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PubMed2002

Workshop on The Epidemiology of the ATM Gene: Impact on Breast Cancer Risk and Treatment, Present Status and Future Focus, Lillehammer, Norway, 29 June 2002.

The role of ataxia-telangiectasia mutated (ATM) heterozygosity in cancer is uncertain. In vitro studies of cells from ATM heterozygotes provide strong evidence of radiation sensitivity. Some, but not all, clinical studies suggest an increased risk of breast cancer among ATM gene carriers, and this risk may be greater among those exposed to radiation. This possible excess risk of breast cancer associated with ATM heterozygosity constitutes the basis for several genetic epidemiological studies designed to clarify the role that the ATM gene plays in the etiology of breast and other cancers. The primary focus of this international, multidisciplinary, National Cancer Institute-sponsored workshop was to discuss ongoing and planned epidemiologic studies aimed at understanding the complexities of the ATM gene and its role in carcinogenesis. The invited participants were from diverse disciplines including molecular and clinical genetics, radiation biology and physics, epidemiology, biostatistics, pathology, and medicine. In the present meeting report, the aims of each project are described.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

SPO11 is required for sex-body formation, and Spo11 heterozygosity rescues the prophase arrest of Atm-/- spermatocytes.

SPO11 introduces double-strand breaks (DSBs) that trigger the phosphorylation of H2AX during meiotic prophase. In mice, SPO11 is strictly required for initiation of meiotic recombination and synapsis, yet SPO11 is still considered to be dispensable for sex-body formation in mouse spermatocytes. We provide conclusive evidence showing that functional SPO11, and consequently recombination and synapsis, are required for phosphorylation of H2AX in the X-Y chromatin and for sex-body formation in mouse spermatocytes. We investigated the role in meiosis of the three kinases [ATM (ataxia telangiectasia mutated), ATR (ataxia-telangiectasia- and Rad-3-related) and DNA-PKcs (DNA-dependent-protein-kinase catalytic subunit)] known to phosphorylate H2AX in mitotic cells. We found that DNA-PKcs can be ruled out as an essential kinase in this process, whereas ATM is strictly required for the chromatin-wide phosphorylation of H2AX occurring in leptotene spermatocytes in response to DSBs. Remarkably, we discovered that Spo11 heterozygosity can rescue the prophase-I-arrest characteristic of ATM-deficient spermatocytes. Characterization of the rescued Atm-/- Spo11+/- mutant indicates that ATM is dispensable for sex-body formation and phosphorylation of H2AX in this subnuclear domain. The co-localization of ATR, phosphorylated H2AX and the sex chromatin observed in the Atm-/- Spo11+/- mutant, along with ATR transcription kinetics during the first wave of spermatogenesis, confirm and expand recent findings indicating that ATR is the kinase involved in H2AX phosphorylation in the sex body.

Animals↗
PubMed2003

ATM-dependent and -independent gene expression changes in response to oxidative stress, gamma irradiation, and UV irradiation.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by progressive cerebellar degeneration, immunodeficiencies, telangiectasias, sensitivity to ionizing radiation, and high predisposition for malignancies. The ataxia telangiectasia mutated (ATM) gene encodes a protein (ATM) with serine/threonine kinase activity. DNA-double strand breaks are known to increase its kinase activity. While cells from individuals with AT are attenuated in their G(1)-, S- and G(2)-phase cell cycle checkpoint functions in response to gamma irradiation and oxidative stress, their response to UV irradiation appears to be equivalent to that of wild-type cells. In this study, we investigated changes in gene expression in response to gamma irradiation, oxidative stress, and UV irradiation, focusing on the dependence on ATM. Doses for all three treatments were selected that resulted in roughly an equivalent induction of a G(1) checkpoint response and inhibition of progression through S phase. To investigate gene expression changes, logarithmically growing wild-type and AT dermal diploid fibroblasts were exposed to either gamma radiation (5 Gy), oxidative stress (75 micro M t-butyl-hydroperoxide), or UV radiation (7.5 J/m(2)), and RNA was harvested 6 h after treatment. Gene expression analysis was performed using the NIEHS Human ToxChip 2.0 with approximately 1900 cDNA clones representing known genes and ESTs. All three treatments resulted in distinct patterns of gene expression changes, as shown previously. ATM-dependent and ATM-independent components were detected within these patterns, as were novel indications of involvement of ATM in regulation of transcription factors such as SP1, AP1 and MTF1.

