigen receptor locus recombination. Mutations in ATM (ataxia-telangiectasia mutated), a kinase that coordinates DSB monitoring and the response to DNA damage, result in impaired T-cell development and predispose to T-cell leukemia. Here, we review recent evidence providing insight into the mechanisms by which ATM promotes normal lymphocyte development and protects from neoplastic transformation.

Animals↗
PubMed1981

Partial inactivation of Na,K-ATPase in cortical brain slices incubated in normal Krebs-Ringer phosphate medium at 1 and at 10 atm oxygen pressures.

Na,K-ATPase (ATP phosphohydrolase EC 3.6.1.3) activity was determined in homogenates of cortical brain slices after incubation in normal Krebs-Ringer phosphate medium at 1 atm oxygen pressure. After 10 min of incubation Na,K-ATPase activity was reduced by approximately 50%. Longer incubation did not cause further change in activity. The presence of 0.1 mM-MnCl2 in the medium offered significant protection, while an excursion to 10 atm oxygen pressure caused further inactivation. Measurements of malonaldehyde levels suggest that the inhibition of Na,K-ATPase is a result of lipid peroxidation. The evidence indicates that brain slices incubated under standard conditions suffer considerable oxidative damage.

Animals↗
PubMed1977

Effect of a novel adenosine deaminase inhibitor (co-vidarabine, co-V) upon the antiviral activity in vitro and in vivo of vidarabine (Vira-Atm) for DNA virus replication.

A new potent inhibitor of adenosine deaminase (co-vidarabine) was used in combination studies with adenine arabinoside (vidarabine, Vira-ATM) to protect this purine nucleoside from enzymatic deamination to the more weakly active metabolite, hypoxanthine arabinoside. Comparing the combination to vidarabine alone, a significant increase (10-fold) of the antiviral activity of the combined drugs was observed against herpes and vaccinia viruses in tissue culture and subcutaneously, against cranial herpesvirus infections in mice. Several other investigators have also recently reported several-fold enhancement of vidarabine activity by newly described deaminase inhibitors. They observed that plaque formation by several large DNA-containing viruses (herpes, vaccinia, varicella zoster) and an RNA-containing oncogenic virus was markedly prevented by the combination compared to vidarabine alone. In animals, enhanced protection (increased survivors) and/or highly significant increase in the life span of dying mice treated with the 2-drug combination, was also observed compared to vidarabine administered singly. These observations in animals clearly indicate that combination studies with vidarabine (Vira-ATM) and co-vidarabine (deaminase inhibitor) deserve serious consideration as future therapy for systemic virus infections in man including herpesvirus encephalitis.

Adenosine Deaminase Inhibitors↗
PubMedDate not supplied

Saturation curve in gases of high atomic number at pressures up to 8 atm. I. Krypton and xenon.

The saturation curve has been studied in xenon and in krypton up to a pressure of 8 atm. An empirical formula has been found that describes the fraction of current collected over a wide range of voltages, pressures, ionization intensities, and electrode spacings. This is of practical value in the design of ionography chambers. For krypton the collection fraction fKr = (1 + 0.25eta-1.74)-1, and for xenon fXe = (1 + 0.16eta-1.88)-1, where eta = Fp-0.7Vd-2q-1/2 with F = 3.61 X 10(-7) and 2.50 X 10(-7) for krypton and xenon, respectively. The ranges of the variables covered in the experiments were p = 1-8 atm, V = 5-25000 V, d = 0.3-1.3 cm, and q = 4 X 10(-9)-6 X 10(-8) A/cm3.

Atmospheric Pressure↗
PubMed2004

ATM-mediated stabilization of hMutL DNA mismatch repair proteins augments p53 activation during DNA damage.

