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At least 145 records · Page 8Linked to original sources
PubMed2003

ATM gene alterations in childhood acute lymphoblastic leukemias.

Hereditary ATM gene mutations cause ataxia-telangiectasia, a pleiotropic disorder associated with a high incidence of lymphoid malignancies. Acquired ATM alterations have been described in sporadic lymphoproliferative disorder suggesting that the ATM gene contributes to lymphomagenesis. To assess the prevalence of genomic ATM alterations in childhood acute lymphoblastic leukemias (ALL), we explored a series of 57 sporadic ALL cases (26 B-precursor ALL and 31 T-ALL) using DHPLC (Denaturing High-Performance Liquid Chromatography). We identified 28 distinct genomic ATM alterations in 14 patients (25%). Ten of them were scored as probably biologically significant and appear to be associated with a high risk of relapse (P<0.01). Six alterations of potential biological significance were observed in 5 cases of B-precursor ALL (19%), while 5 were found in 3 cases of T-ALL (10%). In two cases of B-precursor ALL, the ATM alterations were found in the germline, indicating an ATM carrier status. We report here the high prevalence of genomic ATM alterations in childhood ALL. Our observations lend further support to the postulated contribution of ATM in lymphomagenesis.

Adolescent↗
PubMed2006

ATM is activated by mitotic stress and suppresses centrosome amplification in primary but not in tumor cells.

Centrosome amplification has been proposed to contribute to the development of aneuploidy and genome instability. Here, we show that Ataxia-Telangiectasia Mutated (ATM) is localized to the centrosome and co-purified with gamma-tubulin. The importance of ATM in centrosome duplication is demonstrated in Atm-deficient primary mouse embryonic fibroblasts that display centrosome amplification. Interestingly, centrosome amplification was not observed in tumor cell lines derived from Atm and p21 double deficient mouse. Our results also indicate that both p53 and p21 operate in the same pathway as ATM in regulating centrosome biogenesis. Finally, a potential role of ATM in spindle checkpoint regulation is demonstrated by which ATM protein is activated by mitotic stress. These results suggest a role of ATM in spindle checkpoint regulation and indicate that ATM suppresses genome instability and cellular transformation by regulating centrosome biogenesis.

Animals↗
PubMed1999

Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations.

The failure to find an increased frequency of ATM mutations in large cancer cohorts, especially breast cancer, is contrary to what was anticipated based on the increased cancer susceptibility of obligate ATM heterozygotes from families with ataxia-telangiectasia (A-T). We hypothesize that this paradox might be resolved if two types of ATM heterozygotes exist and the phenotypes differ, i.e., those with truncating types of mutations (ATM(trunc)), that make no protein, and those with missense types of mutations (ATM(mis)), that make reduced amounts of defective protein. The phenotype of ATM(trunc/trunc) mutations is the A-T syndrome; the phenotype of ATM(mis/mis) mutations, judging from the few homozygous patients that have been documented, appears to include some neurological features and cancer susceptibility but not the A-T syndrome. Evidence is reviewed which suggests that ATM(mis/wt) mutations are technically more difficult to detect than ATM(trunc/wt) mutations. Despite this, most large cancer cohort studies have identified mainly missense mutations and few truncating mutations. This model would require a paradigm shift for cancer risk analyses, to recognize the existence of different allele frequencies for the two types of A-T heterozygotes.

Ataxia Telangiectasia↗
PubMed2001

Expression and purification of active recombinant ATM protein from transiently transfected mammalian cells.

The gene mutated in the human disease ataxia telangiectasia (AT), termed ATM, encodes a large protein kinase involved in DNA repair and cell cycle control. Biochemical characterization of ATM function has been somewhat difficult because of its large size (approximately 370 kDa) and relatively low level of expression in several systems. The majority of studies have used immunoprecipitated ATM or purified ATM obtained through relatively complex procedures. Here, we describe an efficient method for the expression and purification of FLAG-epitope-tagged recombinant human ATM protein (F-ATM). This method utilizes the expression of F-ATM in transiently transfected 293T cells followed by anti-FLAG-agarose affinity chromatography. The transfection procedure has been optimized for large (225-cm(2)) culture flasks and F-ATM can be purified to near homogeneity as judged by SDS-PAGE. This procedure yields approximately 1 microg of catalytically active F-ATM protein/225-cm(2) flask that can be used for biochemical studies.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1985

Effects of high hydrostatic pressure per se, 101 atm on eel metabolism.