Algorithms↗
PubMed2006

Qualitative and quantitative analysis of phosphorylated ATM foci induced by low-dose ionizing radiation.

We examined the formation of phosphorylated ataxia telangiectasia mutated (ATM) foci in exponentially growing normal human diploid cells exposed to low doses of X rays. Phosphorylated ATM foci were detected immediately after irradiation, and the number of foci decreased as the time after irradiation increased. The kinetics of phosphorylated ATM foci was comparable to that of phosphorylated histone H2AX. We found that there were fewer spontaneous phosphorylated ATM foci than that phosphorylated histone H2AX foci. Notably, significant numbers of phosphorylated histone H2AX foci, but not phosphorylated ATM foci, were detected in the S-phase cells. The induction of foci showed a linear dose-response relationship with doses ranging for 10 mGy to 1 Gy, and the average number of phosphorylated ATM foci per gray was approximately 50. The average size of the foci was comparable for the cells irradiated with 20 mGy and 1 Gy, and there was no significant difference in the kinetics of disappearance of foci, indicating that DNA double-strand breaks are similarly recognized by DNA damage checkpoints and are repaired irrespective of the dose.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation.

The p53 tumor suppressor protein has a major role in protecting genome integrity. Under normal circumstances Mdmx and Mdm2 control the activity of p53. Both proteins inhibit the transcriptional regulation by p53, while Mdm2 also functions as an E3 ubiquitin ligase to target both p53 and Mdmx for proteasomal degradation. HAUSP counteracts the destabilizing effect of Mdm2 by direct deubiquitination of p53. Subsequently, HAUSP was shown to deubiquitinate Mdm2 and Mdmx, thereby stabilizing these proteins. The ATM protein kinase is a key regulator of the p53 pathway in response to double strand breaks (DSBs) in the DNA. ATM fine-tunes p53's response to DNA damage by directly phosphorylating it, by regulating additional post-translational modifications of this protein, and by affecting two p53 regulators: Mdm2 and Mdmx. ATM directly and indirectly induces Mdm2 and Mdmx phosphorylation, resulting in decreased activity and stability of these proteins. We recently provided a mechanism for the reduced stability of Mdm2 and Mdmx by showing that ATM-dependent phosphorylation lowers their affinity for the deubiquitinating enzyme HAUSP. Altogether, the emerging picture portrays an elaborate, but fine-tuned, ATM-mediated control of p53 activation and stabilization following DNA damage. Further insight into the mechanism by which ATM switches the interactions between HAUSP, Mdmx, Mdm2 and p53, to favor p53 activation may offer new tools for therapeutic intervention in the p53 pathway for cancer treatment.

Adenosine Triphosphate↗
PubMed1999

Loss of the ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled atm function.

The alternative reading frame product (p19ARF) of the mouse INK4a/ARF locus is induced by oncoproteins such as Myc and E1A as part of a checkpoint response that limits cell cycle progression in response to hyperproliferative signals. ARF binds directly to Mdm2 to prevent down-regulation of p53 and thereby promotes p53-dependent transcription and cell cycle arrest. However, ARF is not required for p53 induction in response to ionizing radiation or other forms of DNA damage. Animals lacking a functional ataxia telangiectasia (Atm) gene are exquisitely sensitive to ionizing radiation; Atm-null mouse embryo fibroblasts (MEFs) undergo premature replicative arrest, which is relieved by the loss of p53. Here we show that the loss of ARF expands the life expectancy of Atm-null MEFs, but alters neither the sensitivity of Atm-null mice to ionizing radiation nor their propensity to develop lymphomas early in life. Therefore, whereas ARF and Atm signal to p53 through distinct pathways, the loss of ARF can modify p53-dependent features of the Atm-null phenotype.

