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Sample records for polymerase-1 inhibits atm

  1. Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium.

    PubMed

    Cooper, Karen L; Dashner, Erica J; Tsosie, Ranalda; Cho, Young Mi; Lewis, Johnnye; Hudson, Laurie G

    2016-01-15

    Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; <10 μM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations.

  2. Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

    PubMed Central

    Cooper, Karen L.; Dashner, Erica J.; Tsosie, Ranalda; Cho, Young Mi; Lewis, Johnnye

    2015-01-01

    Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; <10 μM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations. PMID:26627003

  3. Alternative mechanisms of inhibiting activity of poly (ADP-ribose) polymerase-1.

    PubMed

    Sriram, Chandra Shaker; Jangra, Ashok; Bezbaruah, Babul Kumar; V, Athira K; Sykam, Shivaji

    2016-01-01

    Poly ADP-ribose polymerase (PARP-1), a DNA nick-sensor enzyme, is an abundant nuclear protein. Upon sensing DNA breaks, PARP-1 gets activated and cleaves NAD into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors, and PARP-1 itself. Poly(ADP-ribosylation) mainly contributes to DNA repairing mechanism. However, oxidative stress-induced over-activation of PARP-1 consumes excess of NAD and consequently ATP, culminating into cell necrosis. This cellular suicide pathway has been implicated in several conditions such as stroke, myocardial ischemia, diabetes. Thus, it can be a rationale approach to inhibit the activity of PARP-1 for reducing detrimental effects associated with oxidative stress-induced over-activation of PARP-1. Several preclinical as well as clinical studies of PARP-1 inhibitors have been used in conditions such as cancer, stroke and traumatic brain injury. Conventionally, there are many studies which employed the concept of direct inhibition of PARP-1 by competing with NAD. Here, in the present review, we highlight several prospective alternative approaches for the inhibition of PARP-1 activity.

  4. NOTCH1 Inhibits Activation of ATM by Impairing the Formation of an ATM-FOXO3a-KAT5/Tip60 Complex.

    PubMed

    Adamowicz, Marek; Vermezovic, Jelena; d'Adda di Fagagna, Fabrizio

    2016-08-23

    The DNA damage response (DDR) signal transduction pathway is responsible for sensing DNA damage and further relaying this signal into the cell. ATM is an apical DDR kinase that orchestrates the activation and the recruitment of downstream DDR factors to induce cell-cycle arrest and repair. We have previously shown that NOTCH1 inhibits ATM activation upon DNA damage, but the underlying mechanism remains unclear. Here, we show that NOTCH1 does not impair ATM recruitment to DNA double-strand breaks (DSBs). Rather, NOTCH1 prevents binding of FOXO3a and KAT5/Tip60 to ATM through a mechanism in which NOTCH1 competes with FOXO3a for ATM binding. Lack of FOXO3a binding to ATM leads to the loss of KAT5/Tip60 association with ATM. Moreover, expression of NOTCH1 or depletion of ATM impairs the formation of the FOXO3a-KAT5/Tip60 protein complex. Finally, we show that pharmacological induction of FOXO3a nuclear localization sensitizes NOTCH1-driven cancers to DNA-damage-induced cell death.

  5. ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila.

    PubMed

    Petersen, Andrew J; Rimkus, Stacey A; Wassarman, David A

    2012-03-13

    To investigate the mechanistic basis for central nervous system (CNS) neurodegeneration in the disease ataxia-telangiectasia (A-T), we analyzed flies mutant for the causative gene A-T mutated (ATM). ATM encodes a protein kinase that functions to monitor the genomic integrity of cells and control cell cycle, DNA repair, and apoptosis programs. Mutation of the C-terminal amino acid in Drosophila ATM inhibited the kinase activity and caused neuron and glial cell death in the adult brain and a reduction in mobility and longevity. These data indicate that reduced ATM kinase activity is sufficient to cause neurodegeneration in A-T. ATM kinase mutant flies also had elevated expression of innate immune response genes in glial cells. ATM knockdown in glial cells, but not neurons, was sufficient to cause neuron and glial cell death, a reduction in mobility and longevity, and elevated expression of innate immune response genes in glial cells, indicating that a non-cell-autonomous mechanism contributes to neurodegeneration in A-T. Taken together, these data suggest that early-onset CNS neurodegeneration in A-T is similar to late-onset CNS neurodegeneration in diseases such as Alzheimer's in which uncontrolled inflammatory response mediated by glial cells drives neurodegeneration.

  6. Squalene Inhibits ATM-Dependent Signaling in γIR-Induced DNA Damage Response through Induction of Wip1 Phosphatase.

    PubMed

    Tatewaki, Naoto; Konishi, Tetsuya; Nakajima, Yuki; Nishida, Miyako; Saito, Masafumi; Eitsuka, Takahiro; Sakamaki, Toshiyuki; Ikekawa, Nobuo; Nishida, Hiroshi

    2016-01-01

    Ataxia telangiectasia mutated (ATM) kinase plays a crucial role as a master controller in the cellular DNA damage response. Inhibition of ATM leads to inhibition of the checkpoint signaling pathway. Hence, addition of checkpoint inhibitors to anticancer therapies may be an effective targeting strategy. A recent study reported that Wip1, a protein phosphatase, de-phosphorylates serine 1981 of ATM during the DNA damage response. Squalene has been proposed to complement anticancer therapies such as chemotherapy and radiotherapy; however, there is little mechanistic information supporting this idea. Here, we report the inhibitory effect of squalene on ATM-dependent DNA damage signals. Squalene itself did not affect cell viability and the cell cycle of A549 cells, but it enhanced the cytotoxicity of gamma-irradiation (γIR). The in vitro kinase activity of ATM was not altered by squalene. However, squalene increased Wip1 expression in cells and suppressed ATM activation in γIR-treated cells. Consistent with the potential inhibition of ATM by squalene, IR-induced phosphorylation of ATM effectors such as p53 (Ser15) and Chk1 (Ser317) was inhibited by cell treatment with squalene. Thus, squalene inhibits the ATM-dependent signaling pathway following DNA damage through intracellular induction of Wip1 expression.

  7. Inhibition of Ataxia Telangiectasia Mutated (ATM) Kinase Suppresses Herpes Simplex Virus Type 1 (HSV-1) Keratitis

    PubMed Central

    Alekseev, Oleg; Donovan, Kelly; Azizkhan-Clifford, Jane

    2014-01-01

    Purpose. Herpes keratitis (HK) remains the leading cause of cornea-derived blindness in the developed world, despite the availability of effective antiviral drugs. Treatment toxicity and the emergence of drug resistance highlight the need for additional therapeutic approaches. This study examined ataxia telangiectasia mutated (ATM), an apical kinase in the host DNA damage response, as a potential new target for the treatment of HK. Methods. Small molecule inhibitor of ATM (KU-55933) was used to treat herpes simplex virus type 1 (HSV-1) infection in three experimental models: (1) in vitro—cultured human corneal epithelial cells, hTCEpi, (2) ex vivo—organotypically explanted human and rabbit corneas, and (3) in vivo—corneal infection in young C57BL/6J mice. Infection productivity was assayed by plaque assay, real-time PCR, Western blot, and disease scoring. Results. Robust ATM activation was detected in HSV-1-infected human corneal epithelial cells. Inhibition of ATM greatly suppressed viral replication in cultured cells and in explanted human and rabbit corneas, and reduced the severity of stromal keratitis in mice. The antiviral effect of KU-55933 in combination with acyclovir was additive, and KU-55933 suppressed replication of a drug-resistant HSV-1 strain. KU-55933 caused minimal toxicity, as monitored by clonogenic survival assay and fluorescein staining. Conclusions. This study identifies ATM as a potential target for the treatment of HK. ATM inhibition by KU-55933 reduces epithelial infection and stromal disease severity without producing appreciable toxicity. These findings warrant further investigations into the DNA damage response as an area for therapeutic intervention in herpetic ocular diseases. PMID:24370835

  8. Inhibition of TGFbeta1 Signaling Attenutates ATM Activity inResponse to Genotoxic Stress

    SciTech Connect

    Kirshner, Julia; Jobling, Michael F.; Pajares, Maria Jose; Ravani, Shraddha A.; Glick, Adam B.; Lavin, Martin J.; Koslov, Sergei; Shiloh, Yosef; Barcellos-Hoff, Mary Helen

    2006-09-15

    Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor {beta}1 (TGF{beta}), which is activated by radiation, is a potent and pleiotropic mediator of physiological and pathological processes. Here we show that TGF{beta} inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf{beta}1 null murine epithelial cells or human epithelial cells treated with a small molecule inhibitor of TGF{beta} type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17 and p53, reduced {gamma}H2AX radiation-induced foci, and increased radiosensitivity compared to TGF{beta} competent cells. We determined that loss of TGF{beta} signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF{beta} restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM that directs epithelial cell stress responses, cell fate and tissue integrity. Thus, TGF{beta}1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF{beta} may be used to advantage in cancer therapy.

  9. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR.

    PubMed

    Reaper, Philip M; Griffiths, Matthew R; Long, Joanna M; Charrier, Jean-Damien; Maccormick, Somhairle; Charlton, Peter A; Golec, Julian M C; Pollard, John R

    2011-04-13

    Here we report a comprehensive biological characterization of a potent and selective small-molecule inhibitor of the DNA damage response (DDR) kinase ATR. We show a profound synthetic lethal interaction between ATR and the ATM-p53 tumor suppressor pathway in cells treated with DNA-damaging agents and establish ATR inhibition as a way to transform the outcome for patients with cancer treated with ionizing radiation or genotoxic drugs.

  10. Structural basis for the inhibition of poly(ADP-ribose) polymerases 1 and 2 by BMN 673, a potent inhibitor derived from dihydropyridophthalazinone

    SciTech Connect

    Aoyagi-Scharber, Mika; Gardberg, Anna S.; Yip, Bryan K.; Wang, Bing; Shen, Yuqiao; Fitzpatrick, Paul A.

    2014-08-29

    BMN 673, a novel PARP1/2 inhibitor in clinical development with substantial tumor cytotoxicity, forms extensive hydrogen-bonding and π-stacking in the nicotinamide pocket, with its unique disubstituted scaffold extending towards the less conserved edges of the pocket. These interactions might provide structural insight into the ability of BMN 673 to both inhibit catalysis and affect DNA-binding activity. Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2), which are involved in DNA damage response, are targets of anticancer therapeutics. BMN 673 is a novel PARP1/2 inhibitor with substantially increased PARP-mediated tumor cytotoxicity and is now in later-stage clinical development for BRCA-deficient breast cancers. In co-crystal structures, BMN 673 is anchored to the nicotinamide-binding pocket via an extensive network of hydrogen-bonding and π-stacking interactions, including those mediated by active-site water molecules. The novel di-branched scaffold of BMN 673 extends the binding interactions towards the outer edges of the pocket, which exhibit the least sequence homology among PARP enzymes. The crystallographic structural analyses reported here therefore not only provide critical insights into the molecular basis for the exceptionally high potency of the clinical development candidate BMN 673, but also new opportunities for increasing inhibitor selectivity.

  11. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells.

    PubMed

    Kwok, Marwan; Davies, Nicholas; Agathanggelou, Angelo; Smith, Edward; Oldreive, Ceri; Petermann, Eva; Stewart, Grant; Brown, Jeff; Lau, Alan; Pratt, Guy; Parry, Helen; Taylor, Malcolm; Moss, Paul; Hillmen, Peter; Stankovic, Tatjana

    2016-02-04

    TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution, and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53- or ATM-defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53- or ATM-defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53- and ATM-defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53- or ATM-defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53- or ATM-defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53- or ATM-defective CLL that warrants clinical investigation.

  12. Interdependent genotoxic mechanisms of monomethylarsonous acid: Role of ROS-induced DNA damage and poly(ADP-ribose) polymerase-1 inhibition in the malignant transformation of urothelial cells

    SciTech Connect

    Wnek, Shawn M.; Kuhlman, Christopher L.; Camarillo, Jeannie M.; Medeiros, Matthew K.; Liu, Ke J.; Lau, Serrine S.; Gandolfi, A.J.

    2011-11-15

    Exposure of human bladder urothelial cells (UROtsa) to 50 nM of the arsenic metabolite, monomethylarsonous acid (MMA{sup III}), for 12 weeks results in irreversible malignant transformation. The ability of continuous, low-level MMA{sup III} exposure to cause an increase in genotoxic potential by inhibiting repair processes necessary to maintain genomic stability is unknown. Following genomic insult within cellular systems poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger protein, is rapidly activated and recruited to sites of DNA strand breaks. When UROtsa cells are continuously exposed to 50 nM MMA{sup III}, PARP-1 activity does not increase despite the increase in MMA{sup III}-induced DNA single-strand breaks through 12 weeks of exposure. When UROtsa cells are removed from continuous MMA{sup III} exposure (2 weeks), PARP-1 activity increases coinciding with a subsequent decrease in DNA damage levels. Paradoxically, PARP-1 mRNA expression and protein levels are elevated in the presence of continuous MMA{sup III} indicating a possible mechanism to compensate for the inhibition of PARP-1 activity in the presence of MMA{sup III}. The zinc finger domains of PARP-1 contain vicinal sulfhydryl groups which may act as a potential site for MMA{sup III} to bind, displace zinc ion, and render PARP-1 inactive. Mass spectrometry analysis demonstrates the ability of MMA{sup III} to bind a synthetic peptide representing the zinc-finger domain of PARP-1, and displace zinc from the peptide in a dose-dependent manner. In the presence of continuous MMA{sup III} exposure, continuous 4-week zinc supplementation restored PARP-1 activity levels and reduced the genotoxicity associated with MMA{sup III}. Zinc supplementation did not produce an overall increase in PARP-1 protein levels, decrease the levels of MMA{sup III}-induced reactive oxygen species, or alter Cu-Zn superoxide dismutase levels. Overall, these results present two potential interdependent mechanisms in which MMA

  13. Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition.

    PubMed

    Borodkina, Aleksandra V; Shatrova, Alla N; Deryabin, Pavel I; Grukova, Anastasiya A; Nikolsky, Nikolay N; Burova, Elena B

    2016-01-01

    Previously we demonstrated that endometrium-derived human mesenchymal stem cells (hMESCs) via activation of the ATM/p53/p21/Rb pathway enter the premature senescence in response to oxidative stress. Down regulation effects of the key components of this signaling pathway, particularly ATM and p53, on a fate of stressed hMESCs have not yet been investigated. In the present study by using the specific inhibitors Ku55933 and Pifithrin-α, we confirmed implication of both ATM and p53 in H(2)O(2)-induced senescence of hMESCs. ATM or p53 down regulation was shown to modulate differently the cellular fate of H(2)O(2)-treated hMESCs. ATM inhibition allowed H(2)O(2)-stimulated hMESCs to escape the permanent cell cycle arrest due to loss of the functional ATM/p53/p21/Rb pathway, and induced bypass of mitosis and re-entry into S phase, resulting in tetraploid cells. On the contrary, suppression of the p53 transcriptional activity caused a pronounced cell death of H(2)O(2)-treated hMESCs via autophagy induction. The obtained data clearly demonstrate that down regulation of ATM or p53 shifts senescence of human endometrial stem cells toward tetraploidization or autophagy.

  14. ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

    PubMed Central

    Reddy, Vidyavathi; Wu, Min; Ciavattone, Nicholas; McKenty, Nathan; Menon, Mani; Barrack, Evelyn R.; Reddy, G. Prem-Veer; Kim, Sahn-Ho

    2015-01-01

    Androgen receptor (AR) plays a role in maintaining telomere stability in prostate cancer cells, as AR inactivation induces telomere dysfunction within 3 h. Since telomere dysfunction in other systems is known to activate ATM (ataxia telangiectasia mutated)-mediated DNA damage response (DDR) signaling pathways, we investigated the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells. Indeed, the induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation (activation) of ATM and its downstream effector Chk2 and the presenceof phosphorylated ATM at telomeres, indicating activation of DDR signaling at telomeres. Moreover, Casodex washout led to the reversal of telomere dysfunction, indicating repair of damaged telomeres. ATM inhibitor blocked ATM phosphorylation, induced PARP cleavage, abrogated cell cycle checkpoint activation and attenuated the formation of γH2AX foci at telomeres in AR-inactivated cells, suggesting that ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres. Finally, colony formation assay revealed a dramatic decrease in the survival of cells co-treated with Casodex and ATM inhibitor as compared with those treated with either Casodex or ATM inhibitor alone. These observations indicate that inhibitors of DDR signaling pathways may offer a unique opportunity to enhance the potency of AR-targeted therapies for the treatment of androgen-sensitive as well as castration-resistant prostate cancer. PMID:26336104

  15. ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction.

    PubMed

    Reddy, Vidyavathi; Wu, Min; Ciavattone, Nicholas; McKenty, Nathan; Menon, Mani; Barrack, Evelyn R; Reddy, G Prem-Veer; Kim, Sahn-Ho

    2015-10-16

    Androgen receptor (AR) plays a role in maintaining telomere stability in prostate cancer cells, as AR inactivation induces telomere dysfunction within 3 h. Since telomere dysfunction in other systems is known to activate ATM (ataxia telangiectasia mutated)-mediated DNA damage response (DDR) signaling pathways, we investigated the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells. Indeed, the induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation (activation) of ATM and its downstream effector Chk2 and the presenceof phosphorylated ATM at telomeres, indicating activation of DDR signaling at telomeres. Moreover, Casodex washout led to the reversal of telomere dysfunction, indicating repair of damaged telomeres. ATM inhibitor blocked ATM phosphorylation, induced PARP cleavage, abrogated cell cycle checkpoint activation and attenuated the formation of γH2AX foci at telomeres in AR-inactivated cells, suggesting that ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres. Finally, colony formation assay revealed a dramatic decrease in the survival of cells co-treated with Casodex and ATM inhibitor as compared with those treated with either Casodex or ATM inhibitor alone. These observations indicate that inhibitors of DDR signaling pathways may offer a unique opportunity to enhance the potency of AR-targeted therapies for the treatment of androgen-sensitive as well as castration-resistant prostate cancer.