Oxygen consumption (MO2) of confined eels was measured at atmospheric pressure, 1 atm, and at 101 atm of hydrostatic pressure per se (HP). The tolerance of the eels to hypoxia was studied at the two experimental pressures. At atmospheric pressure, when oxygen partial pressure (PWO2) fell below the critical pressure, Pc = 22.4 +/- 1.95 Torr, there was a linear PWO2-related decrease in MO2. At maximal hypoxia, the eels survived for several hours by their efficient anaerobic metabolism. At 101 atm of HP, as soon as the experimental pressure was attained, a linear PWO2-related decrease in MO2 was observed at PWO2 levels much higher than those considered as critical at atmospheric pressure. The relation MO2 = f (PWO2) was similar to that observed at 1 atm when PWO2 less than Pc, that is, when aerobic metabolism was insufficient to ensure the eels' energetic requirement. Moreover, the eels tolerated hypoxia much less well at 101 atm of HP than at 1 atm. In conclusion, the exposure of eels to 101 atm of HP induced a sharp decrease in aerobic metabolism; then, at 101 atm, the energetic requirements must be ensured by anaerobic processes which produced lactates in plasma whose values were similar to those observed at 1 atm when PWO2 less than Pc.

Anaerobiosis↗
PubMed1996

Ultrafast networks (ATM): first clinical experiences.

Ultrafast networks using asynchronous transfer mode (ATM) technology can provide the bandwidth and throughput that may be sufficient to satisfy the medical imaging community. Several trials are underway to assess the effect of ATM network capabilities on the clinical practice of radiology, by providing immediate interactive radiology consultations between subspecialists and general radiologists at affiliated academic institutions. The hardware to build such networks is now commercially available and its cost is decreasing steadily, but the monthly charges for ATM bandwidth use are still high. Nevertheless, given the tremendous increase in communication capability and data transfer rates possible with ATM networks, cost alone should not be the determining factor for selecting this technology. The ATM concept in general is first reviewed, followed by a description of early clinical ATM network installation in four medical environments worldwide. These medical clusters include: the UCLA affiliated hospitals (UCLA Medical Center, West LA VAMC and Olive-View UCLA Medical Center), the UCSF affiliated hospitals, Duke University Hospitals and a cluster of medical centers in Berlin which have all been connected via ATM networks. The use of ATM technology in these realistic clinical environments is discussed and evaluated for its potential impact on patient care and clinical teaching within radiology departments. From this preliminary study it is concluded that image communications over a regional PACS using an ATM network can allow interactive consultations between different subspecialist and general radiologists or other specialized radiologists spread over different medical centers.

Computer Systems↗
PubMed2006

Premeiotic germ cell defect in seminiferous tubules of Atm-null testis.

Lifelong spermatogenesis is maintained by coordinated sequential processes including self-renewal of stem cells, proliferation of spermatogonial cells, meiotic division, and spermiogenesis. It has been shown that ataxia telangiectasia-mutated (ATM) is required for meiotic division of the seminiferous tubules. Here, we show that, in addition to its role in meiosis, ATM has a pivotal role in premeiotic germ cell maintenance. ATM is activated in premeiotic spermatogonial cells and the Atm-null testis shows progressive degeneration. In Atm-null testicular cells, differing from bone marrow cells of Atm-null mice, reactive oxygen species-mediated p16(Ink4a) activation does not occur in Atm-null premeiotic germ cells, which suggests the involvement of different signaling pathways from bone marrow defects. Although Atm-null bone marrow undergoes p16(Ink4a)-mediated cellular senescence program, Atm-null premeiotic germ cells exhibited cell cycle arrest and apoptotic elimination of premeiotic germ cells, which is different from p16(Ink4a)-mediated senescence.