Human DNA mismatch repair (MMR) proteins correct DNA errors and regulate cellular response to DNA damage by signaling apoptosis. Mutations of MMR genes result in genomic instability and cancer development. Nonetheless, how MMR proteins are regulated has not yet been determined. While hMLH1, hPMS2, and hMLH3 are known to participate in MMR, the function of another member of MutL-related proteins, hPMS1, remains unclear. Here we show that DNA damage induces the accumulation of hPMS1, hPMS2, and hMLH1 through ataxia-telangiectasia-mutated (ATM)-mediated protein stabilization. The subcellular localization of PMS proteins is also regulated during DNA damage, which induces nuclear localization of hPMS1 and hPMS2 in an hMLH1-dependent manner. The induced levels of hMLH1 and hPMS1 are important for the augmentation of p53 phosphorylation by ATM in response to DNA damage. These observations identify hMutL proteins as regulators of p53 response and demonstrate for the first time a function of hMLH1-hPMS1 complex in controlling the DNA damage response.

Adaptor Proteins, Signal Transducing↗
PubMed2004

The mouse genomic instability mutation chaos1 is an allele of Polq that exhibits genetic interaction with Atm.

chaos1 (for chromosome aberrations occurring spontaneously 1) is a recessive mutation that was originally identified in a phenotype-based screen for chromosome instability mutants in mice. Mutant animals exhibit significantly higher frequencies of spontaneous and radiation- or mitomycin C-induced micronucleated erythrocytes, indicating a potential defect in homologous recombination or interstrand cross-link repair. The chaos1 allele was genetically associated with a missense mutation in Polq, which encodes DNA polymerase theta;. We demonstrate here that chaos1 is a mutant allele of Polq by using two genetic approaches: chaos1 mutant phenotype correction by a bacterial artificial chromosome carrying wild-type Polq and a failed complementation test between chaos1 and a Polq-disrupted allele generated by gene targeting. To investigate the potential involvement of Polq in DNA double-strand break repair, we introduced chaos1 into an Atm (for ataxia telangiectasia mutated)-deficient background. The majority ( approximately 90%) of double-homozygous mice died during the neonatal period. Surviving double mutants exhibited synergistic phenotypes such as severe growth retardation and enhanced chromosome instability. However, remarkably, double mutants had delayed onset of thymic lymphoma, significantly increasing life span. These data suggest a unique role of Polq in maintaining genomic integrity, which is probably distinctive from the major homologous recombination pathway regulated by ATM.

Alleles↗
PubMed2006

Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia.

We conducted a large-scale association study to identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), analyzing 992 patients and 2707 healthy controls. To increase the likelihood of identifying disease-causing alleles we genotyped 1467 coding nonsynonymous single nucleotide polymorphisms (nsSNPs) in 865 candidate cancer genes, biasing nsSNP selection toward those predicted to be deleterious. Preeminent associations were identified in SNPs mapping to genes pivotal in the DNA damage-response and cell-cycle pathways, including ATM F858L (odds ratio [OR] = 2.28, P < .0001) and P1054R (OR = 1.68, P = .0006), CHEK2 I157T (OR = 14.83, P = .0008), BRCA2 N372H (OR = 1.45, P = .0032), and BUB1B Q349R (OR = 1.42, P = .0038). Our findings implicate variants in the ATM-BRCA2-CHEK2 DNA damage-response axis with risk of CLL.

Aged↗
PubMed2006

Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia.

Although TP53 mutations are rare in B-cell chronic lymphocytic leukemia (CLL), Mdm2 overexpression has been reported as an alternative cause of p53 dysfunction. We investigated the potential therapeutic use of nongenotoxic p53 activation by a small-molecule antagonist of Mdm2, Nutlin-3a, in CLL. Nutlin-3a induced significant apoptosis in 30 (91%) of 33 samples from previously untreated patients with CLL; all resistant samples had TP53 mutations. Low levels of Atm (ataxia telangiectasia mutated) or high levels of Mdm2 (murine double minute 2) did not prevent Nutlin-3a from inducing apoptosis. Nutlin-3a used transcription-dependent and transcription-independent pathways to induce p53-mediated apoptosis. Predominant activation of the transcription-independent pathway induced more pronounced apoptosis than that of the transcription-dependent pathway, suggesting that activation of the transcription-independent pathway is sufficient to initiate p53-mediated apoptosis in CLL. Combination treatment of Nutlin-3a and fludarabine synergistically increased p53 levels, and induced conformational change of Bax and apoptosis in wild-type p53 cells but not in cells with mutant p53. The synergistic apoptotic effect was maintained in samples with low Atm that were fludarabine resistant. Results suggest that the nongenotoxic activation of p53 by targeting the Mdm2-p53 interaction provides a novel therapeutic strategy for CLL.

