Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ATM”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 505 records · Page 28Linked to original sources
PubMed2005

ATM signaling and 53BP1.

The ATM (mutated in Ataxia-Telangiectasia) protein kinase is an important player in signaling the presence of DNA double strand breaks (DSBs) in higher eukaryotes. Recent studies suggest that ATM monitors the presence of DNA DSBs indirectly, through DNA DSB-induced changes in chromatin structure. One of the proteins that sense these chromatin structure changes is 53BP1, a DNA damage checkpoint protein conserved in all eukaryotes and the putative ortholog of the S. cerevisiae RAD9 protein. We review here the mechanisms by which ATM is activated in response to DNA DSBs, as well as key ATM substrates that control cell cycle progression, apoptosis and DNA repair.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2006

ATM polymorphism IVS62+60G>A is not associated with disease aggressiveness in prostate cancer.

OBJECTIVES: ATM is an important protein that protects the genome from double-stranded DNA breaks. Mutations and polymorphisms in the ATM gene have been associated with an increased risk of certain types of malignancies, especially breast cancer. METHODS: We analyzed tissue from 98 white patients with prostate cancer for the presence of IVS62+60G>A polymorphism in the ATM gene. RESULTS: The frequency of the homozygous IVS62+60G/G, heterozygous IVS62+60G/A, and homozygous IVS62+60A/A was 18.37% (18 of 98), 30.61% (30 of 98), and 51.02% (50 of 98), respectively. Using Fisher's exact test, we found the polymorphism IVS62+60G>A was not significantly related to age, tumor grade, prostate-specific antigen level, or clinical stage (P >0.05). No difference was found in relapse-free survival between patients with IVS62+60G/G and those with IVS62+60G/A or IVS62+60A/A (P = 0.4533). CONCLUSIONS: The results of our study indicate that this ATM polymorphism is not associated with the aggressiveness of prostate cancer in white men.

Aged↗
PubMed2001

ATM: genome stability, neuronal development, and cancer cross paths.

One of the cornerstones of the web of signaling pathways governing cellular life and differentiation is the DNA damage response. It spans a complex network of pathways, ranging from DNA repair to modulation of numerous processes in the cell. DNA double-strand breaks (DSBs), which are formed as a result of genotoxic stress or normal recombinational processes, are extremely lethal lesions that rapidly mobilize this intricate defense system. The master controller that pilots cellular responses to DSBs is the ATM protein kinase, which turns on this network by phosphorylating key players in its various branches. ATM is the protein product of the gene mutated in the human genetic disorder ataxia-telangiectasia (A-T), which is characterized by neuronal degeneration, immunodeficiency, sterility, genomic instability, cancer predisposition, and radiation sensitivity. The clinical and cellular phenotype of A-T attests to the numerous roles of ATM, on the one hand, and to the link between the DNA damage response and developmental processes on the other hand. Recent studies of this protein and its effectors, combined with a thorough investigation of animal models of A-T, have led to new insights into the mode of action of this master controller of the DNA damage response. The evidence that ATM is involved in signaling pathways other than those related to damage response, particularly ones relating to cellular growth and differentiation, reinforces the multifaceted nature of this protein, in which genome stability, developmental processes, and cancer cross paths.

Amino Acid Motifs↗
PubMed1997

p53 and ATM: cell cycle, cell death, and cancer.

The development of a normal cell into a tumor cell appears to depend in part on mutations in genes that normally control cell cycle and cell death, thereby resulting in inappropriate cellular survival and tumorigenesis. ATM ("mutated in ataxia-telangiectasia") and p53 are two gene products that are believed to play a major role in maintaining the integrity of the genome such that alterations in these gene products may contribute to increased incidence of genomic changes such as deletions, translocations, and amplifications, which are common during oncogenesis. p53 is a critical participant in a signal transduction pathway that mediates either a G1 arrest or apoptosis in response to DNA damage. In addition, p53 is believed to be involved in the mitotic spindle checkpoint and in the regulation of centrosome function. Following certain cytotoxic stresses, normal ATM function is required for p53-mediated G1 arrest. ATM is also involved in other cellular processes such as S phase and G2-M phase arrest and in radiosensitivity. The understanding of the roles that both p53 and ATM play in cell cycle progression and cell death in response to DNA damage may provide new insights into the molecular mechanisms of cellular transformation and may help identify potential targets for improved cancer therapies.