Animals↗
PubMed2006

ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome.

Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. Transplantation with ATM-/- as compared to ATM+/+ bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM+/+apoE-/- mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.

Animals↗
PubMed1999

ATM immunolocalization in mouse neuronal endosomes: implications for ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a human disorder with pleiotropic manifestations that include neoplasms, immune dysfunction and neurodegeneration. The disorder is due to mutations in the gene known as ATM (A-T, mutated), which causes a deficiency in its protein product (Atm in mice) that is necessary for DNA damage surveillance. This nuclear function of Atm explains in principle the propensity to cancer and immunodeficiency in A-T, but not the neurodegeneration which results in the earliest clinical manifestations and causes progressive disability. Here we report ultrastructural evidence of cytoplasmic localization of Atm-like immunoreactivity (ALI) within endosomes in murine cerebellocortical neurons, one of the principal targets of A-T. The ALI was obtained with two separate monoclonal antibodies that recognize Atm specifically. By contrast, electron-dense endosomes that could be confused with ALI occur in negligible amounts in both wild-type mice and in mice deficient in Atm ("knockout" mice). Furthermore, there was a marked preferential distribution of Atm-immunopositive endosomes in the granule cell layer - where they are present in granule neurons - with a much lower density in the Purkinje and molecular layers. These observations suggest that endosome-bound Atm may be more important for the function of certain neurons than others - or that it is processed differently among them - and that this protein may be involved in molecular sorting in the cytoplasm. This is relevant to elucidating the role of Atm deficiency in the pathobiology of neurodegeneration in A-T.

Animals↗
PubMed2000

ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.

The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity and defects in cell-cycle checkpoints in response to ionizing radiation. The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs, whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks. Here, because of the similarities between AT and NBS, we evaluated the functional interactions between ATM and p95/nbs1. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not be required for signalling to ATM after ionizing radiation. However, p95/nbs1 was phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. A p95/nbs1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.

Ataxia Telangiectasia↗
PubMed1998

ATM associates with and phosphorylates p53: mapping the region of interaction.

The human genetic disorder ataxia-telangiectasia (AT) is characterized by immunodeficiency, progressive cerebellar ataxia, radiosensitivity, cell cycle checkpoint defects and cancer predisposition. The gene mutated in this syndrome, ATM (for AT mutated), encodes a protein containing a phosphatidyl-inositol 3-kinase (PI-3 kinase)-like domain. ATM also contains a proline-rich region and a leucine zipper, both of which implicate this protein in signal transduction. The proline-rich region has been shown to bind to the SH3 domain of c-Abl, which facilitates its phosphorylation and activation by ATM. Previous results have demonstrated that AT cells are defective in the G1/S checkpoint activated after radiation damage and that this defect is attributable to a defective p53 signal transduction pathway. We report here direct interaction between ATM and p53 involving two regions in ATM, one at the amino terminus and the other at the carboxy terminus, corresponding to the PI-3 kinase domain. Recombinant ATM protein phosphorylates p53 on serine 15 near the N terminus. Furthermore, ectopic expression of ATM in AT cells restores normal ionizing radiation (IR)-induced phosphorylation of p53, whereas expression of ATM antisense RNA in control cells abrogates the rapid IR-induced phosphorylation of p53 on serine 15. These results demonstrate that ATM can bind p53 directly and is responsible for its serine 15 phosphorylation, thereby contributing to the activation and stabilization of p53 during the IR-induced DNA damage response.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1997

Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways.