  16. The depletion of ATM inhibits colon cancer proliferation and migration via B56γ2-mediated Chk1/p53/CD44 cascades.

    PubMed

    Liu, Rui; Tang, Jiajia; Ding, Chaodong; Liang, Weicheng; Zhang, Li; Chen, Tianke; Xiong, Yan; Dai, Xiaowei; Li, Wenfeng; Xu, Yunsheng; Hu, Jin; Lu, Liting; Liao, Wanqin; Lu, Xincheng

    2017-04-01

    Ataxia-telangiectasia mutated (ATM) protein kinase is a major guardian of genomic stability, and its well-established function in cancer is tumor suppression. Here, we report an oncogenic role of ATM. Using two isogenic sets of human colon cancer cell lines that differed only in their ATM status, we demonstrated that ATM deficiency significantly inhibits cancer cell proliferation, migration, and invasion. The tumor-suppressive function of ATM depletion is not modulated by the compensatory activation of ATR, but it is associated with B56γ2-mediated Chk1/p53/CD44 signaling pathways. Under normal growth conditions, the depletion of ATM prevents B56γ2 ubiquitination and degradation, which activates PP2A-mediated Chk1/p53/p21 signaling pathways, leading to senescence and cell cycle arrest. CD44 was validated as a novel ATM target based on its ability to rescue cell migration and invasion defects in ATM-depleted cells. The activation of p53 induced by ATM depletion suppresses CD44 transcription, thus resulting in epithelial-mesenchymal transition (EMT) and cell migration suppression. Our study suggests that ATM has tumorigenic potential in post-formed colon neoplasia, and it supports ATM as an appealing target for improving cancer therapy.

  17. Bleomycin-induced over-replication involves sustained inhibition of mitotic entry through the ATM/ATR pathway.

    PubMed

    Nakayama, Yuji; Igarashi, Asae; Kikuchi, Ikue; Obata, Yuuki; Fukumoto, Yasunori; Yamaguchi, Naoto

    2009-09-10

    Polyploid cells result in aneuploidy through aberrant chromosome segregation, possibly leading to tumorigenesis. Although polyploid cells are induced through over-replication by a variety of agents, including DNA-damaging drugs, the mechanisms that induce polyploidy have been hitherto unknown. Here, we show that treatment with bleomycin, a glycopeptide anticancer drug, induces over-replication at low cytotoxic doses. During bleomycin-induced over-replication, mitotic entry is inhibited through tyrosine phosphorylation of CDK1 along the ATM/ATR pathway in the early phase of treatment. Bleomycin-induced over-replication is inhibited by the inhibitors of the ATM/ATR pathway through abrogation of bleomycin-induced G2 arrest, and the ATM/ATR inhibitors promote cell death instead of over-replication. Following the phosphorylation of CDK1, the level of cyclin B1 is decreased in the late phase of treatment. Time-lapse imaging of clone cells that express a live cell marker of endogenous cyclin B1 revealed that cyclin B1 is degraded in G2-arrested cells upon bleomycin treatment. Our findings lead to a model of how the ATM/ATR pathway acts as a molecular switch for regulating cell fates, flipping between cell death via progress into mitosis, and over-replication via sustained G2 arrest upon DNA damage, where cyclin B1 degradation is an important factor for inducing over-replication.

  18. ATM-deficiency sensitizes Mantle Cell Lymphoma cells to PARP-1 inhibitors

    PubMed Central

    Williamson, Chris T.; Muzik, Huong; Turhan, Ali G.; Zamò, Alberto; O’Connor, Mark J.; Bebb, D. Gwyn; Lees-Miller, Susan P.

    2013-01-01

    Poly-ADP ribose polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept, termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The Ataxia-Telangiectasia Mutated (ATM) gene is altered in a number of human cancers including Mantle Cell Lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition, than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (previously known as AZD2281/KU-0059436) significantly decreased tumour growth and increased overall survival in mice bearing subcutaneous xenografts of ATM-deficient Granta-519 cells, while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL and the concept of synthetic lethality extends to human cancers with ATM alterations. PMID:20124459

  19. Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation.

    PubMed

    Vendetti, Frank P; Leibowitz, Brian J; Barnes, Jennifer; Schamus, Sandy; Kiesel, Brian F; Abberbock, Shira; Conrads, Thomas; Clump, David Andy; Cadogan, Elaine; O'Connor, Mark J; Yu, Jian; Beumer, Jan H; Bakkenist, Christopher J

    2017-02-01

    We show that ATM kinase inhibition using AZ31 prior to 9 or 9.25 Gy total body irradiation (TBI) reduced median time to moribund in mice to 8 days. ATR kinase inhibition using AZD6738 prior to TBI did not reduce median time to moribund. The striking finding associated with ATM inhibition prior to TBI was increased crypt loss within the intestine epithelium. ATM inhibition reduced upregulation of p21, an inhibitor of cyclin-dependent kinases, and blocked G1 arrest after TBI thereby increasing the number of S phase cells in crypts in wild-type but not Cdkn1a(p21(CIP/WAF1))-/- mice. In contrast, ATR inhibition increased upregulation of p21 after TBI. Thus, ATM activity is essential for p21-dependent arrest while ATR inhibition may potentiate arrest in crypt cells after TBI. Nevertheless, ATM inhibition reduced median time to moribund in Cdkn1a(p21(CIP/WAF1))-/- mice after TBI. ATM inhibition also increased cell death in crypts at 4 h in Cdkn1a(p21(CIP/WAF1))-/-, earlier than at 24 h in wild-type mice after TBI. In contrast, ATR inhibition decreased cell death in crypts in Cdkn1a(p21(CIP/WAF1))-/- mice at 4 h after TBI. We conclude that ATM activity is essential for p21-dependent and p21-independent mechanisms that radioprotect intestinal crypts and that ATM inhibition promotes GI syndrome after TBI.

  20. Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation

    PubMed Central

    Vendetti, Frank P.; Leibowitz, Brian J.; Barnes, Jennifer; Schamus, Sandy; Kiesel, Brian F.; Abberbock, Shira; Conrads, Thomas; Clump, David Andy; Cadogan, Elaine; O’Connor, Mark J.; Yu, Jian; Beumer, Jan H.; Bakkenist, Christopher J.

    2017-01-01

    We show that ATM kinase inhibition using AZ31 prior to 9 or 9.25 Gy total body irradiation (TBI) reduced median time to moribund in mice to 8 days. ATR kinase inhibition using AZD6738 prior to TBI did not reduce median time to moribund. The striking finding associated with ATM inhibition prior to TBI was increased crypt loss within the intestine epithelium. ATM inhibition reduced upregulation of p21, an inhibitor of cyclin-dependent kinases, and blocked G1 arrest after TBI thereby increasing the number of S phase cells in crypts in wild-type but not Cdkn1a(p21CIP/WAF1)−/− mice. In contrast, ATR inhibition increased upregulation of p21 after TBI. Thus, ATM activity is essential for p21-dependent arrest while ATR inhibition may potentiate arrest in crypt cells after TBI. Nevertheless, ATM inhibition reduced median time to moribund in Cdkn1a(p21CIP/WAF1)−/− mice after TBI. ATM inhibition also increased cell death in crypts at 4 h in Cdkn1a(p21CIP/WAF1)−/−, earlier than at 24 h in wild-type mice after TBI. In contrast, ATR inhibition decreased cell death in crypts in Cdkn1a(p21CIP/WAF1)−/− mice at 4 h after TBI. We conclude that ATM activity is essential for p21-dependent and p21-independent mechanisms that radioprotect intestinal crypts and that ATM inhibition promotes GI syndrome after TBI. PMID:28145510

  1. Activation and Inhibition of ATM by Phytochemicals: Awakening and Sleeping the Guardian Angel Naturally.

    PubMed

    Farooqi, Ammad Ahmad; Wu, Shyh-Jong; Chang, Yung-Ting; Tang, Jen-Yang; Li, Kun-Tzu; Ismail, Muhammad; Liaw, Chih-Chuang; Li, Ruei-Nian; Chang, Hsueh-Wei

    2015-10-01

    Double-stranded breaks (DSBs) are cytotoxic DNA lesions caused by oxygen radicals, ionizing radiation, and radiomimetic chemicals. Increasing understanding of DNA damage signaling has provided an ever-expanding list of modulators reported to orchestrate DNA damage repair and ataxia telangiectasia mutated (ATM) is the master regulator and main transducer of the DSB response. Increasingly, it is being realized that DNA damage response is a synchronized and branched network that functionalizes different molecular cascades to activate special checkpoints, thus temporarily arresting progression of the cell cycle while damage is being assessed and processed. It is noteworthy that both nutrigenetics and nutrigenomics have revolutionized the field of molecular biology and rapidly accumulating experimental evidence has started to shed light on biological activities of a wide range of phytochemicals reported to modulate cell cycle, DNA repair, cell growth, differentiation and apoptosis as evidenced by cell-based studies. In this review, we have attempted to provide an overview of DNA damage signaling, how ATM signaling regulates tumor necrosis factors-related apoptosis inducing ligand (TRAIL)-induced intracellular network. We also illuminate on how resveratrol, epigallocatechin gallate, curcumin, jaceosidin, cucurbitacin, apigenin, genistein, and others trigger activation of ATM in different cancer cells as well as agents for ATM inactivation. Understanding the interplay of TRAIL-induced intracellular signaling and ATM modulation of downstream effectors is very important. This holds particularly for a reconceptualization of the apparently paradoxical roles and therapeutically targetable for enhancing the response to DNA damage-inducing therapy.

  2. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling

    PubMed Central

    Quin, Jaclyn; Chan, Keefe T.; Devlin, Jennifer R.; Cameron, Donald P.; Diesch, Jeannine; Cullinane, Carleen; Ahern, Jessica; Khot, Amit; Hein, Nadine; George, Amee J.; Hannan, Katherine M; Poortinga, Gretchen; Sheppard, Karen E.; Khanna, Kum Kum; Johnstone, Ricky W.; Drygin, Denis; McArthur, Grant A.; Pearson, Richard B.

    2016-01-01

    RNA polymerase I (Pol I)-mediated transcription of the ribosomal RNA genes (rDNA) is confined to the nucleolus and is a rate-limiting step for cell growth and proliferation. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne). Here we demonstrate that CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, our data demonstrate that the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, we show that CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, we propose that acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy. PMID:27391441

  3. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling.

    PubMed

    Quin, Jaclyn; Chan, Keefe T; Devlin, Jennifer R; Cameron, Donald P; Diesch, Jeannine; Cullinane, Carleen; Ahern, Jessica; Khot, Amit; Hein, Nadine; George, Amee J; Hannan, Katherine M; Poortinga, Gretchen; Sheppard, Karen E; Khanna, Kum Kum; Johnstone, Ricky W; Drygin, Denis; McArthur, Grant A; Pearson, Richard B; Sanij, Elaine; Hannan, Ross D

    2016-08-02

    RNA polymerase I (Pol I)-mediated transcription of the ribosomal RNA genes (rDNA) is confined to the nucleolus and is a rate-limiting step for cell growth and proliferation. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne). Here we demonstrate that CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, our data demonstrate that the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, we show that CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, we propose that acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy.

  4. Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair

    PubMed Central

    Soares, Daniele G.; Selle, Frédéric; Morel, Claire; Galmarini, Carlos M.; Henriques, João A. P.; Larsen, Annette K.; Escargueil, Alexandre E.

    2016-01-01

    Trabectedin (Yondelis®, ecteinascidin-743, ET-743) is a marine-derived natural product approved for treatment of advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer. Lurbinectedin is a novel anticancer agent structurally related to trabectedin. Both ecteinascidins generate DNA double-strand breaks that are processed through homologous recombination repair (HRR), thereby rendering HRR-deficient cells particularly sensitive. We here characterize the DNA damage response (DDR) to trabectedin and lurbinectedin in HeLa cells. Our results show that both compounds activate the ATM/Chk2 (ataxia-telangiectasia mutated/checkpoint kinase 2) and ATR/Chk1 (ATM and RAD3-related/checkpoint kinase 1) pathways. Interestingly, pharmacological inhibition of Chk1/2, ATR or ATM is not accompanied by any significant improvement of the cytotoxic activity of the ecteinascidins while dual inhibition of ATM and ATR strongly potentiates it. Accordingly, concomitant inhibition of both ATR and ATM is an absolute requirement to efficiently block the formation of γ-H2AX, MDC1, BRCA1 and Rad51 foci following exposure to the ecteinascidins. These results are not restricted to HeLa cells, but are shared by cisplatin-sensitive and -resistant ovarian carcinoma cells. Together, our data identify ATR and ATM as central coordinators of the DDR to ecteinascidins and provide a mechanistic rationale for combining these compounds with ATR and ATM inhibitors. PMID:27029031

  5. Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair.

    PubMed

    Lima, Michelle; Bouzid, Hana; Soares, Daniele G; Selle, Frédéric; Morel, Claire; Galmarini, Carlos M; Henriques, João A P; Larsen, Annette K; Escargueil, Alexandre E

    2016-05-03

    Trabectedin (Yondelis®, ecteinascidin-743, ET-743) is a marine-derived natural product approved for treatment of advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer. Lurbinectedin is a novel anticancer agent structurally related to trabectedin. Both ecteinascidins generate DNA double-strand breaks that are processed through homologous recombination repair (HRR), thereby rendering HRR-deficient cells particularly sensitive. We here characterize the DNA damage response (DDR) to trabectedin and lurbinectedin in HeLa cells. Our results show that both compounds activate the ATM/Chk2 (ataxia-telangiectasia mutated/checkpoint kinase 2) and ATR/Chk1 (ATM and RAD3-related/checkpoint kinase 1) pathways. Interestingly, pharmacological inhibition of Chk1/2, ATR or ATM is not accompanied by any significant improvement of the cytotoxic activity of the ecteinascidins while dual inhibition of ATM and ATR strongly potentiates it. Accordingly, concomitant inhibition of both ATR and ATM is an absolute requirement to efficiently block the formation of γ-H2AX, MDC1, BRCA1 and Rad51 foci following exposure to the ecteinascidins. These results are not restricted to HeLa cells, but are shared by cisplatin-sensitive and -resistant ovarian carcinoma cells. Together, our data identify ATR and ATM as central coordinators of the DDR to ecteinascidins and provide a mechanistic rationale for combining these compounds with ATR and ATM inhibitors.

  6. Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo

    PubMed Central

    Liu, Feng; Jiang, Ning; Xiao, Zhi-yong; Cheng, Jun-ping; Mei, Yi-zhou; Zheng, Pan; Wang, Li; Zhang, Xiao-rui; Zhou, Xin-bo

    2016-01-01

    Early studies with first-generation poly (ADP-ribose) polymerase (PARP) inhibitors have already indicated some therapeutic potential for sulfur mustard (SM) injuries. The available novel and more potential PARP inhibitors, which are undergoing clinical trials as drugs for cancer treatment, bring it back to the centre of interest. However, the role of PARP-1 in SM-induced injury is not fully understood. In this study, we selected a high potent specific PARP inhibitor ABT-888 as an example to investigate the effect of PARP inhibitor in SM injury. The results showed that in both the mouse ear vesicant model (MEVM) and HaCaT cell model, PARP inhibitor ABT-888 can reduce cell damage induced by severe SM injury. ABT-888 significantly reduced SM induced edema and epidermal necrosis in MEVM. In the HaCaT cell model, ABT-888 can reduce SM-induced NAD+/ATP depletion and apoptosis/necrosis. Then, we studied the mechanism of PARP-1 in SM injury by knockdown of PARP-1 in HaCaT cells. Knockdown of PARP-1 protected cell viability and downregulated the apoptosis checkpoints, including p-JNK, p-p53, Caspase 9, Caspase 8, c-PARP and Caspase 3 following SM-induced injury. Furthermore, the activation of AKT can inhibit autophagy via the regulation of mTOR. Our results showed that SM exposure could significantly inhibit the activation of Akt/mTOR pathway. Knockdown of PARP-1 reversed the SM-induced suppression of the Akt/mTOR pathway. In summary, the results of our study indicated that the protective effects of downregulation of PARP-1 in SM injury may be due to the regulation of apoptosis, necrosis, energy crisis and autophagy. However, it should be noticed that PARP inhibitor ABT-888 further enhanced the phosphorylation of H2AX (S139) after SM exposure, which indicated that we should be very careful in the application of PARP inhibitors in SM injury treatment because of the enhancement of DNA damage. PMID:27077006

  7. Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK

    PubMed Central

    Storozhuk, Y; Hopmans, S N; Sanli, T; Barron, C; Tsiani, E; Cutz, J-C; Pond, G; Wright, J; Singh, G; Tsakiridis, T

    2013-01-01

    Background: We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR). Methods: Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) α1/2-subunit−/− embryos (AMPKα1/2−/−-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (IHC). Results: Metformin (2.5 μℳ–5 mℳ) inhibited proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the ataxia telengiectasia-mutated (ATM)–AMPK–p53/p21cip1 and inhibited the Akt–mammalian target of rapamycin (mTOR)–eIF4E-binding protein 1 (4EBP1) pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer cells with inhibited AMPK and AMPKα1/2−/−-MEFs were resistant to the antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft growth and combined treatment enhanced it further than each treatment alone. Ionising radiation and MET induced (i) sustained activation of ATM–AMPK–p53/p21cip1 and inhibition of Akt–mTOR–4EBP1 pathways in tumours, (ii) reduced expression of angiogenesis and (iii) enhanced expression of apoptosis markers. Conclusion: Clinically achievable MET doses inhibit NSCLC cell and tumour growth and sensitise them to IR. Metformin and IR mediate their action through an ATM–AMPK-dependent pathway. Our results suggest that MET can be a clinically useful adjunct to radiotherapy in NSCLC. PMID:23632475

  8. Inhibition of poly(ADP-ribose) polymerase-1 or poly(ADP-ribose) glycohydrolase individually, but not in combination, leads to improved chemotherapeutic efficacy in HeLa cells

    PubMed Central

    FENG, XIAOXING; KOH, DAVID W.