Animals↗
PubMed2001

Disruption of the ATM gene in breast cancer.

Mutations in the ATM gene, which maps to 11q22-23, cause the multisystem recessive syndrome ataxia-telangiectasia (AT). Breast cancer has been reported in AT patients and carriers. Sporadic breast cancer is associated with loss of heterozygosity at or in the region of ATM and chromosomal abnormalities involving 11q23. We have investigated the chromosomes, nuclei and released chromatin fibers from nine primary breast carcinoma and eight cell lines by fluorescence in situ hybridization with four fluorochrome-labeled cosmids spanning the ATM gene. The ATM gene was disrupted in one primary breast carcinoma and in the cell lines MDA-MB-231 and MCF-7. The role of these aberrations in breast carcinomas, which may lead to gene dosage or dominant negative effects on gene function, requires further investigation.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2003

ATM missense mutations are frequent in patients with breast cancer.

Ataxia telangiectasia (A-T), an autosomal recessive neuro-immunologic disease with cancer susceptibility, results from ATM gene mutations. Most mutations in A-T patients cause protein truncation. Epidemiologic evidence suggests that ATM gene mutation carriers may be at increased risk for breast cancer, but the protein-truncating mutations that compose the majority of mutations in patients with ataxia telangiectasia are not elevated in women with breast cancer. In this report we present evidence that missense mutations in the ATM gene predispose to breast cancer. The analysis was performed in two phases in a total of 90 women with breast cancer and 90 ethnically similar control individuals. DOVAM-S, a robotically enhanced multiplexed, highly redundant form of SSCP in which virtually all mutations within the input amplicons can be detected, was used to scan all the coding exons and flanking splice junctions. Cohort-specific mutations were significantly elevated in women with breast cancer in phase 1 (43 cases) and phase 2 (47 cases). For the 90 patients and 90 controls, total missense mutations were significantly elevated in cases [OR=2.0; 90% CI=1.01-4.15]. Cohort-specific missense variants displayed an odds ratio of 4.0 (90% CI=1.37-13.5). It is estimated that the attributable risk of mutations in the ATM gene is 13% in this cohort of women with breast cancer.

Adult↗
PubMedDate not supplied

Implementation of multi-vendor DICOM standard image transfer in hospital wide ATM network.

At Hamamatsu University Hospital, an ATM + FDDI network was installed in January 1995, when the hospital information system was upgraded. With its unique 'wheel' shape configuration, FDDI automatically backs up in case of an ATM switch failure. The authors implemented a DICOM image database server and DICOM viewer in the Hamamatsu University Hospital ATM + FDDI network. The DICOM standard worked well between different vendor products. In sending 512 x 512, 2 byte CT images, 40% of the transfer time was spent for the network data transfer, which is 70% of the theoretical value of 10 Mb peripheral transfer rate. Meanwhile, ATM load factor increased less than 0.5%. As we have a very fast data transfer network, we must check display speed, hard disc access time, PC bus speed, and display software, in order to enjoy the high speed network transfer fully. The sequence of image transmission within a study is not stated in the DICOM document and is depending on the server. Therefore, there should be an agreement between server and clients, still more than DICOM, in order to make better PACS.

Computer Communication Networks↗
PubMedDate not supplied

Lack of protection by ascorbic acid from lethality resulting from exposure to 1 atm O2.