Atm is part of a pathway that responds to DNA damage from ionizing radiation (IR). This pathway involves p53, as Atm-deficient cell lines and mice are defective in p53 induction after IR. p53 is a multi-functional protein that simultaneously regulates distinct downstream pathways controlling cell-cycle progression and apoptosis. However, the mechanisms by which p53 differentially activates downstream pathways are unknown. To determine the relationship between Atm and p53, we examined cell-cycle and apoptotic responses in Atm-, p53-(ref. 8) and p21-deficient mice after IR in the whole animal. As expected, p53 protein levels were not induced by IR in thymus of Atm-deficient mice. IR-induced cell-cycle checkpoint function was also defective, and induction of p21 was attenuated in thymus from Atm-deficient mice. However, IR-induced apoptosis and Bax induction were completely normal; both of which are mediated by p53. IR-induced thymic apoptosis was suppressed in Atm/p53 double-mutant mice but not in Atm/p21 double mutants, demonstrating p53 dependence and Atm independence. Thus, Atm deficiency results in lack of p53 induction by IR, but only selective disruption of p53-dependent functions. Our results support a model in which upstream effectors such as Atm selectively activate p53 to regulate specific downstream pathways, providing a mechanism for controlling distinct cell-cycle and apoptotic responses.

Animals↗
PubMed2002

Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer.

Ataxia-telangiectasia is characterized by radiosensitivity, genome instability and predisposition to cancer. Heterozygous carriers of ATM, the gene defective in ataxia-telangiectasia, have a higher than normal risk of developing breast and other cancers. We demonstrate here that Atm 'knock-in' (Atm-Delta SRI) heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation show an increased susceptibility to developing tumors. In contrast, no tumors are observed in Atm knockout (Atm(+/-)) heterozygous mice. In parallel, we report the appearance of tumors in 6 humans from 12 families who are heterozygous for the 7636del9 mutation. Expression of ATM cDNA containing the 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. This reduces the survival of these cells after radiation exposure and enhances the level of radiation-induced chromosomal aberrations. These results show for the first time that mouse carriers of a mutated Atm that are capable of expressing Atm have a higher risk of cancer. This finding provides further support for cancer predisposition in human ataxia-telangiectasia carriers.

Animals↗
PubMed1997

Biallelic mutations in the ATM gene in T-prolymphocytic leukemia.

Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, genome instability and predisposition to malignancies, particularly T-cell neoplasms. The responsible gene, designated ataxia-telangiectasia mutated (ATM), was recently identified by positional cloning in the chromosomal region 11q22.3-23.1 (ref. 4, 5) ATM is 150 kb in length, consists of 66 exons and encodes a nuclear phosphoprotein of approximately 350 kDa (ref. 4-9). Although ATM is considered to be a tumorigenic factor in several human cancers, it has not yet been found mutated in tumors of non-AT patients. Given the marked predisposition of AT patients to develop neoplasms of the T-cell lineage, we analyzed a series of T-cell leukemias (T-prolymphocytic leukemia, or T-PLL) in non-AT patients in search of genomic changes associated with the development of this disease. Among the recurrent aberrations identified, deletion of the chromosome arm 11q was very frequent. Subsequent molecular cytogenetic analyses allowed us to define a small commonly deleted segment at 11q22.3-23.1 in 15 of 24 T-PLLs studied. Since this critical region contained ATM, we further analyzed the remaining copy of the gene in six cases showing deletions affecting one ATM allele. In all six cases, mutations of the second ATM allele were identified, leading to the absence, premature truncation or alteration of the ATM gene product. Thus, our study demonstrates disruption of both ATM alleles by deletion or point mutation in T-PLL, suggesting that ATM functions as a tumor-suppressor gene in tumors of non-AT individuals.

Alleles↗
PubMed1999

Rapid and efficient ATM mutation detection by fluorescent chemical cleavage of mismatch: identification of four novel mutations.

Mutations in the Ataxia Telangiectasia Mutated (ATM) gene are responsible for the autosomal recessive disease Ataxia Telangiectasia (A-T). A wide variety of mutations scattered across the entire coding region (9168bp) of ATM have been found, which presents a challenge in developing an efficient mutation screening strategy for detecting unknown mutations. Fluorescent chemical cleavage of mismatch (FCCM) is an ideal mutation screening method, offering a non-radioactive alternative to other techniques such as restriction endonuclease fingerprinting (REF). Using FCCM, we have developed an efficient, accurate and sensitive mutation detection method for screening RT-PCR products for ATM mutations. We have identified seven ATM mutations in five A-T families, four of which are previously unknown. We quantified ATM protein expression in four of the families and found variable ATM protein expression (0-6.4%), further evidence for mutant ATM protein expression in both classic and variant A-T patients. We conclude that FCCM offers a robust ATM mutation detection method and can be used to screen for ATM mutations in cancer-prone populations.