    2013-01-01

    The genome-protecting role of poly(ADP-ribose) (PAR) has identified PAR polymerase-1 (PARP-1) and PAR glycohydrolase (PARG), two enzymes responsible for the synthesis and hydrolysis of PAR, as chemotherapeutic targets. Each has been previously individually evaluated in chemotherapy, but the effects of combination PARP-1 and PARG inhibition in cancer cells are not known. Here we determined the effects of the inhibition of PARP-1 and the absence or RNAi knockdown of PARG on PAR synthesis, cell death after chemotherapy and long-term viability. Using three experimental/clinical PARP-1 inhibitors in PARG-null cells, we show decreased levels of PAR and increased short-term and long-term viability with each inhibitor, with the exception of DPQ. Treatment with the experimental chemotherapeutic agent, N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), led to increased cell death in PARG-null cells, but decreased cell death when pretreated with each PARP-1 inhibitor. Similar results were observed in MNNG-treated HeLa cells, where RNAi knockdown of PARG or pretreatment with ABT-888 led to increased HeLa cell death, whereas combination PARG RNAi knockdown + ABT-888 failed to produce increased cell death. The results demonstrate the ability of the PARP-1 inhibitors to decrease PAR levels, maintain viability and decrease PAR-mediated cell death after chemotherapeutic treatment in the absence of PARG. Further, the results demonstrate that the combination of PARP-1 and PARG inhibition in chemotherapy does not produce increased HeLa cell death. Thus, the results indicate that inhibiting both PARP-1 and PARG, which both are chemotherapeutic targets that increase cancer cell death, does not lead to synergistic cell death in HeLa cells. Therefore, strategies that target PAR metabolism for the improved treatment of cancer may be required to target PARP-1 and PARG individually in order to optimize cancer cell death. PMID:23254695

  9. IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin

    PubMed Central

    O'Flanagan, Ciara H.; O'shea, Sandra; Lyons, Amy; Fogarty, Fionola M.; McCabe, Nuala; Kennedy, Richard D.; O'Connor, Rosemary

    2016-01-01

    The complexity of the IGF-1 signalling axis is clearly a roadblock in targeting this receptor in cancer therapy. Here, we sought to identify mediators of resistance, and potential co-targets for IGF-1R inhibition. By using an siRNA functional screen with the IGF-1R tyrosine kinase inhibitor (TKI) BMS-754807 in MCF-7 cells we identified several genes encoding components of the DNA damage response (DDR) pathways as mediators of resistance to IGF-1R kinase inhibition. These included ATM and Ataxia Telangiectasia and RAD3-related kinase (ATR). We also observed a clear induction of DDR in cells that were exposed to IGF-1R TKIs (BMS-754807 and OSI-906) as indicated by accumulation of γ-H2AX, and phosphorylated Chk1. Combination of the IGF-1R/IR TKIs with an ATR kinase inhibitor VE-821 resulted in additive to synergistic cytotoxicity compared to either drug alone. In MCF-7 cells with stably acquired resistance to the IGF-1R TKI (MCF-7-R), DNA damage was also observed, and again, dual inhibition of the ATR kinase and IGF-1R/IR kinase resulted in synergistic cytotoxicity. Interestingly, dual inhibition of ATR and IGF-1R was more effective in MCF-7-R cells than parental cells. IGF-1R TKIs also potentiated the effects of cisplatin in a panel of breast cancer cell lines. Overall, our findings identify induction of DDR by IGF-1R kinase inhibition as a rationale for co-targeting the IGF-1R with ATR kinase inhibitors or cisplatin, particularly in cells with acquired resistance to TKIs. PMID:27472395

  10. Hyperactivation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage

    PubMed Central

    Finzel, Ana; Grybowski, Andrea; Strasen, Jette; Cristiano, Elena; Loewer, Alexander

    2016-01-01

    A functional DNA damage response is essential for maintaining genome integrity in the presence of DNA double-strand breaks. It is mainly coordinated by the kinases ATM, ATR, and DNA-PKcs, which control the repair of broken DNA strands and relay the damage signal to the tumor suppressor p53 to induce cell cycle arrest, apoptosis, or senescence. Although many functions of the individual kinases have been identified, it remains unclear how they act in concert to ensure faithful processing of the damage signal. Using specific inhibitors and quantitative analysis at the single-cell level, we systematically characterize the contribution of each kinase for regulating p53 activity. Our results reveal a new regulatory interplay in which loss of DNA-PKcs function leads to hyperactivation of ATM and amplification of the p53 response, sensitizing cells for damage-induced senescence. This interplay determines the outcome of treatment regimens combining irradiation with DNA-PKcs inhibitors in a p53-dependent manner. PMID:27280387

  11. Resveratrol inhibits inflammatory signaling implicated in ionizing radiation-induced premature ovarian failure through antagonistic crosstalk between silencing information regulator 1 (SIRT1) and poly(ADP-ribose) polymerase 1 (PARP-1).

    PubMed

    Said, Riham Soliman; El-Demerdash, Ebtehal; Nada, Ahmed Shafik; Kamal, Mohamed M

    2016-03-01

    This study hypothesized that resveratrol, a silencing information regulator 1 (SIRT1) activator, would counteract the inflammatory signaling associated with radiotherapy-induced premature ovarian failure (POF). Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation to induce POF and treated with resveratrol (25mg/kg) once daily for two weeks before and three days post irradiation. Resveratrol preserves the entire ovarian follicle pool manifested by increasing serum anti-Müllerian hormone (AMH) levels. Radiation triggered inflammatory process in the ovary through enhanced NF-κB and poly(ADP-ribose) polymerase (PARP)-1 expression which convinced the expression of inflammatory markers including IL-6, IL-8, and visfatin mRNA levels, as well as inducible nitric oxide synthase and cyclooxygenase-2 protein expression with a concomitant reduction in IL-10 mRNA levels. Resveratrol significantly counteracted the effect of radiation and upregulated the gene expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and SIRT1. Resveratrol-activated SIRT1 expression was associated with inhibition of PARP-1 and NF-κB expression-mediated inflammatory cytokines. Our findings suggest that resveratrol restored ovarian function through increasing AMH levels, and diminishing ovarian inflammation, predominantly via upregulation of PPAR-γ and SIRT1 expression leading to inhibition of NF-κB provoked inflammatory cytokines.

  12. ATM technology and beyond

    NASA Technical Reports Server (NTRS)

    Cheung, Nim K.

    1993-01-01

    Networks based on Asynchronous Transfer Mode (ATM) are expected to provide cost-effective and ubiquitous infrastructure to support broadband and multimedia services. In this paper, we give an overview of the ATM standards and its associated physical layer transport technologies. We use the experimental HIPPI-ATM-SONET (HAS) interface in the Nectar Gigabit Testbed to illustrate how one can use the SONET/ATM public network to provide transport for bursty gigabit applications.

  13. Changes in the response of MCF-7 cells to ionizing radiation after the combination of ATM and DNA-PK inhibition.

    PubMed

    Ćmielová, Jana; Havelek, Radim; Vávrová, Jiřina; Řezáčová, Martina

    2015-05-01

    The aim of the present study is to evaluate the role of ATM (KU55933) and DNA-PK (NU7441) inhibitors in the repair of double-strand breaks and downstream signaling of DNA damage introduced by ionizing radiation. The irradiation of MCF-7 cells alone increased the proportion of cells in the G1 phase in comparison with mock-treated cells. After ATM inhibitor pretreatment, the cells were more accumulated in the G2 phase, whereas DNA-PK inhibitor application increased the percentage of cells in the G1 phase. ATM and DNA-PK inhibitor application alone increased the sensitivity of MCF-7 cells to ionizing radiation; however, combining both inhibitors together resulted in a further enhancement of cell death. Unexpectedly, combining both inhibitors decreased the percentage of senescent cells and increased G2 cell cycle arrest 3 days after treatment. After irradiation, the p21 protein was increased and Chk1 and Chk2 were activated. These proteins were not increased in cells pretreated with the ATM inhibitor prior to ionizing radiation exposure, albeit DNA-PK inhibitor application did not affect the amount of proteins detected. Formation of γH2AX was found to be ATM and DNA-PK dependent, application of the ATM inhibitor suppressed incidence of γH2AX, whereas DNA-PK caused persistence of γH2AX. Our results suggest that the further investigation of the ATM inhibitor in combination with the DNA-PK inhibitor as sensitizers preventing cell senescence and promoting cell death in breast carcinoma MCF-7 cells is warranted.

  14. ATMIN defines an NBS1-independent pathway of ATM signalling

    PubMed Central

    Kanu, Nnennaya; Behrens, Axel

    2007-01-01

    The checkpoint kinase ATM (ataxia telangiectasia mutated) transduces genomic stress signals to halt cell cycle progression and promote DNA repair in response to DNA damage. Here, we report the characterisation of an essential cofactor for ATM, ATMIN (ATM INteracting protein). ATMIN interacts with ATM through a C-terminal motif, which is also present in Nijmegen breakage syndrome (NBS)1. ATMIN and ATM colocalised in response to ATM activation by chloroquine and hypotonic stress, but not after induction of double-strand breaks by ionising radiation (IR). ATM/ATMIN complex disruption by IR was attenuated in cells with impaired NBS1 function, suggesting competition of NBS1 and ATMIN for ATM binding. ATMIN protein levels were reduced in ataxia telangiectasia cells and ATM protein levels were low in primary murine fibroblasts lacking ATMIN, indicating reciprocal stabilisation. Whereas phosphorylation of Smc1, Chk2 and p53 was normal after IR in ATMIN-deficient cells, basal ATM activity and ATM activation by hypotonic stress and inhibition of DNA replication was impaired. Thus, ATMIN defines a novel NBS1-independent pathway of ATM signalling. PMID:17525732

  15. Inhibition of DNA-PKcs enhances radiosensitivity and increases the levels of ATM and ATR in NSCLC cells exposed to carbon ion irradiation.

    PubMed

    Yang, Lina; Liu, Yuanyuan; Sun, Chao; Yang, Xinrui; Yang, Zhen; Ran, Juntao; Zhang, Qiuning; Zhang, Hong; Wang, Xinyu; Wang, Xiaohu

    2015-11-01

    Non-small cell lung cancer (NSCLC) exhibits radioresistance to conventional rays, due to its DNA damage repair systems. NSCLC may potentially be sensitized to radiation treatment by reducing those factors that continuously enhance the repair of damaged DNA. In the present study, normal lung fibroblast MRC-5 and lung cancer A549 cells were treated with NU7026 and CGK733, which are inhibitors of the DNA-dependent protein kinase catalytic subunit (PKcs) and ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), respectively, followed by exposure to X-rays and carbon ion irradiation. The cytotoxic activity, cell survival rate, DNA damage repair ability, cell cycle arrest and apoptosis rate of the treated cells were analyzed with MTT assay, colony formation assay, immunofluorescence and flow cytometry, respectively. The transcription and translation levels of the ATM, ATR and DNA-PKcs genes were detected by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The results indicated that the radiosensitivity and DNA repair ability of A549 cells were reduced, and the percentages of apoptotic cells and those arrested at the G2/M phase of the cell cycle were significantly increased, following ionizing radiation with inhibitor-pretreatment. The expression levels of ATM, ATR, DNA-PKcs and phosphorylated histone H2AX, a biomarker for DNA double-strand breaks, were all upregulated at the transcriptional or translational level in A549 cells treated with carbon ion irradiation, compared with the control and X-rays-treated cells. In addition, the treatment with 5-50 µM NU7026 or CGK733 did not produce any obvious cytotoxicity in MRC-5 cells, and the effect of the DNA-PKcs-inhibitor on enhancing the radiosensitivity of A549 cells was stronger than that observed for the ATM and ATR-inhibitor. These findings demonstrated a minor role for ATM and ATR in radiation-induced cell death, since the upregulation of

  16. Aven-dependent activation of ATM following DNA damage

    PubMed Central

    Guo, Jessie Yanxiang; Yamada, Ayumi; Kajino, Taisuke; Wu, Judy Qiju; Tang, Wanli; Freel, Christopher D.; Feng, Junjie; Chau, B. Nelson; Wang, Michael Zhuo; Margolis, Seth; Yoo, Hae Yong; Wang, Xiao-Fan; Dunphy, William G.; Irusta, Pablo M.; Hardwick, J. Marie; Kornbluth, Sally

    2009-01-01

    Summary Background In response to DNA damage, cells either undergo cell cycle arrest or apoptosis, depending on the extent of damage and the cell’s capacity for DNA repair. Cell cycle arrest induced by double-stranded DNA breaks depends on activation of the ataxia-telangiectasia (ATM) protein kinase, which phosphorylates cell cycle effectors such as Chk2 and p53 to inhibit cell cycle progression. ATM is recruited to double stranded DNA breaks by a complex of sensor proteins including Mre11/Rad50/Nbs1, resulting in autophosphorylation, monomerization, and activation of ATM kinase. Results In characterizing Aven protein, a previously reported apoptotic inhibitor, we have found that Aven can function as an ATM activator to inhibit G2/M progression. Aven bound to ATM and Aven overexpression in cycling Xenopus egg extracts prevented mitotic entry and induced phosphorylation of ATM and its substrates. Immunodepletion of endogenous Aven allowed mitotic entry even in the presence of damaged DNA, and RNAi-mediated knock-down of Aven in human cells prevented autophosphorylation of ATM at an activating site (S1981) in response to DNA damage. Interestingly, Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM following DNA damage is enhanced by ATM-mediated Aven phosphorylation. Conclusions These results identify Aven as a new ATM activator and describe a positive feedback loop operating between Aven and ATM. In aggregate, these findings place Aven, a known apoptotic inhibitor, as a critical transducer of the DNA damage signal. PMID:18571408

  17. The role of ATM mutations and 11q deletions in disease progression in chronic lymphocytic leukemia.

    PubMed

    Stankovic, Tatjana; Skowronska, Anna

    2014-06-01

    Abstract ATM gene alteration is a frequent event in pathogenesis of chronic lymphocytic leukemia (CLL) and occurs as monoallelic loss in the form of 11q23 deletion, with and without mutation in the remaining ATM allele. ATM is a principal DNA damage response gene and biallelic ATM alterations lead to ATM functional loss and chemoresistance. The introduction of new therapies, such as intensive chemoimmunotherapy and inhibition of B-cell receptor (BCR) signaling, has changed clinical responses for the majority of CLL tumors including those with 11q deletion, but it remains to be determined whether these strategies can prevent clonal evolution of tumors with biallelic ATM alterations. In this review we discuss ATM function and the consequences of its loss during CLL pathogenesis, differences in clinical behavior of tumors with monoallelic and biallelic ATM alterations, and we outline possible approaches for targeting the ATM null CLL phenotype.

  18. ATMS Step By Step.

    ERIC Educational Resources Information Center

    National Library of Australia, Canberra.

    This manual is designed to provide an introduction and basic guide to the use of IBM's Advanced Text Management System (ATMS), the text processing system to be used for the creation of Australian data bases within AUSINET. Instructions are provided for using the system to enter, store, retrieve, and modify data, which may then be displayed at the…

  19. Hyperoxia activates ATM independent from mitochondrial ROS and dysfunction

    PubMed Central

    Resseguie, Emily A.; Staversky, Rhonda J.; Brookes, Paul S.; O’Reilly, Michael A.