The role of ascorbic acid in protecting animals against the toxic effects of exposure to 1 atm. of O2 was examined. The mean time until death resulting from exposure to one atm. O2 was not different in rats treated intraperitoneally 3 times per day with 1.5 g/kg ascorbic acid compared to saline injected controls. Exposure of rats to one atm. O2 for 48 hr did not alter ascorbic acid or non-protein thiol concentration in lung or liver compared to room air controls. Lung ascorbic acid concentration was markedly depressed in guinea pigs fed an ascorbic acid-deficient diet for 6 days prior to O2 exposure. However, the mean time until death of ascorbic acid-deficient guinea pigs did not significantly differ from those fed an ascorbic acid-supplemented diet. Exposure to one atm. O2 of guinea pigs fed an ascorbic acid-deficient diet or an ascorbic acid-supplemented diet failed to decrease the concentration of ascorbic acid or of non-protein thiol in lung. Results from this study do not support an involvement of ascorbic acid in protection from pulmonary oxygen toxicity.

Animals↗
PubMed1998

Expression of the ataxia-telangiectasia gene (ATM) product in human cerebellar neurons during development.

Ataxia-telangiectasia (A-T) is a hereditary disorder, exhibiting progressive cerebellar ataxia. We investigated the expression of the ATM protein in the human CNS. By western blotting, the ATM protein was detected in the cerebellar cortex, but not in the cerebral cortex, at the late gestational stage. Immunohistochemistry revealed that cerebellar neurons, particularly Purkinje cells, were markedly immunoreactive during late prenatal and early postnatal periods, followed by persistent and moderate reactivity in Purkinje cells. The ATM protein was distributed within the cytoplasm of Purkinje cells, but not within the nuclei. The ATM protein seems to play a role as a cytoplasmic protein in neurons of the cerebellar cortex.

Adolescent↗
PubMed2000

Atm-deficient mice Purkinje cells show age-dependent defects in calcium spike bursts and calcium currents.

Ataxia telangiectasia in humans results from homozygous loss-of-function mutations in ATM. Neurological deterioration is the major cause of death in ataxia telangiectasia patients: in the cerebellum, mainly Purkinje cells are affected. We have generated Atm-deficient mice which display neurological abnormalities by several tests of motor function consistent with an abnormality of cerebellar function, but without histological evidence of neuronal degeneration. Here we performed a more detailed morphological analysis and an electrophysiological study on Purkinje cells from Atm-deficient mice of different ages. We found no histological or immunohistochemical abnormalities. Electrophysiology revealed no abnormalities in resting membrane potential, input resistance or anomalous rectification. In contrast, there was a significant decrease in the duration of calcium and sodium firing. The calcium deficit became significant between six to eight and 12-20 weeks of age, and appeared to be progressive. By voltage-clamp recording, we found that the firing deficits were due to a significant decrease in calcium currents, while inactivating potassium currents seem unaffected. In other mutant mice, calcium current deficits have been shown to be related to cell death.Our experiments suggest that the electrophysiological defects displayed by Atm-deficient mice are early predegenerative lesions and may be a precursor of Purkinje cell degeneration displayed by ataxia telangiectasia patients.

Action Potentials↗
PubMed2001

Altering telomere structure allows telomerase to act in yeast lacking ATM kinases.