Adolescent↗
PubMed1997

Influence of ATM function on telomere metabolism.

The ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia, has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination and cell cycle control. The ATM gene has homology with the TEL1 gene of yeast, mutations of which lead to shortened telomeres. To test the hypothesis that the ATM gene product is involved in telomere metabolism, we examined telomeric associations (TA), telomere length, and telomerase activity in human cells expressing either dominant-negative or complementing fragments of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper (LZ) motif mimics that of ataxia telangiectasia (A-T) cells. These transfected RKO cells relative to transfected controls had a higher frequency of cells with TA and shortened telomeres, but no detectable change in telomerase activity. In addition, the percentage of cells with TA after gamma irradiation was higher in the transfected RKO cells with dominant negative activity of the ATM gene, compared to control cells. SV40 transformed fibroblasts derived from an A-T patient and transfected with a complementing carboxyl terminal kinase region of the ATM gene had a reduced frequency of cells with TA, with no effect on the telomere length or telomerase activity. The present studies using isogenic cells with manipulated ATM function demonstrate a role for the ATM gene product in telomere metabolism.

Animals↗
PubMed1999

Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation.

ATM is a member of the large phosphatidylinositol-3 kinase family and plays an important role in cellular response to DNA damage. To further define the physiological roles of ATM at the cellular level, we created an isogenic set of stable cell lines differing only in their ATM status from the chicken B cell line DT40 by targeted integration. These stable DT40 cell lines, as most of transformed chicken cell lines, do not express p53. However, ATM-/- DT40 cells displayed retarded cellular proliferation, defective G2/M checkpoint control and radio-resistant DNA synthesis. Furthermore, ATM-/- DT40 cells were sensitive to ionizing radiation and showed highly elevated frequencies of both spontaneous and radiation-induced chromosomal aberrations. In addition, a slight but significant reduction in targeted integration frequency was observed in ATM-/- DT40 cells. These results suggest that ATM has multiple p53-independent functions in cell cycle checkpoint control and in maintenance of chromosomal DNA. These ATM deficient DT40 clones therefore provide a useful model system for analysing p53-independent ATM functions.

Animals↗
PubMed2001

Transcriptional downregulation of ATM by EGF is defective in ataxia-telangiectasia cells expressing mutant protein.

There is evidence that ATM plays a wider role in intracellular signalling in addition to DNA damage recognition and cell cycle control. In this report we show that activation of the EGF receptor is defective in ataxia-telangiectasia (A-T) cells and that sustained stimulation of cells with EGF downregulates ATM protein in control cells but not in A-T cells expressing mutant protein. Concomitant with the downregulation of ATM, DNA-binding activity of the transcription factor Sp1 decreased in controls after EGF treatment but increased from a lower basal level in A-T cells to that in untreated control cells. Mutation in two Sp1 consensus sequences in the ATM promoter reduced markedly the capacity of the promoter to support luciferase activity in a reporter assay. Overexpression of anti-sense ATM cDNA in control cells decreased the basal level of Sp1, which in turn was increased by subsequent treatment of cells with EGF, similar to that observed in A-T cells. On the other hand full-length ATM cDNA increased the basal level of Sp1 binding in A-T cells, and in response to EGF Sp1 binding decreased, confirming that this is an ATM-dependent process. Contrary to that observed in control cells there was no radiation-induced change in ATM protein in EGF-treated A-T cells and likewise no alteration in Sp1 binding activity. The results demonstrate that EGF-induced downregulation of ATM (mutant) protein in A-T cells is defective and this appears to be due to less efficient EGFR activation and abnormal Sp1 regulation.

Ataxia Telangiectasia Mutated Proteins↗