    2015-01-01

    High levels of oxygen (hyperoxia) are often used to treat individuals with respiratory distress, yet prolonged hyperoxia causes mitochondrial dysfunction and excessive reactive oxygen species (ROS) that can damage molecules such as DNA. Ataxia telangiectasia mutated (ATM) kinase is activated by nuclear DNA double strand breaks and delays hyperoxia-induced cell death through downstream targets p53 and p21. Evidence for its role in regulating mitochondrial function is emerging, yet it has not been determined if mitochondrial dysfunction or ROS activates ATM. Because ATM maintains mitochondrial homeostasis, we hypothesized that hyperoxia induces both mitochondrial dysfunction and ROS that activate ATM. In A549 lung epithelial cells, hyperoxia decreased mitochondrial respiratory reserve capacity at 12 h and basal respiration by 48 h. ROS were significantly increased at 24 h, yet mitochondrial DNA double strand breaks were not detected. ATM was not required for activating p53 when mitochondrial respiration was inhibited by chronic exposure to antimycin A. Also, ATM was not further activated by mitochondrial ROS, which were enhanced by depleting manganese superoxide dismutase (SOD2). In contrast, ATM dampened the accumulation of mitochondrial ROS during exposure to hyperoxia. Our findings suggest that hyperoxia-induced mitochondrial dysfunction and ROS do not activate ATM. ATM more likely carries out its canonical response to nuclear DNA damage and may function to attenuate mitochondrial ROS that contribute to oxygen toxicity. PMID:25967673

  20. Hyperoxia activates ATM independent from mitochondrial ROS and dysfunction.

    PubMed

    Resseguie, Emily A; Staversky, Rhonda J; Brookes, Paul S; O'Reilly, Michael A

    2015-08-01

    High levels of oxygen (hyperoxia) are often used to treat individuals with respiratory distress, yet prolonged hyperoxia causes mitochondrial dysfunction and excessive reactive oxygen species (ROS) that can damage molecules such as DNA. Ataxia telangiectasia mutated (ATM) kinase is activated by nuclear DNA double strand breaks and delays hyperoxia-induced cell death through downstream targets p53 and p21. Evidence for its role in regulating mitochondrial function is emerging, yet it has not been determined if mitochondrial dysfunction or ROS activates ATM. Because ATM maintains mitochondrial homeostasis, we hypothesized that hyperoxia induces both mitochondrial dysfunction and ROS that activate ATM. In A549 lung epithelial cells, hyperoxia decreased mitochondrial respiratory reserve capacity at 12h and basal respiration by 48 h. ROS were significantly increased at 24h, yet mitochondrial DNA double strand breaks were not detected. ATM was not required for activating p53 when mitochondrial respiration was inhibited by chronic exposure to antimycin A. Also, ATM was not further activated by mitochondrial ROS, which were enhanced by depleting manganese superoxide dismutase (SOD2). In contrast, ATM dampened the accumulation of mitochondrial ROS during exposure to hyperoxia. Our findings suggest that hyperoxia-induced mitochondrial dysfunction and ROS do not activate ATM. ATM more likely carries out its canonical response to nuclear DNA damage and may function to attenuate mitochondrial ROS that contribute to oxygen toxicity.

  1. Mode of ATM-dependent suppression of chromosome translocation

    SciTech Connect

    Yamauchi, Motohiro; Suzuki, Keiji; Oka, Yasuyoshi; Suzuki, Masatoshi; Kondo, Hisayoshi; Yamashita, Shunichi

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer We addressed how ATM suppresses frequency of chromosome translocation. Black-Right-Pointing-Pointer We found ATM/p53-dependent G1 checkpoint suppresses translocation frequency. Black-Right-Pointing-Pointer We found ATM and DNA-PKcs function in a common pathway to suppress translocation. -- Abstract: It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition or RNAi-mediated knockdown of ATM causes 2 to 2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.

  2. Poly(ADP-ribose) polymerase 1 at the crossroad of metabolic stress and inflammation in aging

    PubMed Central

    Altmeyer, Matthias; Hottiger, Michael O.

    2009-01-01

    Poly(ADP-ribose) polymerase 1 (PARP1) is a chromatin-associated nuclear protein, which functions as molecular stress sensor. Reactive oxygen species, responsible for the most plausible and currently acceptable global mechanism to explain the aging process, strongly activate the enzymatic activity of PARP1 and the formation of poly(ADP-ribose) (PAR) from NAD+. Consumption of NAD+ links PARP1 to energy metabolism and to a large number of NAD+-dependent enzymes, such as the sirtuins. As transcriptional cofactor for NF-κB-dependent gene expression, PARP1 is also connected to the immune response, which is implicated in almost all age-related or associated diseases. Accordingly, numerous experimental studies have demonstrated the beneficial effects of PARP inhibition for several age-related diseases. This review summarizes recent findings on PARP1 and puts them in the context of metabolic stress and inflammation in aging. PMID:20157531

  3. RAM-589.555 a new Polymerase-1 inhibitor as innovative targeted-treatment for multiple sclerosis.

    PubMed

    Achiron, A; Zilkha-Falb, R; Mashiach, R; Gurevich, M

    2017-01-15

    Targeting Polymerase-1 (POL1) transcription machinery is a new strategy for suppression of multiple sclerosis (MS) disease activity that is based on suppression of ribosomal biogenesis and subsequent activation of apoptosis. We developed an oral POL1 inhibiting compound RAM-589.555, that suppress ribosomal biogenesis as an innovative therapeutic approach to ameliorate MS. RAM-589.555 shows high permeability, specificity to POL1 pathway, ability to induce apoptosis and to inhibit proliferation and viability of activated lymphocytes both in-vitro and in-vivo. Moreover, oral administration of RAM-589.555 blocks ribosomal RNA transcription and significantly suppresses and ameliorates experimental autoimmune encephalomyelitis (EAE).

  4. Satellite Communications for ATM

    NASA Technical Reports Server (NTRS)

    Shamma, Mohammed A.

    2003-01-01

    This presentation is an overview on Satellite Communication for the Aeronautical Telecommunication Management (ATM) research. Satellite Communications are being considered by the FAA and NASA as a possible alternative to the present and future ground systems supporting Air Traffic Communications. The international Civil Aviation Organization (ICAO) have in place Standards and Recommended Practices (SARPS) for the Aeronautical Mobile Satellite Services (AMSS) which is mainly derived from the pre-existing Inmarsat service that has been in service since the 1980s. The Working Group A of the Aeronautical Mobile Communication Panel of ICAO has also been investigating SARPS for what is called the Next Generation Satellite Service (NGSS) which conforms less to the Inmarsat based architecture and explores wider options in terms of satellite architectures. Several designs are being proposed by Firms such as Boeing, ESA, NASA that are geared toward full or secondary usage of satellite communications for ATM. Satellite communications for ATM can serve several purposes ranging from primary usage where ground services would play a minimal backup role, to an integrated solution where it will be used to cover services, or areas that are less likely to be supported by the proposed and existing ground infrastructure. Such Integrated roles can include usage of satellite communications for oceanic and remote land areas for example. It also can include relieving the capacity of the ground network by providing broadcast based services of Traffic Information Services messages (TIS-B), or Flight Information Services (FIS-B) which can take a significant portion of the ground system capacity. Additionally, satellite communication can play a backup role to support any needs for ground replacement, or additional needed capacity even after the new digital systems are in place. The additional bandwidth that can be provided via satellite communications can also open the door for many new

  5. Structure of the intact ATM/Tel1 kinase

    NASA Astrophysics Data System (ADS)

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-05-01

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents.

  6. Structure of the intact ATM/Tel1 kinase.

    PubMed

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-05-27

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents.

  7. Structure of the intact ATM/Tel1 kinase

    PubMed Central

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-01-01

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents. PMID:27229179

  8. Connecting Remote Clusters with ATM

    SciTech Connect

    Hu, T.C.; Wyckoff, P.S.

    1998-10-01

    Sandia's entry into utilizing clusters of networked workstations is called Computational Plant or CPlant for short. The design of CPlant uses Ethernet to boot the individual nodes, Myrinet to communicate within a node cluster, and ATM to connect between remote clusters. This SAND document covers the work done to enable the use of ATM on the CPlant nodes in the Fall of 1997.

  9. ATM CMG bearing failure analysis

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The cause or causes for the failure of ATM CMG S/N 5 (Skylab 1) and the anomalies associated with ATM CMG S/N 6 (Skylab 2) were investigated. Skylab telemetry data were reviewed and presented in the form of parameter distributions. The theory that the problems were caused by marginal bearing lubrication was studied along with the effects of orbital conditions on lubricants. Bearing tests were performed to investigate the effect of lubricant or lack of lubricant in the ATM CMG bearings and the dispersion and migration of the lubricant. The vacuum and weightless conditions of space were simulated in the bearing tests. Analysis of the results of the tests conducted points to inadequate lubrication as the predominant factor causing the failure of ATM CMG S/N 5 (Skylab 1) and the anomalies associated with ATM CMG S/N 6 (Skylab 2).

  10. Small Molecule Inhibition of miR-544 Biogenesis Disrupts Adaptive Responses to Hypoxia by Modulating ATM-mTOR Signaling

    PubMed Central

    Haga, Christopher L.; Velagapudi, Sai Pradeep; Strivelli, Jacqueline R.; Yang, Wang-Yong

    2016-01-01

    Hypoxia induces a complex circuit of gene expression that drives tumor progression and increases drug resistance. Defining these changes allows for an understanding of how hypoxia alters tumor biology and informs design of lead therapeutics. We probed the role of microRNA-544 (miR-544), which silences mammalian target of rapamycin (mTOR), in a hypoxic breast cancer model by using a small molecule (1) that selectively impedes the microRNA's biogenesis. Application of 1 to hypoxic tumor cells selectively inhibited production of the mature microRNA, sensitized cells to 5-fluorouracil, and derepressed mRNAs affected by miR-544 in cellulo and in vivo, including boosting mTOR expression. Thus, small molecule inhibition of miR-544 reverses a tumor cell's physiological response to hypoxia. Importantly, 1 sensitized tumor cells to hypoxia-associated apoptosis at a 25-fold lower concentration than a 2′-O-methyl RNA antagomir and was as selective. Further, the apoptotic effect of 1 was suppressed by treatment of cell with rapamycin, a well-known inhibitor of the mTOR signaling pathway, illustrating the selectivity of the compound. Thus, RNA-directed chemical probes, which could also serve as lead therapeutics, enable interrogation of complex cellular networks in cells and animals. PMID:26181590

  11. Non-apoptotic programmed cell death with paraptotic-like features in bleomycin-treated plant cells is suppressed by inhibition of ATM/ATR pathways or NtE2F overexpression.

    PubMed

    Smetana, Ondřej; Široký, Jiří; Houlné, Guy; Opatrný, Zdeněk; Chabouté, Marie-Edith

    2012-04-01

    In plants, different forms of programmed cell death (PCD) have been identified, but they only partially correspond to those described for animals, which is most probably due to structural differences between animal and plant cells. Here, the results show that in tobacco BY-2 cells, bleomycin (BLM), an inducer of double-strand breaks (DSBs), triggers a novel type of non-apoptotic PCD with paraptotic-like features. Analysis of numerous PCD markers revealed an extensive vacuolization, vacuolar rupture, and chromatin condensation, but no apoptotic DNA fragmentation, fragmentation of the nuclei, or sensitivity to caspase inhibitors. BLM-induced PCD was cell cycle regulated, occurring predominantly upon G(2)/M cell cycle checkpoint activation. In addition, this paraptotic-like PCD was at least partially inhibited by caffeine, a known inhibitor of DNA damage sensor kinases ATM and ATR. Interestingly, overexpression of one NtE2F transcriptional factor, whose homologues play a dual role in animal apoptosis and DNA repair, reduced PCD induction and modulated G(2)/M checkpoint activation in BY-2 cells. These observations provide a solid ground for further investigations into the paraptotic-like PCD in plants, which might represent an ancestral non-apoptotic form of PCD conserved among animals, protists, and plants.

  12. Mode of ATM-dependent suppression of chromosome translocation.

    PubMed

    Yamauchi, Motohiro; Suzuki, Keiji; Oka, Yasuyoshi; Suzuki, Masatoshi; Kondo, Hisayoshi; Yamashita, Shunichi

    2011-12-09

    It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition or RNAi-mediated knockdown of ATM causes 2 to 2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.

  13. Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM.

    PubMed

    Zhou, Yi; Lee, Ji-Hoon; Jiang, Wenxia; Crowe, Jennie L; Zha, Shan; Paull, Tanya T

    2017-01-05

    Ataxia-telangiectasia mutated (ATM) regulates the DNA damage response as well as DNA double-strand break repair through homologous recombination. Here we show that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells. Pre-incubation of ATM protein with active DNA-PKcs also significantly reduces ATM activity in vitro. We characterize several phosphorylation sites in ATM that are targets of DNA-PKcs and show that phospho-mimetic mutations at these residues significantly inhibit ATM activity and impair ATM signaling upon DNA damage. In contrast, phospho-blocking mutations at one cluster of sites increase the frequency of apoptosis during normal cell growth. DNA-PKcs, which is integral to the non-homologous end joining pathway, thus negatively regulates ATM activity through phosphorylation of ATM. These observations illuminate an important regulatory mechanism for ATM that also controls DNA repair pathway choice.

  14. Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration

    PubMed Central

    Brochier, Camille; Jones, James I.; Willis, Dianna E.; Langley, Brett

    2015-01-01

    Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of multiple growth-inhibitory signals. We show that exposure of neurons to growth-limiting molecules—such as myelin-derived Nogo and myelin-associated glycoprotein—or reactive astrocyte-produced chondroitin sulfate proteoglycans activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, we find that pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration over nonpermissive substrates. Together, our findings provide critical insights into the molecular mechanisms of axon growth inhibition and identify PARP1 as an effective target to promote axon regeneration. PMID:26598704

  15. Sandia ATM SONET Interface Logic

    SciTech Connect

    Kitta, Joseph P.

    1994-07-21

    SASIL is used to program the EPLD's (Erasable Programmable Logic Devices) and PAL's (Programmable Array Logic) that make up a large percentage of the Sandia ATM SONET Interface (OC3 version) for the INTEL Paragon.

  16. ATM and GLUT1-S490 Phosphorylation Regulate GLUT1 Mediated Transport in Skeletal Muscle

    PubMed Central

    Andrisse, Stanley; Patel, Gaytri D.; Chen, Joseph E.; Webber, Andrea M.; Spears, Larry D.; Koehler, Rikki M.; Robinson-Hill, Rona M.; Ching, James K.; Jeong, Imju; Fisher, Jonathan S.

    2013-01-01

    Objective The glucose and dehydroascorbic acid (DHA) transporter GLUT1 contains a phosphorylation site, S490, for ataxia telangiectasia mutated (ATM). The objective of this study was to determine whether ATM and GLUT1-S490 regulate GLUT1. Research Design and Methods L6 myoblasts and mouse skeletal muscles were used to study the effects of ATM inhibition, ATM activation, and S490 mutation on GLUT1 localization, trafficking, and transport activity. Results In myoblasts, inhibition of ATM significantly diminished cell surface GLUT1, glucose and DHA transport, GLUT1 externalization, and association of GLUT1 with Gα-interacting protein-interacting protein, C-terminus (GIPC1), which has been implicated in recycling of endosomal proteins. In contrast, ATM activation by doxorubicin (DXR) increased DHA transport, cell surface GLUT1, and the GLUT1/GIPC1 association. S490A mutation decreased glucose and DHA transport, cell surface GLUT1, and interaction of GLUT1 with GIPC1, while S490D mutation increased transport, cell surface GLUT1, and the GLUT1/GIPC1 interaction. ATM dysfunction or ATM inhibition reduced DHA transport in extensor digitorum longus (EDL) muscles and decreased glucose transport in EDL and soleus. In contrast, DXR increased DHA transport in EDL. Conclusions These results provide evidence that ATM and GLUT1-S490 promote cell surface GLUT1 and GLUT1-mediated transport in skeletal muscle associated with upregulation of the GLUT1/GIPC1 interaction. PMID:23776597

  17. Using ATM over SATCOM links

    NASA Technical Reports Server (NTRS)

    Comparetto, Gary M.

    1995-01-01

    The Asynchronous Transfer Mode (ATM) protocol is studied from the standpoint of determining what limitations, if any, exist in using it over satellite links. It is concluded that, while there is nothing intrinsic about ATM that would generally preclude its use over satellite links, there are, however, several intrinsic characteristics of satellite links, as well as some satellite system configuration-specific issues, that must be taken into account.

  18. Security Services Discovery by ATM Endsystems

    SciTech Connect

    Sholander, Peter; Tarman, Thomas

    1999-07-15

    This contribution proposes strawman techniques for Security Service Discovery by ATM endsystems in ATM networks. Candidate techniques include ILMI extensions, ANS extensions and new ATM anycast addresses. Another option is a new protocol based on an IETF service discovery protocol, such as Service Location Protocol (SLP). Finally, this contribution provides strawman requirements for Security-Based Routing in ATM networks.

  19. A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1

    PubMed Central

    Wang, Yingfei; An, Ran; Umanah, George K.; Park, Hyejin; Nambiar, Kalyani; Eacker, Stephen M.; Kim, BongWoo; Bao, Lei; Harraz, Maged M.; Chang, Calvin; Chen, Rong; Wang, Jennifer E.; Kam, Tae-In; Jeong, Jun Seop; Xie, Zhi; Neifert, Stewart; Qian, Jiang; Andrabi, Shaida A.; Blackshaw, Seth; Zhu, Heng; Song, Hongjun; Ming, Guo-li; Dawson, Valina L.; Dawson, Ted M.