BACKGROUND: Telomerase is a ribonucleoprotein that copies a short RNA template into telomeric DNA, maintaining eukaryotic chromosome ends and preventing replicative senescence. Telomeres differentiate chromosome ends from DNA double-stranded breaks. Nevertheless, the DNA damage-responsive ATM kinases Tel1p and Mec1p are required for normal telomere maintenance in Saccharomyces cerevisiae. We tested whether the ATM kinases are required for telomerase enzyme activity or whether it is their action on the telomere that allows telomeric DNA synthesis. RESULTS: Cells lacking Tel1p and Mec1p had wild-type levels of telomerase activity in vitro. Furthermore, altering telomere structure in three different ways showed that telomerase can function in ATM kinase-deleted cells: tel1 mec1 cells senesced more slowly than tel1 mec1 cells that also lacked TLC1, which encodes telomerase RNA, suggesting that tel1 mec1 cells have residual telomerase function; deleting the telomere-associated proteins Rif1p and Rif2p in tel1 mec1 cells prevented senescence; we isolated a point mutation in the telomerase RNA template domain (tlc1-476A) that altered telomeric DNA sequences, causing uncontrolled telomeric DNA elongation and increasing single strandedness. In tel1 mec1 cells, tlc1-476A telomerase was also capable of uncontrolled synthesis, but only after telomeres had shortened for >30 generations. CONCLUSION: Our results show that, without Tel1p and Mec1p, telomerase is still active and can act in vivo when the telomere structure is disrupted by various means. Hence, a primary function of the ATM-family kinases in telomere maintenance is to act on the substrate of telomerase, the telomere, rather than to activate the enzymatic activity of telomerase.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1998

Circular chromosome formation in a fission yeast mutant defective in two ATM homologues.

Telomeres, found at chromosomal ends, are essential for stable maintenance of linear chromosomes in eukaryotes. The ATM family of genes, including budding yeast TEL1 (refs 1,2), fission yeast rad3+ (ref. 3) and human ATM (ref. 4), have been reported to be involved in telomere length regulation, although the significance of the telomere phenotypes observed with the mutated genes remains elusive. We have cloned tel1+, another fission yeast ATM homologue, and found that a tel1rad3 double mutant lost all telomeric DNA sequences. Thus, the ATM homologues are essential in telomere maintenance. The mutant grew poorly and formed irregular-shaped colonies, probably due to chromosome instability, however, during prolonged culture of the double mutant, cells forming normal round-shaped colonies arose at a relatively high frequency. All three chromosomes in these derivative cells were circular and lacked telomeric sequences. To our knowledge, this is the first report of eukaryotic cells whose chromosomes are all circular. Upon meiosis, these derivative cells produced few viable spores. Therefore, the exclusively circular genome lacking telomeric sequences is proficient for mitotic growth, but does not permit meiosis.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2001

The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.

When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the IR-induced S-phase checkpoint cause 'radioresistant DNA synthesis', a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia, a disease caused by mutations in the ATM gene. The Cdc25A phosphatase activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) and Cdc25A, and implicate this mechanism in controlling the S-phase checkpoint. We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. An IR-induced loss of Cdc25A protein prevents dephosphorylation of Cdk2 and leads to a transient blockade of DNA replication. We also show that tumour-associated Chk2 alleles cannot bind or phosphorylate Cdc25A, and that cells expressing these Chk2 alleles, elevated Cdc25A or a Cdk2 mutant unable to undergo inhibitory phosphorylation (Cdk2AF) fail to inhibit DNA synthesis when irradiated. These results support Chk2 as a candidate tumour suppressor, and identify the ATM-Chk2-Cdc25A-Cdk2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.

Alleles↗
PubMed2006

Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway.

The cellular DNA-damage response is a signaling network that is vigorously activated by cytotoxic DNA lesions, such as double-strand breaks (DSBs). The DSB response is mobilized by the nuclear protein kinase ATM, which modulates this process by phosphorylating key players in these pathways. A long-standing question in this field is whether DSB formation affects chromatin condensation. Here, we show that DSB formation is followed by ATM-dependent chromatin relaxation. ATM's effector in this pathway is the protein KRAB-associated protein (KAP-1, also known as TIF1beta, KRIP-1 or TRIM28), previously known as a corepressor of gene transcription. In response to DSB induction, KAP-1 is phosphorylated in an ATM-dependent manner on Ser 824. KAP-1 is phosphorylated exclusively at the damage sites, from which phosphorylated KAP-1 spreads rapidly throughout the chromatin. Ablation of the phosphorylation site of KAP-1 leads to loss of DSB-induced chromatin decondensation and renders the cells hypersensitive to DSB-inducing agents. Knocking down KAP-1, or mimicking a constitutive phosphorylation of this protein, leads to constitutive chromatin relaxation. These results suggest that chromatin relaxation is a fundamental pathway in the DNA-damage response and identify its primary mediators.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

ATM regulates target switching to escalating doses of radiation in the intestines.