Animals↗
PubMed1999

Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations.

Ataxia telangiectasia (AT) carrier-derived lymphoblastoid cell lines (AT-LCLs/hetero) with suboptimal ATM protein expression were examined for the regulation of radiosensitivity, apoptosis, and mitotic spindle checkpoint in response to DNA-damaging agents. Although AT-LCLs/hetero showed intermediate radiation sensitivity, as determined by clonogenic assay, they were resistant to early-onset apoptosis, as much as AT patient-derived LCLs (AT-LCLs/homo). Furthermore, two of three AT-LCLs/hetero showed defective mitotic spindle checkpoint control in response to X-ray irradiation, which is a recently characterized biological feature in AT-LCLs/homo. Our findings indicate that carriers of ATM mutation have biological abnormalities due to haploinsufficiency of ATM protein or dominant-negative effect of mutant ATM protein. Thus, although it is still controversial whether ATM mutation carriers are at higher risk for cancer during adulthood, our findings based on in vitro biological indicators support the notion that at least some of such carriers are at a higher risk for cancer development than those without ATM mutation. Our findings may help to reevaluate epidemiological studies on cancer susceptibility in AT carriers.

Apoptosis↗
PubMedDate not supplied

Immunoblot analysis for laboratory diagnosis of ataxia-telangiectasia: use of Epstein-Barr virus-transformed or phytohemagglutinin-stimulated lymphoblasts for detection of ATM protein.

Ataxia-telangiectasia (A-T) is a genetic disorder characterized by a progressive ataxia, immunodeficiency, neurological abnormalities, hypersensitivity to ionizing radiation, and predisposition to cancer. The gene responsible for A-T (ATM) has been cloned and shown to code for a 350 kDa polypeptide containing 3,056 amino acid residues. Detection of ATM mutations for laboratory diagnosis of A-T is laborious and not practical, unless there are common mutations in a population. We describe here immunoblot analysis for the detection of ATM in seven Japanese A-T patients from five families and in controls using ATM3BA antibody. ATM protein was routinely and clearly detected in Epstein-Barr virus (EBV)-transformed or phytohemagglutinin (PHA)-stimulated lymphoblasts from controls. However, it could not be detected consistently in unstimulated peripheral blood mononuclear cells (PBMCs) from controls. We also detected ATM protein in control fibroblasts, but the background was relatively higher than in control lymphoblasts. ATM protein was not detected or dramatically decreased in EBV-transformed lymphoblasts from all seven patients tested and in fibroblasts from one patient. Immunoblot analysis using EBV-transformed or PHA-stimulated lymphoblasts represents a useful approach for laboratory diagnosis for A-T. The latter is especially preferable since it takes only 3 days to obtain sufficient cells for analysis.

Adult↗
PubMed2001

[What do we know about ATM protein expression in breast tissue?].

The great majority of breast cancer cases are not associated with a mutated gene of high penetrance such as BRCA1, BRCA2 and TP53. Genes of low penetrance, frequently mutated in the general population, might play an important role in breast cancer development. The ATM gene, which encodes the ATM protein, mutated in the disorder ataxia telangiectasia (AT) could be such a susceptibility gene. Indeed, 1% of the general population is estimated to be AT heterozygote and females have an increased risk of developing breast cancer. The ATM protein is involved in the signalling pathway of DNA double-strand breaks. Studies on its expression in normal breast tissues have shown that ATM is expressed in the epithelial cells of breast ducts, but not in the myoepithelial cells. In sclerosing adenosis, a benign lesion of the breast, the ATM protein is expressed in both cell types whereas its expression is absent or reduced in tumour epithelial cells in about 30-50% of invasive carcinomas. Moreover, the study of the p53 status in some of these tumours has revealed that the ATM/p53 signalling pathway is frequently altered either by a very low ATM expression or by the presence of a mutated p53. It remains to be determined whether alterations in the expression of other proteins also involved in this DNA damage signalling cascade are specifically associated with breast cancer development and/or a radiosensitive phenotype seen in some breast cancer patients after radiotherapy.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2002

Prevention of thymic lymphoma development in Atm-/- mice by dexamethasone.