    2016-01-01

    Inhibition or genetic deletion of poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) is protective against toxic insults in many organ systems. The molecular mechanisms underlying PARP-1–dependent cell death involve release of mitochondrial apoptosis-inducing factor (AIF) and its translocation to the nucleus, which results in chromatinolysis. We identified macrophage migration inhibitory factor (MIF) as a PARP-1–dependent AIF-associated nuclease (PAAN). AIF was required for recruitment of MIF to the nucleus, where MIF cleaves genomic DNA into large fragments. Depletion of MIF, disruption of the AIF-MIF interaction, or mutation of glutamic acid at position 22 in the catalytic nuclease domain blocked MIF nuclease activity and inhibited chromatinolysis, cell death induced by glutamate excitotoxicity, and focal stroke. Inhibition of MIF's nuclease activity is a potential therapeutic target for diseases caused by excessive PARP-1 activation. PMID:27846469

  20. Traffic Management for Satellite-ATM Networks

    NASA Technical Reports Server (NTRS)

    Goyal, Rohit; Jain, Raj; Fahmy, Sonia; Vandalore, Bobby; Goyal, Mukul

    1998-01-01

    Various issues associated with "Traffic Management for Satellite-ATM Networks" are presented in viewgraph form. Specific topics include: 1) Traffic management issues for TCP/IP based data services over satellite-ATM networks; 2) Design issues for TCP/IP over ATM; 3) Optimization of the performance of TCP/IP over ATM for long delay networks; and 4) Evaluation of ATM service categories for TCP/IP traffic.

  1. Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation.

    PubMed

    Bakr, A; Oing, C; Köcher, S; Borgmann, K; Dornreiter, I; Petersen, C; Dikomey, E; Mansour, W Y

    2015-03-31

    Ataxia-telangiectasia mutated (ATM) is needed for the initiation of the double-strand break (DSB) repair by homologous recombination (HR). ATM triggers DSB end resection by stimulating the nucleolytic activity of CtIP and MRE11 to generate 3'-ssDNA overhangs, followed by RPA loading and RAD51 nucleofilament formation. Here we show for the first time that ATM is also needed for later steps in HR after RAD51 nucleofilament formation. Inhibition of ATM after completion of end resection did not affect RAD51 nucleofilament formation, but resulted in HR deficiency as evidenced by (i) an increase in the number of residual RAD51/γH2AX foci in both S and G2 cells, (ii) the decrease in HR efficiency as detected by HR repair substrate (pGC), (iii) a reduced SCE rate and (iv) the radiosensitization of cells by PARP inhibition. This newly described role for ATM was found to be dispensable in heterochromatin-associated DSB repair, as KAP1-depletion did not alleviate the HR-deficiency when ATM was inhibited after end resection. Moreover, we demonstrated that ATR can partly compensate for the deficiency in early, but not in later, steps of HR upon ATM inhibition. Taken together, we describe here for the first time that ATM is needed not only for the initiation but also for the completion of HR.

  2. Poly (ADP-ribose) Polymerase 1 Protein Expression in Normal and Neoplastic Prostatic Tissue

    PubMed Central

    Salemi, M.; Galia, A.; Fraggetta, F.; La Corte, C.; Pepe, P.; La Vignera, S.; Improta, G.; Bosco, P.; Calogero, A.E.

    2013-01-01

    A genetic background has been implicated in the development of prostate cancer. Protein microarrays have enabled the identification of proteins, some of which associated with apoptosis, that may play a role in the development of such a tumor. Inhibition of apoptosis is a co-factor that contributes to the onset and progression of prostate cancer, though the molecular mechanisms are not entirely understood. Poly (ADP-ribose) polymerase 1 (PARP-1) gene is required for translocation of the apoptosis-inducing factor (AIF) from the mitochondria to the nucleus. Hence, it is involved in programmed cell death. Different PARP-1 gene expression has been observed in various tumors such as glioblastoma, lung, ovarian, endometrial, and skin cancers. We evaluated the expression of PARP-1 protein in prostatic cancer and normal prostate tissues by immunohistochemistry in 40 men with prostate cancer and in 37 normal men. Positive nuclear PARP-1 staining was found in all samples (normal prostate and prostate cancer tissues). No cytoplasmic staining was observed in any sample. PARP-1-positive cells resulted significantly higher in patients with prostate carcinoma compared with controls (P<0.001). PARP-1 over-expression in prostate cancer tissue compared with normal prostate suggests a greater activity of PARP-1 in these tumors. These findings suggest that PARP-1 expression in prostate cancer is an attempt to trigger apoptosis in this type of tumor similarly to what reported in other cancers. PMID:23807292

  3. ATM may be a protective factor in endometrial carcinogenesis with the progesterone pathway.

    PubMed

    Shan, Weiwei; Wang, Chao; Zhang, Zhenbo; Luo, Xuezhen; Ning, Chengcheng; Yu, Yinhua; Feng, Youji; Gu, Chao; Chen, Xiaojun

    2015-03-01

    The purpose of the study was to explore the role and mechanism of ataxia-telangiectasia mutated (ATM) protein in endometrial carcinogenesis. A reverse-phase protein array (RPPA) was used to analyze the expression of ATM signal pathway proteins in Ishikawa and progesterone-insensitive Ishikawa. ATM expression was detected in endometrium specimens by immunohistochemistry, including 8 cases with proliferative endometrium, 6 cases with secretory endometrium, 10 cases with simple hyperplasia (SH), 13 cases of complex hyperplasia (CH), 11 cases of endometrial atypical hyperplasia (EAH), and 83 cases with type I endometrial cancer. The relationship between ATM expression and other clinicopathological indicators was also examined in type I endometrial cancer patients. The mechanisms of ATM were explored in vitro with the endometrial cell lines Ishikawa and RL95-2. A cell counting kit-8 (CCK-8) test and Western blot analysis were performed to test proliferation and protein expression. Statistical analysis was performed with SPSS19.0. The significance level was set at 0.05. ATM was increased with medroxyprogesterone acetate (MPA) stimulation in Ishikawa in RPPA. ATM expression gradually decreased in endometrial hyperplasic lesions compared with the normal proliferative and secretory endometrium and was the lowest in type I endometrial cancer. ATM expression was negatively correlated with pathological grades in type I endometrial cancer. In vitro, ATM silencing retarded proliferation inhibition in Ishikawa and RL95-2 treated with MPA. ATM silencing could down-regulate the MPA-stimulated signal proteins, including Chk2, P53, and caspase-3 in vitro. MPA might exert its role through activating the ATM-associated pathway, ATM-Chk2-P53-caspase-3 (active), preserving normal endometrium and protecting it from malignancies. ATM might be a promising indicator for endometrial hyperplasia and cancer.

  4. Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

    SciTech Connect

    Fukumoto, Yasunori Kuki, Kazumasa; Morii, Mariko; Miura, Takahito; Honda, Takuya; Ishibashi, Kenichi; Hasegawa, Hitomi; Kubota, Sho; Ide, Yudai; Yamaguchi, Noritaka; Nakayama, Yuji; Yamaguchi, Naoto

    2014-09-26

    Highlights: • Inhibition of Src family kinases decreased γ-H2AX signal. • Inhibition of Src family increased ATM-dependent phosphorylation of Chk2 and Kap1. • shRNA-mediated knockdown of Lyn increased phosphorylation of Kap1 by ATM. • Ectopic expression of Src family kinase suppressed ATM-mediated Kap1 phosphorylation. • Src is involved in upstream signaling for inactivation of ATM signaling. - Abstract: DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the process by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint.

  5. Poly(ADP-ribose) polymerase-1 protects from oxidative stress induced endothelial dysfunction

    SciTech Connect

    Gebhard, Catherine; Staehli, Barbara E.; Shi, Yi; Camici, Giovanni G.; Akhmedov, Alexander; Hoegger, Lisa; Lohmann, Christine; Matter, Christian M.; Hassa, Paul O.; Hottiger, Michael O.; Malinski, Tadeusz; Luescher, Thomas F.; and others

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer The nuclear enzyme PARP-1 is a downstream effector of oxidative stress. Black-Right-Pointing-Pointer PARP-1 protects from oxidative stress induced endothelial dysfunction. Black-Right-Pointing-Pointer This effect is mediated through inhibition of vasoconstrictor prostanoid production. Black-Right-Pointing-Pointer Thus, PARP-1 may play a protective role as antioxidant defense mechanism. -- Abstract: Background: Generation of reactive oxygen species (ROS) is a key feature of vascular disease. Activation of the nuclear enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase-1 (PARP-1) is a downstream effector of oxidative stress. Methods: PARP-1(-/-) and PARP-1(+/+) mice were injected with paraquat (PQ; 10 mg/kg i.p.) to induce intracellular oxidative stress. Aortic rings were suspended in organ chambers for isometric tension recording to analyze vascular function. Results: PQ treatment markedly impaired endothelium-dependent relaxations to acetylcholine in PARP-1(-/-), but not PARP-1(+/+) mice (p < 0.0001). Maximal relaxation was 45% in PQ treated PARP-1(-/-) mice compared to 79% in PARP-1(+/+) mice. In contrast, endothelium-independent relaxations to sodium nitroprusside (SNP) were not altered. After PQ treatment, L-NAME enhanced contractions to norepinephrine by 2.0-fold in PARP-1(-/-) mice, and those to acetylcholine by 3.3-fold, respectively, as compared to PARP-1(+/+) mice. PEG-superoxide dismutase (SOD) and PEG-catalase prevented the effect of PQ on endothelium-dependent relaxations to acetylcholine in PARP-1(-/-) mice (p < 0.001 vs. PQ treated PARP-1(+/+) mice. Indomethacin restored endothelium-dependent relaxations to acetylcholine in PQ treated PARP-1(-/-) mice (p < 0.05 vs. PQ treated PARP-1(+/+). Conclusion: PARP-1 protects from acute intracellular oxidative stress induced endothelial dysfunction by inhibiting ROS induced production of vasoconstrictor prostanoids.

  6. Somatic inactivation of ATM in hematopoietic cells predisposes mice to cyclin D3 dependent T cell acute lymphoblastic leukemia.

    PubMed

    Ehrlich, Lori A; Yang-Iott, Katherine; DeMicco, Amy; Bassing, Craig H

    2015-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of immature T cells that exhibits heterogeneity of oncogenic lesions, providing an obstacle for development of more effective and less toxic therapies. Inherited deficiency of ATM, a regulator of the cellular DNA damage response, predisposes young humans and mice to T-ALLs with clonal chromosome translocations. While acquired ATM mutation or deletion occurs in pediatric T-ALLs, the role of somatic ATM alterations in T-ALL pathogenesis remains unknown. We demonstrate here that somatic Atm inactivation in haematopoietic cells starting as these cells differentiate in utero predisposes mice to T-ALL at similar young ages and harboring analogous translocations as germline Atm-deficient mice. However, some T-ALLs from haematopoietic cell specific deletion of Atm were of more mature thymocytes, revealing that the developmental timing and celluar origin of Atm inactivation influences the phenotype of ATM-deficient T-ALLs. Although it has been hypothesized that ATM suppresses cancer by preventing deletion and inactivation of TP53, we find that Atm inhibits T-ALL independent of Tp53 deletion. Finally, we demonstrate that the Cyclin D3 protein that drives immature T cell proliferation is essential for transformation of Atm-deficient thymocytes. Our study establishes a pre-clinical model for pediatric T-ALLs with acquired ATM inactivation and identifies the cell cycle machinery as a therapeutic target for this aggressive childhood T-ALL subtype.

  7. ATM promotes apoptosis and suppresses tumorigenesis in response to Myc

    NASA Astrophysics Data System (ADS)

    Pusapati, Raju V.; Rounbehler, Robert J.; Hong, Sungki; Powers, John T.; Yan, Mingshan; Kiguchi, Kaoru; McArthur, Mark J.; Wong, Paul K.; Johnson, David G.

    2006-01-01

    Overexpression of the c-myc oncogene contributes to the development of a significant number of human cancers. In response to deregulated Myc activity, the p53 tumor suppressor is activated to promote apoptosis and inhibit tumor formation. Here we demonstrate that p53 induction in response to Myc overexpression requires the ataxia-telangiectasia mutated (ATM) kinase, a major regulator of the cellular response to DNA double-strand breaks. In a transgenic mouse model overexpressing Myc in squamous epithelial tissues, inactivation of Atm suppresses apoptosis and accelerates tumorigenesis. Deregulated Myc expression induces DNA damage in primary transgenic keratinocytes and the formation of H2AX and phospho-SMC1 foci in transgenic tissue. These findings suggest that Myc overexpression causes DNA damage in vivo and that the ATM-dependent response to this damage is critical for p53 activation, apoptosis, and the suppression of tumor development. p53 | DNA damage

  8. Block loss for ATM video

    NASA Astrophysics Data System (ADS)

    Chan, Sze K.; Leon-Garcia, Alberto

    1993-10-01

    In BISDN, the asynchronous transfer mode (ATM) requires all information to be represented as a sequence of standard data units called cells. Cell los is inherent in ATM networks due to the cell header corruption and buffer overflow in the network. Several studies have shown that cell losses are bursty for an ATM network. In this work, we encoded real video sequences with a variable bit-rate (VBR) version of the H.261 video encoder in order for us to determine the relationship between blocks in a video frame and the number of ATM cells generated. We then considered the impact of bursty cell losses on image block loss probability. Block loss distributions are given at different codec and channel parameters. We also obtained block loss results using a cell loss correction scheme. Three sequences were analyzed to obtain the cumulative block loss probability distribution. Similar maximum and minimum block loss probability values were obtained for each sequence. The block loss probability distribution varies according to the amount and type of motion present in each sequence. We show that the block loss is confined to one group of blocks (GOB). The maximum block loss probability can be two orders of magnitude larger than the channel cell loss probability. By using the cell loss correction scheme, block loss was reduced to a level equivalent to reducing cell loss probability by five orders of magnitude.

  9. [Progress of the ATM Crew

    NASA Technical Reports Server (NTRS)

    2003-01-01

    Activities for each of the following programs are discussed in separate sections for the bimonthly reporting period: Airborne Oceanographic Lidar (AOL); Airborne Topographic Mapper (ATM); Other Mission Support Activities, including modeling activities, EAARL activities, and the Scanning Radar Altimeter (SAR); Tropical Rain Measuring Mission (TRMM). The tasks undertaken for each program are discussed in the pertinent section of the report.

  10. NPP ATMS Snowfall Rate Product

    NASA Technical Reports Server (NTRS)

    Meng, Huan; Ferraro, Ralph; Kongoli, Cezar; Wang, Nai-Yu; Dong, Jun; Zavodsky, Bradley; Yan, Banghua

    2015-01-01

    Passive microwave measurements at certain high frequencies are sensitive to the scattering effect of snow particles and can be utilized to retrieve snowfall properties. Some of the microwave sensors with snowfall sensitive channels are Advanced Microwave Sounding Unit (AMSU), Microwave Humidity Sounder (MHS) and Advance Technology Microwave Sounder (ATMS). ATMS is the follow-on sensor to AMSU and MHS. Currently, an AMSU and MHS based land snowfall rate (SFR) product is running operationally at NOAA/NESDIS. Based on the AMSU/MHS SFR, an ATMS SFR algorithm has been developed recently. The algorithm performs retrieval in three steps: snowfall detection, retrieval of cloud properties, and estimation of snow particle terminal velocity and snowfall rate. The snowfall detection component utilizes principal component analysis and a logistic regression model. The model employs a combination of temperature and water vapor sounding channels to detect the scattering signal from falling snow and derive the probability of snowfall (Kongoli et al., 2015). In addition, a set of NWP model based filters is also employed to improve the accuracy of snowfall detection. Cloud properties are retrieved using an inversion method with an iteration algorithm and a two-stream radiative transfer model (Yan et al., 2008). A method developed by Heymsfield and Westbrook (2010) is adopted to calculate snow particle terminal velocity. Finally, snowfall rate is computed by numerically solving a complex integral. NCEP CMORPH analysis has shown that integration of ATMS SFR has improved the performance of CMORPH-Snow. The ATMS SFR product is also being assessed at several NWS Weather Forecast Offices for its usefulness in weather forecast.

  11. Molecular Imaging of the ATM Kinase Activity

    SciTech Connect

    Williams, Terence M.; Nyati, Shyam; Ross, Brian D.; Rehemtulla, Alnawaz

    2013-08-01

    Purpose: Ataxia telangiectasia mutated (ATM) is a serine/threonine kinase critical to the cellular DNA-damage response, including from DNA double-strand breaks. ATM activation results in the initiation of a complex cascade of events including DNA damage repair, cell cycle checkpoint control, and survival. We sought to create a bioluminescent reporter that dynamically and noninvasively measures ATM kinase activity in living cells and subjects. Methods and Materials: Using the split luciferase technology, we constructed a hybrid cDNA, ATM-reporter (ATMR), coding for a protein that quantitatively reports on changes in ATM kinase activity through changes in bioluminescence. Results: Treatment of ATMR-expressing cells with ATM inhibitors resulted in a dose-dependent increase in bioluminescence activity. In contrast, induction of ATM kinase activity upon irradiation resulted in a decrease in reporter activity that correlated with ATM and Chk2 activation by immunoblotting in a time-dependent fashion. Nuclear targeting improved ATMR sensitivity to both ATM inhibitors and radiation, whereas a mutant ATMR (lacking the target phosphorylation site) displayed a muted response. Treatment with ATM inhibitors and small interfering (si)RNA-targeted knockdown of ATM confirm the specificity of the reporter. Using reporter expressing xenografted tumors demonstrated the ability of ATMR to report in ATM activity in mouse models that correlated in a time-dependent fashion with changes in Chk2 activity. Conclusions: We describe the development and validation of a novel, specific, noninvasive bioluminescent reporter that enables monitoring of ATM activity in real time, in vitro and in vivo. Potential applications of this reporter include the identification and development of novel ATM inhibitors or ATM-interacting partners through high-throughput screens and in vivo pharmacokinetic/pharmacodynamic studies of ATM inhibitors in preclinical models.