Apoptosis↗
PubMed2000

An experimental teleradiology transmission system using a high-speed ATM backbone network.

We evaluated the performance of an experimental teleradiology system based on a high-speed ATM backbone network. Image acquisition, transmission and the disk-to-display processing times were measured. Computerized tomography (CT) scans printed on 14 inch x 17 inch (36 cm x 43 cm) films were digitized and transferred over the network. The average time for the entire process was 1 min 30 s. Three radiologists interpreted 20 cases. For CT image interpretation, the reading time for one case ranged from 2 to 12 min (mean 6 min 46 s) on a monitor, and from 1 to 3 min (mean 1 min 31 s) with the original film. The ATM backbone network operating at 156 Mbit/s provided sufficient speed for remote consultation. However, further improvements in the operability of the system, especially the image viewing station, are necessary before it will be satisfactory for clinical use.

Computer Systems↗
PubMed1996

RETAIN--an ATM pilot project for applications in health care.

The availability of ATM-based broadband wide-area networks facilitates a range of new applications in health care, especially the performance of videoconferences combined with software for computer-supported cooperative discussion and diagnosis of digital medical images. This report about a research project for applications of the 'European ATM pilot network' in radiology describes the technical, economic and structural framework for the application of broadband technology in health care.

Computer Communication Networks↗
PubMed2004

ATM and ATR: sensing DNA damage.

Cellular response to genotoxic stress is a very complex process, and it usually starts with the "sensing" or "detection" of the DNA damage, followed by a series of events that include signal transduction and activation of transcription factors. The activated transcription factors induce expressions of many genes which are involved in cellular functions such as DNA repair, cell cycle arrest, and cell death. There have been extensive studies from multiple disciplines exploring the mechanisms of cellular genotoxic responses, which have resulted in the identification of many cellular components involved in this process, including the mitogen-activated protein kinases (MAPKs) cascade. Although the initial activation of protein kinase cascade is not fully understood, human protein kinases ATM (ataxia-telangiectasia, mutated) and ATR (ATM and Rad3-related) are emerging as potential sensors of DNA damage. Current progresses in ATM/ATR research and related signaling pathways are discussed in this review, in an effort to facilitate a better understanding of genotoxic stress response.

Animals↗
PubMed2006

2-deoxy-D-glucose reduces the level of constitutive activation of ATM and phosphorylation of histone H2AX.

Histone H2AX phosphorylated on Ser-139, defined as gammaH2AX, is a reporter of DNA double-strand breaks (DSBs). While H2AX undergoes phosphorylation after induction of DNA damage by genotoxic agents or during physiological events that involve DNA recombination, it also is phosphorylated in untreated normal and tumor cells. We recently reported that this constitutive H2AX phosphorylation (CHP) is markedly reduced by the antioxidant N-acetyl-L-cysteine (NAC), and postulated that it reflects the oxidative DNA damage ("endogenous DSBs") induced by reactive oxygen species (ROS) generated by metabolic activity during progression through the cell cycle. In the present study, we provide evidence that growth of cells from three human lymphoblastoid cell lines TK6, NH32 and WTK1 in the presence of the glucose antimetabolite 2-deoxy-D-glucose (2-DG) led to a distinct reduction in the level of CHP. The reduction of CHP was more pronounced in S and G(2)M than in G(1) phase cells. Constitutive activation of ATM was also reduced. The data suggest that a decrease in a cell's metabolic activity as a result of inhibition of glycolysis by 2-DG reduces generation of ROS which leads to the reduction of oxidative DNA damage. The data also point out that ATM may play a role in CHP induced by oxidative DNA damage. Therefore, the assay of CHP by multiparameter cytometry provides the means to measure effects of antioxidants and metabolic inhibitors on endogenous oxidative DNA damage in relation to cell cycle phase.