We have reported (M. Yan et al., FASEB J., 15: 1132-1138, 2001) that spontaneous DNA synthesisis markedly increased in the thymocytes from the atrophied thymi of young Atm-/- mice. We, therefore, set out to determine whether this elevated DNA synthesis is responsible for the development of thymic lymphomas in all Atm-/- mice by 4-5 months of age. We show here that in Atm-/- mice: (a) increased DNA synthesis occurs, especially in the immature CD4(-) CD8(-) (dominant negative) and CD8(+) thymocyte populations; (b) the relative percentage of dominant negative cells increases significantly during postnatal development, with a sharp peak at 4 weeks of age; and (c) dexamethasone suppresses DNA synthesis in these thymocytes and prevents thymic lymphoma development. These observations suggest that ataxia telangiectasia mutated (ATM) down-regulates the proliferation of thymocytes, allowing T-cell development and differentiation. The results also show that dexamethasone, like ATM, checks DNA synthesis in developing thymocytes. Finally, the data document for the first time that dexamethasone prevents or slows thymic lymphoma development in Atm-/- mice.

Animals↗
PubMed2003

[Expression of ATM protein in nasopharyngeal carcinoma cell lines with different radiosensitivity].

BACKGROUND & OBJECTIVE: It has been reported that ataxia- telangiectasia mutant(ATM) protein is closely correlated with cellular radiosensitivity in several malignant tumors. This study was designed to determine the expression of ATM protein in two nasopharyngeal carcinoma (NPC) cell lines with different radiosensitivity. METHODS: Two NPC cell lines, CNE1 and CNE2, with different radiosensitivity were established. The localization and quantity of ATM protein were analyzed by fluorescence immunohistochemical method and laser scanning confocal microscope(LSCM). RESULTS: ATM protein was located in both karyon and cytoplasm, especially strongly expressed in karyon. The intense fluorescence of ATM protein was stronger in karyon of CNE1 than that in CNE2. CONCLUSION: The expression levels of ATM protein differ in CNE1 and CNE2. The variance may be a potential factor, which links with their different radiosensitivity.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2003

Atm-, p53-, and Gadd45a-deficient mice show an increased frequency of homologous recombination at different stages during development.

Atm, p53, and Gadd45a form part of a DNA-damage cellular response pathway; the absence of any one of these components results in increased genomic instability. We conducted an in vivo examination of the frequency of spontaneous homologous recombination in Atm-, p53-, or Gadd45a-deficient mice. In the absence of p53, we observed the greatest increase in events, a lesser increase in the absence of Atm, and only a modest increase in the absence of Gadd45a. The striking observation was the difference in the time at which the spontaneous events occurred in atm and trp53 mutant mice. The frequency of homologous recombination in atm mutant mice was increased later during development. In contrast, p53 appears to have a role in suppressing homologous recombination early during development, when p53 is known to spontaneously promote p21 activity. The timing of the increased spontaneous recombination was similar in the Gadd45a- and p53-deficient mice. This temporal resolution suggests that Atm and p53 can act to maintain genomic integrity by different mechanisms in certain in vivo contexts.

Animals↗
PubMed2003

Absence of ATM deletions in 16 cases of splenic marginal-zone B-cell lymphoma (SMZBCL).