  12. The over expression of long non-coding RNA ANRIL promotes epithelial-mesenchymal transition by activating the ATM-E2F1 signaling pathway in pancreatic cancer: an in vivo and in vitro study.

    PubMed

    Chen, Shi; Zhang, Jia-Qiang; Chen, Jiang-Zhi; Chen, Hui-Xing; Qiu, Fu-Nan; Yan, Mao-Lin; Chen, Yan-Ling; Peng, Cheng-Hong; Tian, Yi-Feng; Wang, Yao-Dong

    2017-03-23

    This study aims to investigate the roles of lncRNA ANRIL in epithelial-mesenchymal transition (EMT) by regulating the ATM-E2F1 signaling pathway in pancreatic cancer (PC). PC rat models were established and ANRIL overexpression and interference plasmids were transfected. The expression of ANRIL, EMT markers (E-cadherin, N-cadherin and Vimentin) and ATM-E2F1 signaling pathway-related proteins (ATM, E2F1, INK4A, INK4B and ARF) were detected. Small molecule drugs were applied to activate and inhibit the ATM-E2F1 signaling pathway. Transwell assay and the scratch test were adopted to detect cell invasion and migration abilities. ANRIL expression in the PC cells was higher than in normal pancreatic duct epithelial cells. In the PC rat models and PC cells, ANRIL interference promoted the expressions of INK4B, INK4A, ARF and E-cadherin, while reduced N-cadherin and Vimentin expression. Over-expressed ANRIL decreased the expression of INK4B, INK4A, ARF and E-cadherin, but raised N-cadherin and Vimentin expressions. By inhibiting the ATM-E2F1 signaling pathway in PC cells, E-cadherin expression increased but N-cadherin and Vimentin expressions decreased. After ANRIL was silenced or the ATM-E2F1 signaling pathway inhibited, PC cell migration and invasion abilities were decreased. In conclusion, over-expression of lncRNA ANRIL can promote EMT of PC cells by activating the ATM-E2F1 signaling pathway.

  13. Running TCP/IP over ATM Networks.

    ERIC Educational Resources Information Center

    Witt, Michael

    1995-01-01

    Discusses Internet protocol (IP) and subnets and describes how IP may operate over asynchronous transfer mode (ATM). Topics include TCP (transmission control protocol), ATM cells and adaptation layers, a basic architectural model for IP over ATM, address resolution, mapping IP to a subnet technology, and connection management strategy. (LRW)

  14. Adaptive Neural Network Controller for ATM Traffic

    DTIC Science & Technology

    1996-12-01

    IEEE Communications Magazine (October 1995). 2. Baum, Eric B...Adaptive Control in ATM Networks," IEEE Communications Magazine (October 1995). 9. Evanowsky, John B. "Information for the Warrior," IEEE Communications Magazine (October...Network Applications in ATM," IEEE Communications Magazine (October 1995). 78 16. Imrich, et al. "A counter based congestion control for ATM

  15. Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM.

    PubMed

    McCabe, Nuala; Hanna, Conor; Walker, Steven M; Gonda, David; Li, Jie; Wikstrom, Katarina; Savage, Kienan I; Butterworth, Karl T; Chen, Clark; Harkin, D Paul; Prise, Kevin M; Kennedy, Richard D

    2015-06-01

    Ataxia telangiectasia mutated (ATM) is an important signaling molecule in the DNA damage response (DDR). ATM loss of function can produce a synthetic lethal phenotype in combination with tumor-associated mutations in FA/BRCA pathway components. In this study, we took an siRNA screening strategy to identify other tumor suppressors that, when inhibited, similarly sensitized cells to ATM inhibition. In this manner, we determined that PTEN and ATM were synthetically lethal when jointly inhibited. PTEN-deficient cells exhibited elevated levels of reactive oxygen species, increased endogenous DNA damage, and constitutive ATM activation. ATM inhibition caused catastrophic DNA damage, mitotic cell cycle arrest, and apoptosis specifically in PTEN-deficient cells in comparison with wild-type cells. Antioxidants abrogated the increase in DNA damage and ATM activation in PTEN-deficient cells, suggesting a requirement for oxidative DNA damage in the mechanism of cell death. Lastly, the ATM inhibitor KU-60019 was specifically toxic to PTEN mutant cancer cells in tumor xenografts and reversible by reintroduction of wild-type PTEN. Together, our results offer a mechanistic rationale for clinical evaluation of ATM inhibitors in PTEN-deficient tumors.

  16. ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress

    SciTech Connect

    Pauklin, Siim . E-mail: spauklin@ut.ee; Kristjuhan, Arnold; Maimets, Toivo; Jaks, Viljar

    2005-08-26

    Induction of apoptosis is pivotal for eliminating cells with damaged DNA or deregulated proliferation. We show that tumor suppressor ARF and ATM/ATR kinase pathways cooperate in the induction of apoptosis in response to elevated expression of c-myc, {beta}-catenin or human papilloma virus E7 oncogenes. Overexpression of oncogenes leads to the formation of phosphorylated H2AX foci, induction of Rad51 protein levels and ATM/ATR-dependent phosphorylation of p53. Inhibition of ATM/ATR kinases abolishes both induction of Rad51 and phosphorylation of p53, and remarkably reduces the level of apoptosis induced by co-expression of oncogenes and ARF. However, the induction of apoptosis is downregulated in p53-/- cells and does not depend on activities of ATM/ATR kinases, indicating that efficient induction of apoptosis by oncogene activation depends on coordinated action of ARF and ATM/ATR pathways in the regulation of p53.

  17. Absence of ERK5/MAPK7 delays tumorigenesis in Atm-/- mice.

    PubMed

    Granados-Jaén, Alba; Angulo-Ibáñez, Maria; Rovira-Clavé, Xavier; Gamez, Celina Paola Vasquez; Soriano, Francesc X; Reina, Manuel; Espel, Enric

    2016-11-15

    Ataxia-telangiectasia mutated (ATM) is a cell cycle checkpoint kinase that upon activation by DNA damage leads to cell cycle arrest and DNA repair or apoptosis. The absence of Atm or the occurrence of loss-of-function mutations in Atm predisposes to tumorigenesis. MAPK7 has been implicated in numerous types of cancer with pro-survival and pro-growth roles in tumor cells, but its functional relation with tumor suppressors is not clear. In this study, we show that absence of MAPK7 delays death due to spontaneous tumor development in Atm-/- mice. Compared with Atm-/- thymocytes, Mapk7-/-Atm-/- thymocytes exhibited an improved response to DNA damage (increased phosphorylation of H2AX) and a restored apoptotic response after treatment of mice with ionizing radiation. These findings define an antagonistic function of ATM and MAPK7 in the thymocyte response to DNA damage, and suggest that the lack of MAPK7 inhibits thymic lymphoma growth in Atm-/- mice by partially restoring the DNA damage response in thymocytes.

  18. Development of a cell-based, high-throughput screening assay for ATM kinase inhibitors.

    PubMed

    Guo, Kexiao; Shelat, Anang A; Guy, R Kiplin; Kastan, Michael B

    2014-04-01

    The ATM (ataxia-telangiectasia, mutated) protein kinase is a major regulator of cellular responses to DNA double-strand breaks (DSBs), DNA lesions that can be caused by ionizing irradiation (IR), oxidative damage, or exposure to certain chemical agents. In response to DSBs, the ATM kinase is activated and subsequently phosphorylates numerous downstream substrates, including p53, Chk2, BRCA1, and KAP1, which affect processes such as cell cycle progression and DNA repair. Numerous studies have demonstrated that loss of ATM function results in enhanced sensitivity to ionizing irradiation in clinically relevant dose ranges, suggesting that ATM kinase is an attractive therapeutic target for enhancing tumor cell kill with radiotherapy. Previously identified small-molecule ATM kinase inhibitors, such as CP466722 and Ku55933, were identified using in vitro kinase assays carried out with recombinant ATM kinase isolated from mammalian cells. Since it has not been feasible to express full-length recombinant ATM in bacterial or baculovirus systems, a robust in vitro screening tool has been lacking. We have developed a cell-based assay that is robust, straightforward, and sensitive. Using this high-throughput assay, we screened more than 7000 compounds and discovered additional small molecules that inhibit the ATM kinase and further validated these hits by secondary assays.

  19. 3-aminobenzamide, one of poly(ADP-ribose)polymerase-1 inhibitors, rescuesapoptosisin rat models of spinal cord injury.

    PubMed

    Meng, Xianqing; Song, Wenqi; Deng, Bin; Xing, Ziling; Zhang, Weihong

    2015-01-01

    Poly(ADP-ribose)polymerase-1 (PARP-1) is anubiquitous, DNA repair-associated enzyme, which participates in gene expression, cell death, central nerve system (CNS) disorders and oxidative stress. According to the previous studies, PARP-1 over-activation may lead to over-consumption of ATP and even cell apoptosis. Spinal cord injury (SCI) is an inducement towards PARP-1 over-activation due to its massive damage to DNA. 3-aminobenzamide (3-AB) is a kind of PARP-1 inhibitors. The relationship among PARP-1, 3-AB, SCI and apoptosis has not been fully understood. Hence, in the present study, we focused on the effects of 3-AB on cell apoptosis after SCI. Accordingly, SCI model was constructed artificially, and 3-AB was injected intrathecally into the Sprague-Dawley (SD) rats. The results demonstrated an increase in cell apoptosis after SCI. Furthermore, PARP-1 was over-activated after SCI but inhibited by 3-AB injection. In addition, apoptosis-inducing factor (AIF) was inhibited but B-cell lymphoma-2 (Bcl-2) was up-regulated by 3-AB. Interestingly, caspase-3 was not significantly altered with or without 3-AB. In conclusion, our experiments showed that 3-AB, as a PARP-1 inhibitor, could inhibit cell apoptosis after SCI in caspase-independent way, which could provide a better therapeutic target for the treatment of SCI.

  20. Poly(ADP-ribose) polymerase 1 contributes to oxidative stress through downregulation of sirtuin 3 during cisplatin nephrotoxicity

    PubMed Central

    Yoon, Sang Pil

    2016-01-01

    Enhanced oxidative stress is a hallmark of cisplatin nephrotoxicity, and inhibition of poly(ADP-ribose) polymerase 1 (PARP1) attenuates oxidative stress during cisplatin nephrotoxicity; however, the precise mechanisms behind its action remain elusive. Here, using an in vitro model of cisplatin-induced injury to human kidney proximal tubular cells, we demonstrated that the protective effect of PARP1 inhibition on oxidative stress is associated with sirtuin 3 (SIRT3) activation. Exposure to 400 µM cisplatin for 8 hours in cells decreased activity and expression of manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase (GPX), and SIRT3, while it increased their lysine acetylation. However, treatment with 1 µM PJ34 hydrochloride, a potent PARP1 inhibitor, restored activity and/or expression in those antioxidant enzymes, decreased lysine acetylation of those enzymes, and improved SIRT3 expression and activity in the cisplatin-injured cells. Using transfection with SIRT3 double nickase plasmids, SIRT3-deficient cells given cisplatin did not show the ameliorable effect of PARP1 inhibition on lysine acetylation and activity of antioxidant enzymes, including MnSOD, catalase and GPX. Furthermore, SIRT3 deficiency in cisplatin-injured cells prevented PARP1 inhibition-induced increase in forkhead box O3a transcriptional activity, and upregulation of MnSOD and catalase. Finally, loss of SIRT3 in cisplatin-exposed cells removed the protective effect of PARP1 inhibition against oxidative stress, represented by the concentration of lipid hydroperoxide and 8-hydroxy-2'-deoxyguanosine; and necrotic cell death represented by a percentage of propidium iodide–positively stained cells. Taken together, these results indicate that PARP1 inhibition protects kidney proximal tubular cells against oxidative stress through SIRT3 activation during cisplatin nephrotoxicity. PMID:27722009

  1. Ultrafast networks (ATM): first clinical experiences.

    PubMed

    Duerinckx, A J; Valentino, D J; Hayrapetian, A; Hagan, G; Grant, E G

    1996-06-01

    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.

  2. Deregulation of mTOR signaling is involved in thymic lymphoma development in Atm-/- mice

    SciTech Connect

    Kuang, Xianghong; Shen, Jianjun; Wong, Paul K.Y.; Yan, Mingshan

    2009-06-05

    Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/- mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.

  3. ATM: Restructing Learning for Deaf Students.

    ERIC Educational Resources Information Center

    Keefe, Barbara; Stockford, David

    Governor Baxter School for the Deaf is one of six Maine pilot sites chosen by NYNEX to showcase asynchronous transfer mode (ATM) technology. ATM is a network connection that allows high bandwidth transmission of data, voice, and video. Its high speed capability allows for high quality two-way full-motion video, which is especially beneficial to a…

  4. Buffer Management Simulation in ATM Networks

    NASA Technical Reports Server (NTRS)

    Yaprak, E.; Xiao, Y.; Chronopoulos, A.; Chow, E.; Anneberg, L.

    1998-01-01

    This paper presents a simulation of a new dynamic buffer allocation management scheme in ATM networks. To achieve this objective, an algorithm that detects congestion and updates the dynamic buffer allocation scheme was developed for the OPNET simulation package via the creation of a new ATM module.

  5. Dynamics of TCP traffic over ATM networks

    SciTech Connect

    Floyd, S.; Romanow, A.

    1994-08-01

    The authors investigate the performance of TCP (Transport Control Protocol) connections over ATM (Asynchronous Transfer Mode) networks without ATM-level congestion control, and compare it to the performance of TCP over packet-based networks. For simulations of congested networks, the effective throughput of TCP over ATM can be quite low when cells are dropped at the congested ATM switch. The low throughput is due to wasted bandwidth as the congested link transmits cells from ``corrupted`` packets, i.e., packets in which at least one cell is dropped by the switch. This fragmentation effect can be corrected and high throughput can be achieved if the switch drops whole packets prior to buffer overflow; they call this strategy Early Packet Discard. They also discuss general issues of congestion avoidance for best-effort traffic in ATM networks.

  6. The Aspergillus nidulans ATM Kinase Regulates Mitochondrial Function, Glucose Uptake and the Carbon Starvation Response

    PubMed Central

    Krohn, Nadia Graciele; Brown, Neil Andrew; Colabardini, Ana Cristina; Reis, Thaila; Savoldi, Marcela; Dinamarco, Taísa Magnani; Goldman, Maria Helena S.; Goldman, Gustavo Henrique

    2013-01-01

    Mitochondria supply cellular energy and also perform a role in the adaptation to metabolic stress. In mammals, the ataxia-telangiectasia mutated (ATM) kinase acts as a redox sensor controlling mitochondrial function. Subsequently, transcriptomic and genetic studies were utilized to elucidate the role played by a fungal ATM homolog during carbon starvation. In Aspergillus nidulans, AtmA was shown to control mitochondrial function and glucose uptake. Carbon starvation responses that are regulated by target of rapamycin (TOR) were shown to be AtmA-dependent, including autophagy and hydrolytic enzyme secretion. AtmA also regulated a p53-like transcription factor, XprG, inhibiting starvation-induced XprG-dependent protease secretion and cell death. Thus, AtmA possibly represents a direct or indirect link between mitochondrial stress, metabolism, and growth through the influence of TOR and XprG function. The coordination of cell growth and division with nutrient availability is crucial for all microorganisms to successfully proliferate in a heterogeneous environment. Mitochondria supply cellular energy but also perform a role in the adaptation to metabolic stress and the cross-talk between prosurvival and prodeath pathways. The present study of Aspergillus nidulans demonstrated that AtmA also controlled mitochondrial mass, function, and oxidative phosphorylation, which directly or indirectly influenced glucose uptake. Carbon starvation responses, including autophagy, shifting metabolism to the glyoxylate cycle, and the secretion of carbon scavenging enzymes were AtmA-dependent. Transcriptomic profiling of the carbon starvation response demonstrated how TOR signaling and the retrograde response, which signals mitochondrial dysfunction, were directly or indirectly influenced by AtmA. The AtmA kinase was also shown to influence a p53-like transcription factor, inhibiting starvation-induced XprG-dependent protease secretion and cell death. Therefore, in response to metabolic

  7. The Aspergillus nidulans ATM kinase regulates mitochondrial function, glucose uptake and the carbon starvation response.