Acetylcysteine↗
PubMed2002

Phosphorylation of serine 1387 in Brca1 is specifically required for the Atm-mediated S-phase checkpoint after ionizing irradiation.

Although it is well established that inheritance of mutations in the Brca1 gene significantly increases the chances of developing breast or ovarian cancers, the mechanisms underlying this specific tumor susceptibility remain to be clarified. It is clear that one of the roles of the Brca1 protein is to facilitate cellular responses to DNA damage. We recently reported that Brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. We also found that mutation of serine 1423 in Brca1, a target of Atm phosphorylation, abrogates the G2-M checkpoint but not the ionizing irradiation-induced S-phase checkpoint. Here we demonstrate that mutation of serine 1387 in Brca1, another target of Atm phosphorylation, conversely abrogates the radiation-induced S-phase arrest but does not affect the G2-M checkpoint. Thus, these two posttranslational modifications of Brca1 have two distinct functional roles in the protein. In addition, although mutation of this site abrogates the ionizing irradiation-induced S-phase arrest, it does not adversely affect cell survival after irradiation. This demonstrates that loss of this checkpoint function by itself does not affect cell survival and suggests that some other function of Brca1 alters cell survival after DNA damage.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2003

Asian traditional medicine (ATM) based on in vivo microcirculation evidence.

Asian traditional medicine (ATM) (herbal medicine, acupuncture or moxibution) has gained some popularity among communities in Asia, but there are still few evidences to prove the effectiveness of such therapeutic measures. A symposium was held with aim at the effectiveness of Asian traditional therapies in views of in vivo microcirculation. This report is concerned with the symposium, including Asian activities for ATM.

Holistic Health↗
PubMed2005

Combined haploinsufficiency for ATM and RAD9 as a factor in cell transformation, apoptosis, and DNA lesion repair dynamics.

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.

Animals↗
PubMed1991

O2 pressures between 0.12 and 2.5 atm abs, circulatory function, and N2 elimination.

To study the effects of inhaled oxygen pressures on N2 elimination, 72, 2-h washouts were performed in 6 subjects at oxygen pressures of 0.12, 0.2, 1.0, 2.0, and 2.5 atm abs using a closed circuit system that supplied an O2-argon mixture and collected the N2 off-gassed. Hypoxia induced a significant (9.4%, P less than 0.05) increase in nitrogen eliminated as compared to normoxia. Pure oxygen breathing induced a small, insignificant (3.5%) decrease in nitrogen yields, but further increases in oxygen pressure induced significant decreases in nitrogen yields (-8.9% and -16.9% for 2.0 and 2.5 atm abs, respectively). Heart rate, cardiac output, skin perfusion and leg blood flow decreased, whereas mean arterial pressure increased with increasing oxygen pressure. We conclude, therefore, that perfusion-dependent N2 elimination decreases secondary to vasoconstriction induced by increasing oxygen pressures. Changes in inhaled oxygen pressures during different phases of compression-decompression may induce alterations in the rate of inert gas uptake and elimination. Although not currently quantifiable, such alterations would imply added uncertainties in the computation of decompression schedules. Oxygen breathing during decompression should be performed at the lowest possible ambient pressure compatible with freedom from pathogenic bubble formation.

Adult↗
PubMed1995

Genomic organization of the ATM locus involved in ataxia-telangiectasia.

The ATM gene, involved in the genetic disorder ataxia-telangiectasia (AT), has been identified recently. This gene is suspected to predispose to malignancy and is located in a chromosomal region that we have recently found deleted in 50 to 60% of breast and lung carcinomas. Because of its location and its function, the ATM gene is a strong candidate tumor suppressor or modifier gene of chromosome region 11q23. In this study, we define its genomic structure. The aim was to establish the basis for the development of mutation scanning methods based on DNA instead of RNA. We found that the gene spans a region of approximately 70-80 kb and is composed of 37 exons, ranging in size from 64 to 324 bp. Nucleotide sequences of all exon/intron boundaries were determined. With this information, it will be possible to develop simple genetic tests for the identification of homozygotes and heterozygotes, as well as determine whether the gene is involved in the pathogenesis of breast and other carcinomas.

Ataxia Telangiectasia↗