We present the study of 16 cases of splenic marginal zone B-cell lymphoma (SMZBL) combining conventional cytogenetics and fluorescence in situ hybridization technique (FISH). We used a locus specific probe (11q22.3) that hybridizes with Ataxia Telangiectasia Mutated gene (ATM) and a centromeric probe of chromosome 11 as a control. Deletions in ATM gene region have been found in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) and have been considered as an independent prognosis factor in these pathologies. The aim of our study was to determine the ATM status in SMZBL because no specific studies concerning ATM status in SMZBL have been reported and other B-cell malignances have shown ATM deletions. No deletions were detected in any of the 16 cases. ATM deletions could be considered a rare event in SMZBCL.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1988

Identification of a tumor-associated target antigen, ATM-1, for a human T-cell clone with activated killer activity and its existence in sera of cancer patients.

Three human T-cell clones with activated killer activity (5B5, 5C1, and 7B5) which could lyse various tumor cell lines were established. The cytotoxic activity of these clones was decreased by incubation with anti-CD3 monoclonal antibody, suggesting that they recognized tumor cells by T-cell antigen receptor. A monoclonal antibody which blocked the cytotoxic activity of clone 5B5 was obtained. This antibody (N1977) blocked the binding and cytotoxic activity of clone 5B5 at the target cell level, suggesting that the antigen defined by N1977 antibody, designated as ATM-1, was a target molecule recognized by 5B5 cells. ATM-1 in the conditioned medium of a cancer cell line (NBT-2) and serum from a patient with lung cancer was characterized by following its immunoreactivity. On gel filtration, both the conditioned medium and the serum gave three peaks of ATM-1 immunoreactivity, corresponding to approximate molecular weights of 1,200,000, 700,000, and 120,000, respectively. They were chromatofocused at pH 4.0, 4.8, and 6.5, respectively. The high molecular weight forms were shown to be molecules with the disulfide-linked elementary glycoprotein with ATM-1 immunoreactivity and approximate molecular weight of 120,000. Most of the molecules with ATM-1 immunoreactivity bound to both concanavalin A and wheat germ agglutinin, and their binding activity to the antibodies was lost by treatment at 60 degrees C for 30 min. An assay of ATM-1 level in sera was performed by a sandwich enzyme immunoassay. The following positive percentages were obtained from preliminary clinical studies: breast cancer, 67% (8 of 12 cases); hepatocellular carcinoma, 83% (10 of 12 cases); gastric cancer, 58% (7 of 12 cases); lung cancer, 41% (5 of 12 cases); hematological malignancies, 0% (0 of 9 cases); systemic lupus erythematosus, 0% (0 of 8 cases); rheumatoid arthritis, 0% (0 of 8 cases).

Animals↗
PubMed1995

Diurnal renal responses in man to water loading at sea level and 31 atm abs.

The hyperbaric environment causes a sustained diuresis accompanied by normal water intake and a decrease in insensible water loss. The maintained water intake may be necessary for the maintenance of water balance because of a reduced ability of the kidney to retain water, or may be causal in the diuresis. This problem was studied in four male subjects. Each ingested 1 liter of water (15 degrees C) at 0800 and 2000 h on different days, at 1 atm abs during a predive control, at 31 atm abs, and at 1 atm abs during the postdive control period. Urine was collected 30 min before and 3 h after the drink. Plasma vasopressin (VP) showed a circadian rhythm only at 1 atm abs, higher during the daytime. Because of this, and slightly lower VP levels at hyperbaria, a decrease in VP in response to the water load was significantly detectable only at 1 atm abs during the daytime. At 60 min after all water loads, there were no differences in plasma VP or plasma or urinary osmolality. Variability in the length of time of similarly reduced urine osmolality and increased free water excretion accounted for the increased urine flow during day compared to night (P < 0.05) at 120 and 150 min after the water load. The ability to excrete a water load both day (free water clear-ance, P < 0.05 at 60 min post-drink) and night (free water clearance, P < 0.05 at 60, 90, and 120 min post-drink) at 31 atm abs was enhanced. It is concluded that maintained water intake at hyperbaria is necessary to maintain water balance because there is a reduced ability of the body through renal mechanisms to retain a water load.

Adult↗
PubMed1996

The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation.