Although stem cells succumbing to reproductive death are assumed to be the single relevant targets in radiation tissue damage, recent studies showed intestinal stem cell damage is conditionally linked to crypt endothelial apoptosis, defining a two-target model. Here we report that when mouse intestines were protected against microvascular apoptosis, radiation switched as the dose escalated to a previously unrecognized crypt stem cell target, activating ceramide synthase-mediated apoptosis to initiate intestinal damage. Whereas ataxia telangiectasia-mutated (ATM) kinase normally represses ceramide synthase, its derepression in Atm(-/-) mice increased crypt stem cell radiosensitivity 3.7-fold without sensitizing the microvascular response. Discovery of this intestinal radiosensitivity mechanism allowed design of an antisense Atm oligonucleotide treatment which phenocopied the Atm(-/-) mouse, reordering ceramide synthase-mediated stem cell death to become the first-line gastrointestinal response of wild-type littermates. These experiments indicate that tissues operate multiple potential targets activated consecutively according to their inherent radiosensitivities that may be reordered therapeutically to control radiation tissue responses.

Animals↗
PubMed2004

Molecular variants of the ATM gene in Hodgkin's disease in children.

Ataxia telangiectasia is an autosomal recessive disease with a striking predisposition of lymphoid malignancies. ATM mutations have been reported in adult sporadic lymphoma and leukaemia. The aim of this study was to investigate the possible involvement of the ATM gene in the carcinogenesis of Hodgkin disease in children. Tumours were obtained from 23 patients and were subjected to mutation screening and loss of heterozygosity analysis. Eight base substitutions were identified in seven patients. Of them, Y54Y, a silent change, was observed in two patients and a known polymorphism, D1853N, in three patients. Of the other two patients, one harboured a combined genotype P604S/F1463C, identified previously in two patients with Hodgkin lymphoma, and the other a novel missense mutation, V595A. The alterations were present in the germ line, and both had a more aggressive disease. In all, 100 matched normal ethnic controls were screened for these mutations and P604S/F1463C was identified in one healthy control. Loss of heterozygosity was identified in four patients and in three of them it was located centromeric to the ATM gene, and, in one, it spanned a large region, indicating the involvement of other tumour-suppressor genes in this disease. Missense variants of the ATM gene are a rare event in childhood Hodgkin disease.

Adolescent↗
PubMed2001

ATM, a central controller of cellular responses to DNA damage.

Mutations in the ATM gene lead to the genetic disorder ataxia-telangiectasia. ATM encodes a protein kinase that is mainly distributed in the nucleus of proliferating cells. Recent studies reveal that ATM regulates multiple cell cycle checkpoints by phosphorylating different targets at different stages of the cell cycle. ATM also functions in the regulation of DNA repair and apoptosis, suggesting that it is a central regulator of responses to DNA double-strand breaks.

Animals↗
PubMed1997

Cellular localisation of the ataxia-telangiectasia (ATM) gene product and discrimination between mutated and normal forms.

The recently cloned gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) is involved in DNA damage response at different cell cycle checkpoints and also appears to have a wider role in signal transduction. Antibodies prepared against peptides from the predicted protein sequence detected a approximately 350 kDa protein corresponding to the open reading frame, which was absent in 13/23 A-T homozygotes. Subcellular fractionation, immunoelectronmicroscopy and immunofluorescence showed that the ATM protein is present in the nucleus and cytoplasmic vesicles. This distribution did not change after irradiation. We also provide evidence that ATM protein binds to p53 and this association is defective in A-T cells compatible with the defective p53 response in these cells. These results provide further support for a role for the ATM protein as a sensor of DNA damage and in a more general role in cell signalling, compatible with the broader phenotype of the syndrome.

Antibodies↗