    PubMed

    Krohn, Nadia Graciele; Brown, Neil Andrew; Colabardini, Ana Cristina; Reis, Thaila; Savoldi, Marcela; Dinamarco, Taísa Magnani; Goldman, Maria Helena S; Goldman, Gustavo Henrique

    2014-01-10

    Mitochondria supply cellular energy and also perform a role in the adaptation to metabolic stress. In mammals, the ataxia-telangiectasia mutated (ATM) kinase acts as a redox sensor controlling mitochondrial function. Subsequently, transcriptomic and genetic studies were utilized to elucidate the role played by a fungal ATM homolog during carbon starvation. In Aspergillus nidulans, AtmA was shown to control mitochondrial function and glucose uptake. Carbon starvation responses that are regulated by target of rapamycin (TOR) were shown to be AtmA-dependent, including autophagy and hydrolytic enzyme secretion. AtmA also regulated a p53-like transcription factor, XprG, inhibiting starvation-induced XprG-dependent protease secretion and cell death. Thus, AtmA possibly represents a direct or indirect link between mitochondrial stress, metabolism, and growth through the influence of TOR and XprG function. The coordination of cell growth and division with nutrient availability is crucial for all microorganisms to successfully proliferate in a heterogeneous environment. Mitochondria supply cellular energy but also perform a role in the adaptation to metabolic stress and the cross-talk between prosurvival and prodeath pathways. The present study of Aspergillus nidulans demonstrated that AtmA also controlled mitochondrial mass, function, and oxidative phosphorylation, which directly or indirectly influenced glucose uptake. Carbon starvation responses, including autophagy, shifting metabolism to the glyoxylate cycle, and the secretion of carbon scavenging enzymes were AtmA-dependent. Transcriptomic profiling of the carbon starvation response demonstrated how TOR signaling and the retrograde response, which signals mitochondrial dysfunction, were directly or indirectly influenced by AtmA. The AtmA kinase was also shown to influence a p53-like transcription factor, inhibiting starvation-induced XprG-dependent protease secretion and cell death. Therefore, in response to metabolic

  8. Poly(ADP-ribose) polymerase 1 regulates both the exonuclease and helicase activities of the Werner syndrome protein.

    PubMed

    von Kobbe, Cayetano; Harrigan, Jeanine A; Schreiber, Valérie; Stiegler, Patrick; Piotrowski, Jason; Dawut, Lale; Bohr, Vilhelm A

    2004-01-01

    Werner syndrome (WS) is a genetic premature aging disorder in which patients appear much older than their chronological age. The gene mutated in WS encodes a nuclear protein (WRN) which possesses 3'-5' exonuclease and ATPase-dependent 3'-5' helicase activities. The genomic instability associated with WS cells and the biochemical characteristics of WRN suggest that WRN plays a role in DNA metabolic pathways such as transcription, replication, recombination and repair. Recently we have identified poly(ADP-ribose) polymerase-1 (PARP-1) as a new WRN interacting protein. In this paper, we further mapped the interacting domains. We found that PARP-1 bound to the N-terminus of WRN and to the C-terminus containing the RecQ-conserved (RQC) domain. WRN bound to the N-terminus of PARP-1 containing DNA binding and BRCA1 C-terminal (BRCT) domains. We show that unmodified PARP-1 inhibited both WRN exonuclease and helicase activities, and to our knowledge is the only known WRN protein partner that inactivates both of the WRN's catalytic activities suggesting a biologically significant regulation. Moreover, this dual inhibition seems to be specific for PARP-1, as PARP-2 did not affect WRN helicase activity and only slightly inhibited WRN exonuclease activity. The differential effect of PARP-1 and PARP-2 on WRN catalytic activity was not due to differences in affinity for WRN or the DNA substrate. Finally, we demonstrate that the inhibition of WRN by PARP-1 was influenced by the poly(ADP-ribosyl)ation state of PARP-1. The biological relevance of the specific modulation of WRN catalytic activities by PARP-1 are discussed in the context of pathways in which these proteins may function together, namely in the repair of DNA strand breaks.

  9. Nitric oxide induces ataxia telangiectasia mutated (ATM) protein-dependent γH2AX protein formation in pancreatic β cells.

    PubMed

    Oleson, Bryndon J; Broniowska, Katarzyna A; Schreiber, Katherine H; Tarakanova, Vera L; Corbett, John A

    2014-04-18

    In this study, the effects of cytokines on the activation of the DNA double strand break repair factors histone H2AX (H2AX) and ataxia telangiectasia mutated (ATM) were examined in pancreatic β cells. We show that cytokines stimulate H2AX phosphorylation (γH2AX formation) in rat islets and insulinoma cells in a nitric oxide- and ATM-dependent manner. In contrast to the well documented role of ATM in DNA repair, ATM does not appear to participate in the repair of nitric oxide-induced DNA damage. Instead, nitric oxide-induced γH2AX formation correlates temporally with the onset of irreversible DNA damage and the induction of apoptosis. Furthermore, inhibition of ATM attenuates cytokine-induced caspase activation. These findings show that the formation of DNA double strand breaks correlates with ATM activation, irreversible DNA damage, and ATM-dependent induction of apoptosis in cytokine-treated β cells.

  10. Satellite ATM Networks: Architectures and Guidelines Developed

    NASA Technical Reports Server (NTRS)

    vonDeak, Thomas C.; Yegendu, Ferit

    1999-01-01

    An important element of satellite-supported asynchronous transfer mode (ATM) networking will involve support for the routing and rerouting of active connections. Work published under the auspices of the Telecommunications Industry Association (http://www.tiaonline.org), describes basic architectures and routing protocol issues for satellite ATM (SATATM) networks. The architectures and issues identified will serve as a basis for further development of technical specifications for these SATATM networks. Three ATM network architectures for bent pipe satellites and three ATM network architectures for satellites with onboard ATM switches were developed. The architectures differ from one another in terms of required level of mobility, supported data rates, supported terrestrial interfaces, and onboard processing and switching requirements. The documentation addresses low-, middle-, and geosynchronous-Earth-orbit satellite configurations. The satellite environment may require real-time routing to support the mobility of end devices and nodes of the ATM network itself. This requires the network to be able to reroute active circuits in real time. In addition to supporting mobility, rerouting can also be used to (1) optimize network routing, (2) respond to changing quality-of-service requirements, and (3) provide a fault tolerance mechanism. Traffic management and control functions are necessary in ATM to ensure that the quality-of-service requirements associated with each connection are not violated and also to provide flow and congestion control functions. Functions related to traffic management were identified and described. Most of these traffic management functions will be supported by on-ground ATM switches, but in a hybrid terrestrial-satellite ATM network, some of the traffic management functions may have to be supported by the onboard satellite ATM switch. Future work is planned to examine the tradeoffs of placing traffic management functions onboard a satellite as

  11. AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM-deficiency in gastric cancer cells.

    PubMed

    Min, Ahrum; Im, Seock-Ah; Jang, Hyemin; Kim, Seongyeong; Lee, Miso; Kim, Debora Keunyoung; Yang, Yaewon; Kim, Hee-Jun; Lee, Kyung-Hun; Kim, Jin Won; Kim, Tae-Yong; Oh, Do-Youn; Brown, Jeff; Lau, Alan; O Connor, Mark J; Bang, Yung-Jue

    2017-01-30

    Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect (HRD). The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer. In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in an in vivo tumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis. These findings suggest synthetic lethality between ATR inhibition and ATM-deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM-deficiency are warranted to develop novel treatment strategies for gastric cancer.

  12. MSFC institutional area network and ATM technology

    NASA Technical Reports Server (NTRS)

    Amin, Ashok T.

    1994-01-01

    The New Institutional Area Network (NEWIAN) at Marshall supports over 5000 end users with access to 26 file servers providing work presentation services. It is comprised of some 150 Ethernet LAN's interconnected by bridges/routers which are in turn connected to servers over two dual FDDI rings. The network supports various higher level protocols such as IP, IPX, AppleTalk (AT), and DECNet. At present IPX and AT protocols packets are routed, and IP protocol packets are bridged; however, work is in progress to route all IP packets. The impact of routing IP packets on network operation is examined. Broadband Integrated Services Data Network (BISDN), presently at various stages of development, is intended to provide voice, video, and data transfer services over a single network. BISDN will use asynchronous transfer mode (ATM) as a data transfer technique which provides for transmission, multiplexing, switching, and relaying of small size data units called cells. Limited ATM Wide Area Network (WAN) services are offered by Wiltel, AT&T, Sprint, and others. NASA is testing a pilot ATM WAN with a view to provide Program Support Communication Network services using ATM. ATM supports wide range of data rates and quality of service requirements. It is expected that ATM switches will penetrate campus networks as well. However, presently products in these areas are at various stages of development and standards are not yet complete. We examine development of ATM to help assess its role in the evolution of NEWIAN.

  13. The influence of RNA-dependent RNA polymerase 1 on potato virus Y infection and on other antiviral response genes.

    PubMed

    Rakhshandehroo, Farshad; Takeshita, Minoru; Squires, Julie; Palukaitis, Peter

    2009-10-01

    The gene encoding RNA-dependent RNA polymerase 1 (RDR1) is involved in basal resistance to several viruses. Expression of the RDR1 gene also is induced in resistance to Tobacco mosaic virus (TMV) mediated by the N gene in tobacco (Nicotiana tabacum cv. Samsun NN) in an incompatible hypersensitive response, as well as in a compatible response against Potato virus Y (PVY). Reducing the accumulation of NtRDR1 transcripts by RNA inhibition mediated by transgenic expression of a double-stranded RNA hairpin corresponding to part of the RDR1 gene resulted in little or no induction of accumulation of RDR1 transcripts after infection by PVY. Plants with lower accumulation of RDR1 transcripts showed much higher accumulation levels of PVY. Reduced accumulation of NtRDR1 transcripts also resulted in lower or no induced expression of three other antiviral, defense-related genes after infection by PVY. These genes encoded a mitochondrial alternative oxidase, an inhibitor of virus replication (IVR), and a transcription factor, ERF5, all involved in resistance to infection by TMV, as well as RDR6, involved in RNA silencing. The extent of the effect on the induced NtIVR and NtERF5 genes correlated with the extent of suppression of the NtRDR1 gene.

  14. SASIL. Sandia ATM SONET Interface Logic

    SciTech Connect

    Kitta, J P

    1994-07-01

    SASIL is used to program the EPLD`s (Erasable Programmable Logic Devices) and PAL`s (Programmable Array Logic) that make up a large percentage of the Sandia ATM SONET Interface (OC3 version) for the INTEL Paragon.

  15. A survey of IP over ATM architectures

    SciTech Connect

    Chen, H.; Tsang, R.; Brandt, J.; Hutchins, J.

    1997-07-01

    Over the past decade, the Internet has burgeoned into a worldwide information highway consisting of approximately 5 million hosts on over 45,000 interconnected networks. This unprecedented growth, together with the introduction of multimedia workstations, has spurred the development of innovative applications that require high speed, low latency, and real-time transport. Today`s Internet can neither scale in its bandwidth nor guarantee the Quality of Services (QoS) necessary to meet these performance requirements. Many network researchers propose to use the Asynchronous Transfer Mode (ATM) technology as the underlying infrastructure for the next generation of workgroup, campus, and enterprise IP networks. Since ATM is significantly different from today`s legacy network technologies, efficient implementation of IP over ATM is especially challenging. This tutorial paper covers several existing proposals that integrate IP over ATM.

  16. Sodium tungstate modulates ATM function upon DNA damage.

    PubMed

    Rodriguez-Hernandez, C J; Llorens-Agost, M; Calbó, J; Murguia, J R; Guinovart, J J

    2013-05-21

    Both radiotherapy and most effective chemotherapeutic agents induce different types of DNA damage. Here we show that tungstate modulates cell response to DNA damaging agents. Cells treated with tungstate were more sensitive to etoposide, phleomycin and ionizing radiation (IR), all of which induce DNA double-strand breaks (DSBs). Tungstate also modulated the activation of the central DSB signalling kinase, ATM, in response to these agents. These effects required the functionality of the Mre11-Nbs1-Rad50 (MRN) complex and were mimicked by the inhibition of PP2A phosphatase. Therefore, tungstate may have adjuvant activity when combined with DNA-damaging agents in the treatment of several malignancies.

  17. ATM mediates repression of DNA end-degradation in an ATP-dependent manner.

    PubMed

    Rahal, Elias A; Henricksen, Leigh A; Li, Yuling; Turchi, John J; Pawelczak, Katherine S; Dixon, Kathleen

    2008-03-01

    Ataxia telangiectasia mutated (ATM) is a PI3-kinase-like kinase (PIKK) associated with DNA double-strand break (DSB) repair and cell cycle control. We have previously reported comparable efficiencies of DSB repair in nuclear extracts from both ATM deficient (A-T) and control (ATM+) cells; however, the repair products from the A-T nuclear extracts contained deletions encompassing longer stretches of DNA compared to controls. These deletions appeared to result from end-joining at sites of microhomology. These data suggest that ATM hinders error-prone repair pathways that depend on degradation of DNA ends at a break. Such degradation may account for the longer deletions we formerly observed in A-T cell extracts. To address this possibility we assessed the degradation of DNA duplex substrates in A-T and control nuclear extracts under DSB repair conditions. We observed a marked shift in signal intensity from full-length products to shorter products in A-T nuclear extracts, and addition of purified ATM to A-T nuclear extracts restored full-length product detection. This repression of degradation by ATM was both ATP-dependent and inhibited by the PIKK inhibitors wortmannin and caffeine. Addition of pre-phosphorylated ATM to an A-T nuclear extract in the presence of PIKK inhibitors was insufficient in repressing degradation, indicating that kinase activities are required. These results demonstrate a role for ATM in preventing the degradation of DNA ends possibly through repressing nucleases implicated in microhomology-mediated end-joining.

  18. Contribution of canonical nonhomologous end joining to chromosomal rearrangements is enhanced by ATM kinase deficiency.

    PubMed

    Bhargava, Ragini; Carson, Caree R; Lee, Gabriella; Stark, Jeremy M

    2017-01-24

    A likely mechanism of chromosomal rearrangement formation involves joining the ends from two different chromosomal double-strand breaks (DSBs). These events could potentially be mediated by either of two end-joining (EJ) repair pathways [canonical nonhomologous end joining (C-NHEJ) or alternative end joining (ALT-EJ)], which cause distinct rearrangement junction patterns. The relative role of these EJ pathways during rearrangement formation has remained controversial. Along these lines, we have tested whether the DNA damage response mediated by the Ataxia Telangiectasia Mutated (ATM) kinase may affect the relative influence of C-NHEJ vs. ALT-EJ on rearrangement formation. We developed a reporter in mouse cells for a 0.4-Mbp deletion rearrangement that is formed by EJ between two DSBs induced by the Cas9 endonuclease. We found that disruption of the ATM kinase causes an increase in the frequency of the rearrangement as well as a shift toward rearrangement junctions that show hallmarks of C-NHEJ. Furthermore, ATM suppresses rearrangement formation in an experimental condition, in which C-NHEJ is the predominant EJ repair event (i.e., expression of the 3' exonuclease Trex2). Finally, several C-NHEJ factors are required for the increase in rearrangement frequency caused by inhibition of the ATM kinase. We also examined ATM effectors and found that H2AX shows a similar influence as ATM, whereas the influence of ATM on this rearrangement seems independent of 53BP1. We suggest that the contribution of the C-NHEJ pathway to the formation of a 0.4-Mbp deletion rearrangement is enhanced in ATM-deficient cells.

  19. Serine 249 phosphorylation by ATM protein kinase regulates hepatocyte nuclear factor-1α transactivation.

    PubMed

    Zhao, Long; Chen, Hui; Zhan, Yi-Qun; Li, Chang-Yan; Ge, Chang-Hui; Zhang, Jian-Hong; Wang, Xiao-Hui; Yu, Miao; Yang, Xiao-Ming

    2014-07-01

    Hepatocyte nuclear factor-1 alpha (HNF1α) exerts important effects on gene expression in multiple tissues. Several studies have directly or indirectly supported the role of phosphorylation processes in the activity of HNF1α. However, the molecular mechanism of this phosphorylation remains largely unknown. Using microcapillary liquid chromatography MS/MS and biochemical assays, we identified a novel phosphorylation site in HNF1α at Ser249. We also found that the ATM protein kinase phosphorylated HNF1α at Ser249 in vitro in an ATM-dependent manner and that ATM inhibitor KU55933 treatment inhibited phosphorylation of HNF1α at Ser249 in vivo. Coimmunoprecipitation assays confirmed the association between HNF1α and ATM. Moreover, ATM enhanced HNF1α transcriptional activity in a dose-dependent manner, whereas the ATM kinase-inactive mutant did not. The use of KU55933 confirmed our observation. Compared with wild-type HNF1α, a mutation in Ser249 resulted in a pronounced decrease in HNF1α transactivation, whereas no dominant-negative effect was observed. The HNF1αSer249 mutant also exhibited normal nuclear localization but decreased DNA-binding activity. Accordingly, the functional studies of HNF1αSer249 mutant revealed a defect in glucose metabolism. Our results suggested that ATM regulates the activity of HNF1α by phosphorylation of serine 249, particularly in glucose metabolism, which provides valuable insights into the undiscovered mechanisms of ATM in the regulation of glucose homeostasis.

  20. Asynchronous Transfer Mode (ATM) Switch Technology and Vendor Survey

    NASA Technical Reports Server (NTRS)

    Berry, Noemi

    1995-01-01

    Asynchronous Transfer Mode (ATM) switch and software features are described and compared in order to make switch comparisons meaningful. An ATM switch's performance cannot be measured solely based on its claimed switching capacity; traffic management and congestion control are emerging as the determining factors in an ATM network's ultimate throughput. Non-switch ATM products and experiences with actual installations of ATM networks are described. A compilation of select vendor offerings as of October 1994 is provided in chart form.

  1. EGb 761 protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury and exerts inhibitory effect on ATM pathway.

    PubMed

    Zhang, Chao; Wang, Deng-Feng; Zhang, Zhuang; Han, Dong; Yang, Kan

    2016-12-14

    Ginkgo biloba extract (EGb 761) has been widely clinically used to reduce myocardial ischemia reperfusion injury (MIRI). Microvascular endothelial cells (MVECs) may be a proper cellular model in vitro for the effect and mechanism study against MIRI. However, the effect of EGb 761 on MVECs resisting hypoxia/reoxygenation (H/R) injury is little reported. In this study, H/R-injuried MVECs were treated with EGb 761, then cell viability, apoptosis, ROS production, SOD activity, caspase-3 activity, and the protein level of ATM, γ-H2AX, p53, Bax were measured. ATM siRNA was transfected to study the changes of protein in ATM pathway. EGb 761 presented protective effect on H/R-injuried MVECs with decreasing cell death, apoptosis and ROS, and elevated SOD activity. Next, EGb 761 could inhibit H/R-induced ATM, γ-H2AX, p53, Bax in a dose-dependent manner. Moreover, ATM siRNA also could inhibit H/R-induced ATM, γ-H2AX, p53, Bax. Overall, these findings verify EGb 761 protects cardiac MVECs from H/R injury, and for the first time, illustrate the influence on ATM pathway and apoptosis of EGb 761 via dampening ROS.