Heterozygosity for ataxia-telangiectasia (A-T), a cancer-prone recessive syndrome, has been associated with an increased risk of breast cancer. The gene for A-T (ATM) is located at chromosomal region 11q22-q23, a region of frequent loss of constitutional heterozygosity in breast and other tumors. Loss of constitutional heterozygosity at 1lq22-q23 was found in 47% of informative cases in the series of primary tumors analyzed in this study. To investigate the role of ATM in breast cancer, we have determined the complete genomic organization of the gene, developed an exon-scanning PCR single-strand conformation polymorphism (PCR-SSCP) assay for mutation detection of ATM, and screened 38 consecutive breast tumors for mutations using both genomic DNA- and cDNA-based assays. In addition to common ATM polymorphisms detected both in the coding sequence and in flanking introns, seven unique SSCP alleles were identified in six tumor DNAs. Sequence analysis of these alleles revealed rive nucleotide substitutions that were predicted to change the encoded amino acid. However, PCR-SSCP and nucleotide sequencing analysis of the paired blood samples and of an extended sample size of a total of 224 chromosomes indicated that these SSCP patterns represent constitutional rare polymorphisms with a frequency between 0.005 and 0.023. Because the majority of A-T mutations are null mutations and none of the ATM alleles found in breast cancer samples would lead to the truncation of the translation product, we conclude that, in this initial sample of sporadic breast cancer patients, there was no evidence for an increased number of A-T carriers. In addition, because no somatic mutations were found, our study rules out the ATM gene as the frequently altered tumor suppressor gene at 11q23.

Ataxia Telangiectasia↗
PubMed1997

ATM gene product phosphorylates I kappa B-alpha.

The recently cloned ATM gene is mutated in patients with ataxia telangiectasia, but its biological functions remain to be experimentally determined. Structural analysis has revealed ATM sequence similarities to the catalytic domains of phosphatidyl-3 kinase and other members of this family of yeast and mammalian proteins. Rabbit polyclonal antibodies raised against polypeptide regions unique to the COOH terminus and to the NH2 terminus of the published ATM sequence confirm ATM as M(r) approximately 350,000 protein in normal cells, which is missing in AT cells. Immunoprecipitated protein(s) is capable of phosphorylating I kappa B-alpha in an in vitro kinase assay. However, we did not observe a phosphatidyl-3 kinase or a DNA-dependent protein kinase function by ATM immunoprecipitates. These data support a protein kinase activity for ATM and suggest a role in NF-kappa B activation.

Antibodies, Monoclonal↗
PubMed1998

Assessment of cardiac autonomic nervous activities during heliox exposure at 24 atm abs.

BACKGROUND: This experiment was designed to examine the involvement of the autonomic nervous system in the production of hyperbaric bradycardia. METHODS: Four male divers were exposed to a He-O2 (heliox) environment at 24 atmosphere absolute (atm abs) for 7 d. The heart rate (HR) and respiratory rate were recorded at rest in the morning (0700 h) and at night (2230 h) on 1 d during a 5-d predive control, 2 d during a 7-d saturation dive at 24 atm abs, 2 d during decompression, and on 1 d during a 4-d postdive period. Cardiac sympathetic and parasympathetic activities were estimated by using a spectral analysis of the variability of R-R intervals. RESULTS: The morning HR did not fluctuate throughout the experimental days. The night time HR decreased (p < 0.05) by 11.8% on the first day at 24 atm abs compared with that of the predive control. The bradycardia diminished gradually and returned to the predive level with continued exposure at 24 atm abs. The high-frequency power of the cardiac variability, an index of cardiac parasympathetic activity, increased (p < 0.05) only in the first night at 24 atm abs, whereas the low-frequency power and a ratio of low- to high-frequency power, an index of cardiac sympathetic activity, were unchanged. CONCLUSIONS: The present results suggest that an increased parasympathetic activity rather than a decrease in the sympathetic activity is responsible for the bradycardia on exposure to heliox dry saturation dive at 24 atm abs. The mechanism of the gradual disappearance of the bradycardia is unknown, but perhaps it may be related to the development of cardiovascular deconditioning.

Adult↗