  2. Regulation of microglial expression of integrins by poly(ADP-ribose) polymerase-1.

    PubMed

    Ullrich, O; Diestel, A; Eyüpoglu, I Y; Nitsch, R

    2001-12-01

    Excitotoxic brain lesions initially result in the primary destruction of brain parenchyma, after which microglial cells migrate towards the sites of injury. At these sites, the cells produce large quantities of oxygen radicals and cause secondary damage that accounts for most of the loss of brain function. Here we show that this microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, regulated by the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) through the formation of a nuclear PARP-NF-kappaB-protein complex. Downregulation of PARP or CD11a by transfection with antisense DNA abrogated microglial migration almost completely and prevented neurons from secondary damage.

  3. Emerging role of polymerase-1 and transcript release factor (PTRF/ Cavin-1) in health and disease.

    PubMed

    Low, Jin-Yih; Nicholson, Helen D

    2014-09-01

    Polymerase-1 and release transcript factor (PTRF) was initially reported to be involved in the termination of the transcription process. More recently, it has been implicated in the formation of caveolae, cave-like structures in the plasma membrane. The effects of PTRF related to caveolae suggest that this protein may play important roles in health and disease. PTRF is highly expressed in various cells, including adipocytes, osteoblasts and muscle (cardiac, skeletal and smooth) cells. The role of PTRF in prostate cancer has been recently reviewed but there is growing evidence that PTRF is involved in other physiological processes such as cell repair and the regulation of glucose and lipid metabolism and, furthermore, altered expression of PTRF may be associated with disease. This review discusses the emerging role of PTRF in health and disease.

  4. ATM kinase sustains HER2 tumorigenicity in breast cancer.

    PubMed

    Stagni, Venturina; Manni, Isabella; Oropallo, Veronica; Mottolese, Marcella; Di Benedetto, Anna; Piaggio, Giulia; Falcioni, Rita; Giaccari, Danilo; Di Carlo, Selene; Sperati, Francesca; Cencioni, Maria Teresa; Barilà, Daniela

    2015-04-16

    ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitro and in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATM's tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor.

  5. Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages.

    PubMed

    Shrestha, Elina; Hussein, Maryem A; Savas, Jeffery N; Ouimet, Mireille; Barrett, Tessa J; Leone, Sarah; Yates, John R; Moore, Kathryn J; Fisher, Edward A; Garabedian, Michael J

    2016-05-20

    Liver X receptors (LXR) are oxysterol-activated nuclear receptors that play a central role in reverse cholesterol transport through up-regulation of ATP-binding cassette transporters (ABCA1 and ABCG1) that mediate cellular cholesterol efflux. Mouse models of atherosclerosis exhibit reduced atherosclerosis and enhanced regression of established plaques upon LXR activation. However, the coregulatory factors that affect LXR-dependent gene activation in macrophages remain to be elucidated. To identify novel regulators of LXR that modulate its activity, we used affinity purification and mass spectrometry to analyze nuclear LXRα complexes and identified poly(ADP-ribose) polymerase-1 (PARP-1) as an LXR-associated factor. In fact, PARP-1 interacted with both LXRα and LXRβ. Both depletion of PARP-1 and inhibition of PARP-1 activity augmented LXR ligand-induced ABCA1 expression in the RAW 264.7 macrophage line and primary bone marrow-derived macrophages but did not affect LXR-dependent expression of other target genes, ABCG1 and SREBP-1c. Chromatin immunoprecipitation experiments confirmed PARP-1 recruitment at the LXR response element in the promoter of the ABCA1 gene. Further, we demonstrated that LXR is poly(ADP-ribosyl)ated by PARP-1, a potential mechanism by which PARP-1 influences LXR function. Importantly, the PARP inhibitor 3-aminobenzamide enhanced macrophage ABCA1-mediated cholesterol efflux to the lipid-poor apolipoprotein AI. These findings shed light on the important role of PARP-1 on LXR-regulated lipid homeostasis. Understanding the interplay between PARP-1 and LXR may provide insights into developing novel therapeutics for treating atherosclerosis.

  6. NPP After Launch: Characterizing ATMS Performance

    NASA Technical Reports Server (NTRS)

    Lambrigtsen, Bjorn

    2011-01-01

    The NPOESS Preparatory Project (NPP) mission is scheduled to launch in the fall of 2011. Although several teams from the government and the instrument contractor will be assessing and characterizing the performance of the Advanced Technology Microwave Sounder (ATMS) and the Cross-track Infrared Sounder (CrIS) sounding suite, the NASA NPP Science Team will be paying particular attention to the aspects of these sensors that affect their utility for atmospheric and climate research. In this talk we discuss relevant aspects of ATMS and our post launch analysis approach.

  7. Co-targeting Deoxyribonucleic Acid–Dependent Protein Kinase and Poly(Adenosine Diphosphate-Ribose) Polymerase-1 Promotes Accelerated Senescence of Irradiated Cancer Cells

    SciTech Connect

    Azad, Arun; Bukczynska, Patricia; Jackson, Susan; Haput, Ygal; Cullinane, Carleen; McArthur, Grant A.; Solomon, Benjamin

    2014-02-01

    Purpose: To examine the effects of combined blockade of DNA-dependent protein kinase (DNA-PK) and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) on accelerated senescence in irradiated H460 and A549 non-small cell lung cancer cells. Methods and Materials: The effects of KU5788 and AG014699 (inhibitors of DNA-PK and PARP-1, respectively) on clonogenic survival, DNA double-strand breaks (DSBs), apoptosis, mitotic catastrophe, and accelerated senescence in irradiated cells were examined in vitro. For in vivo experiments, H460 xenografts established in athymic nude mice were treated with BEZ235 (a DNA-PK, ATM, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor) and AG014699 to determine effects on proliferation, DNA DSBs, and accelerated senescence after radiation. Results: Compared with either inhibitor alone, combination treatment with KU57788 and AG014699 reduced postradiation clonogenic survival and significantly increased persistence of Gamma-H2AX (γH2AX) foci in irradiated H460 and A549 cells. Notably, these effects coincided with the induction of accelerated senescence in irradiated cells as reflected by positive β-galactosidase staining, G2-M cell-cycle arrest, enlarged and flattened cellular morphology, increased p21 expression, and senescence-associated cytokine secretion. In irradiated H460 xenografts, concurrent therapy with BEZ235 and AG014699 resulted in sustained Gamma-H2AX (γH2AX) staining and prominent β-galactosidase activity. Conclusion: Combined DNA-PK and PARP-1 blockade increased tumor cell radiosensitivity and enhanced the prosenescent properties of ionizing radiation in vitro and in vivo. These data provide a rationale for further preclinical and clinical testing of this therapeutic combination.

  8. Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation

    PubMed Central

    Blake, Sophia M; Stricker, Stefan H; Halavach, Hanna; Poetsch, Anna R; Cresswell, George; Kelly, Gavin; Kanu, Nnennaya; Marino, Silvia; Luscombe, Nicholas M; Pollard, Steven M; Behrens, Axel

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors. DOI: http://dx.doi.org/10.7554/eLife.08711.001 PMID:26984279

  9. Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation.

    PubMed

    Blake, Sophia M; Stricker, Stefan H; Halavach, Hanna; Poetsch, Anna R; Cresswell, George; Kelly, Gavin; Kanu, Nnennaya; Marino, Silvia; Luscombe, Nicholas M; Pollard, Steven M; Behrens, Axel

    2016-03-17

    Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors.

  10. Role of ATM in bystander signaling between human monocytes and lung adenocarcinoma cells.

    PubMed

    Ghosh, Somnath; Ghosh, Anu; Krishna, Malini

    2015-12-01

    The response of a cell or tissue to ionizing radiation is mediated by direct damage to cellular components and indirect damage mediated by radiolysis of water. Radiation affects both irradiated cells and the surrounding cells and tissues. The radiation-induced bystander effect is defined by the presence of biological effects in cells that were not themselves in the field of irradiation. To establish the contribution of the bystander effect in the survival of the neighboring cells, lung carcinoma A549 cells were exposed to gamma-irradiation, 2Gy. The medium from the irradiated cells was transferred to non-irradiated A549 cells. Irradiated A549 cells as well as non-irradiated A549 cells cultured in the presence of medium from irradiated cells showed decrease in survival and increase in γ-H2AX and p-ATM foci, indicating a bystander effect. Bystander signaling was also observed between different cell types. Phorbol-12-myristate-13-acetate (PMA)-stimulated and gamma-irradiated U937 (human monocyte) cells induced a bystander response in non-irradiated A549 (lung carcinoma) cells as shown by decreased survival and increased γ-H2AX and p-ATM foci. Non-stimulated and/or irradiated U937 cells did not induce such effects in non-irradiated A549 cells. Since ATM protein was activated in irradiated cells as well as bystander cells, it was of interest to understand its role in bystander effect. Suppression of ATM with siRNA in A549 cells completely inhibited bystander effect in bystander A549 cells. On the other hand suppression of ATM with siRNA in PMA stimulated U937 cells caused only a partial inhibition of bystander effect in bystander A549 cells. These results indicate that apart from ATM, some additional factor may be involved in bystander effect between different cell types.

  11. WWOX guards genome stability by activating ATM.

    PubMed

    Hazan, Idit; Abu-Odeh, Mohammad; Hofmann, Thomas G; Aqeilan, Rami I

    2015-01-01

    Common fragile sites (CFSs) tend to break upon replication stress and have been suggested to be "hot spots" for genomic instability. Recent evidence, however, implies that in the wake of DNA damage, WW domain-containing oxidoreductase (WWOX, the gene product of the FRA16D fragile site), associates with ataxia telangiectasia-mutated (ATM) and regulates its activation to maintain genomic integrity.

  12. Asynchronous Transfer Mode (ATM) Technology: An Overview

    DTIC Science & Technology

    1993-06-04

    IEEE Communications Magazine , April 1992, pp. 60 - 68. [5] Stallings, W.: Handbook of Computer-Communications Standards, Volume 1: The Open Systems...Conf. Digest, paper ThH3, San Jose. CA, Feb. 2-7, 1992, p.225. [14] Newman, P.: ATM Technology for Corporate Networks. IEEE Communications Magazine . April

  13. Terminal Area ATM Research at NASA Ames

    NASA Technical Reports Server (NTRS)

    Tobias, Leonard

    1997-01-01

    The presentation will highlight the following: (1) A brief review of ATC research underway 15 years ago; (2) A summary of Terminal Area ATM Tool Development ongoing at NASA Ames; and (3) A projection of research activities 10-15 years from now.

  14. Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

    PubMed Central

    Zaremba, T; Ketzer, P; Cole, M; Coulthard, S; Plummer, E R; Curtin, N J

    2009-01-01

    Background: Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding enzyme activated by DNA breaks and involved in DNA repair and other cellular processes. Poly(ADP-ribose) polymerase activity can be higher in cancer than in adjacent normal tissue, but cancer predisposition is reported to be greater in individuals with a single-nucleotide polymorphism (SNP) V762A (T2444C) in the catalytic domain that reduces PARP-1 activity. Methods: To resolve these divergent observations, we determined PARP-1 polymorphisms, PARP-1 protein expression and activity in a panel of 19 solid and haematological, adult and paediatric human cancer cell lines. Results: There was a wide variation in PARP activity in the cell line panel (coefficient of variation, CV=103%), with the lowest and the highest activity being 2460 pmol PAR/106 (HS-5 cells) and 85 750 pmol PAR/106 (NGP cells). Lower variation (CV=32%) was observed in PARP-1 protein expression with the lowest expression being 2.0 ng μg−1 (HS-5 cells) and the highest being 7.1 ng μg−1 (ML-1 cells). The mean activity in the cancer cells was 45-fold higher than the mean activity in normal human lymphocytes and the PARP-1 protein levels were 23-fold higher. Conclusions: Surprisingly, there was no significant correlation between PARP activity and PARP-1 protein level or the investigated polymorphisms, T2444C and CA. PMID:19568233

  15. Remote facility sharing with ATM networks [PC based ATM Link Delay Simulator (LDS)]. Final report

    SciTech Connect

    Kung, H. T.

    2001-06-01

    The ATM Link Delay Simulator (LDS) adds propagation delay to the ATM link on which it is installed, to allow control of link propagation delay in network protocol experiments simulating an adjustable piece of optical fiber. Our LDS simulates a delay of between 1.5 and 500 milliseconds and is built with commodity PC hardware, only the ATM network interface card is not generally available. Our implementation is special in that it preserves the exact spacing of ATM data cells a feature that requires sustained high performance. Our implementation shows that applications demanding sustained high performance are possible on commodity PC hardware. This illustrates the promise that PC hardware has for adaptability to demanding specialized testing of high speed network.

  16. FACET: Future ATM Concepts Evaluation Tool

    NASA Technical Reports Server (NTRS)

    Bilmoria, Karl D.; Banavar, Sridhar; Chatterji, Gano B.; Sheth, Kapil S.; Grabbe, Shon

    2000-01-01

    FACET (Future ATM Concepts Evaluation Tool) is an Air Traffic Management research tool being developed at the NASA Ames Research Center. This paper describes the design, architecture and functionalities of FACET. The purpose of FACET is to provide E simulation environment for exploration, development and evaluation of advanced ATM concepts. Examples of these concepts include new ATM paradigms such as Distributed Air-Ground Traffic Management, airspace redesign and new Decision Support Tools (DSTs) for controllers working within the operational procedures of the existing air traffic control system. FACET is currently capable of modeling system-wide en route airspace operations over the contiguous United States. Airspace models (e.g., Center/sector boundaries, airways, locations of navigation aids and airports) are available from databases. A core capability of FACET is the modeling of aircraft trajectories. Using round-earth kinematic equations, aircraft can be flown along flight plan routes or great circle routes as they climb, cruise and descend according to their individual aircraft-type performance models. Performance parameters (e.g., climb/descent rates and speeds, cruise speeds) are obtained from data table lookups. Heading, airspeed and altitude-rate dynamics are also modeled. Additional functionalities will be added as necessary for specific applications. FACET software is written in Java and C programming languages. It is platform-independent, and can be run on a variety of computers. FACET has been designed with a modular software architecture to enable rapid integration of research prototype implementations of new ATM concepts. There are several advanced ATM concepts that are currently being implemented in FACET airborne separation assurance, dynamic density predictions, airspace redesign (re-sectorization), benefits of a controller DST for direct-routing, and the integration of commercial space transportation system operations into the U.S. National

  17. ATM protein is deficient in over 40% of lung adenocarcinomas.

    PubMed

    Villaruz, Liza C; Jones, Helen; Dacic, Sanja; Abberbock, Shira; Kurland, Brenda F; Stabile, Laura P; Siegfried, Jill M; Conrads, Thomas P; Smith, Neil R; O'Connor, Mark J; Pierce, Andrew J; Bakkenist, Christopher J

    2016-09-06

    Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year.

  18. A Managerial Analysis of ATM in Facilitating Distance Education.

    ERIC Educational Resources Information Center

    Littman, Marlyn Kemper

    In this paper, the fundamental characteristics and capabilities of ATM (Asynchronous Transfer Mode) networks in a distance learning environment are examined. Current and projected ATM applications are described, and issues and challenges associated with developing ATM networking solutions for instructional delivery are explored. Other topics…

  19. Transcriptional regulation by Poly(ADP-ribose) polymerase-1 during T cell activation

    PubMed Central

    Saenz, Luis; Lozano, Juan J; Valdor, Rut; Baroja-Mazo, Alberto; Ramirez, Pablo; Parrilla, Pascual; Aparicio, Pedro; Sumoy, Lauro; Yélamos, José

    2008-01-01

    Background Accumulating evidence suggests an important role for the enzyme poly(ADP-ribose) polymerase-1 (PARP-1) as an integral part of the gene expression regulatory machinery during development and in response to specific cellular signals. PARP-1 might modulate gene expression through its catalytic activity leading to poly(ADP-ribosyl)ation of nuclear proteins or by its physical association with relevant proteins. Recently, we have shown that PARP-1 is activated during T cell activation. However, the proposed role of PARP-1 in reprogramming T cell gene expression upon activation remains largely unexplored. Results In the present study we use oligonucleotide microarray analysis to gain more insight into the role played by PARP-1 during the gene expression reprogramming that takes place in T cells upon activation with anti-CD3 stimulation alone, or in combination with anti-CD28 co-stimulation. We have identified several groups of genes with expression modulated by PARP-1. The expression of 129 early-response genes to anti-CD3 seems to be regulated by PARP-1 either in a positive (45 genes) or in a negative manner (84 genes). Likewise, in the presence of co-stimulation (anti-CD3 + anti-CD28 stimulation), the expression of 203 genes is also regulated by PARP-1 either up (173 genes) or down (30 genes). Interestingly, PARP-1 deficiency significantly alters expression of genes associated with the immune response such as chemokines and genes involved in the Th1/Th2 balance. Conclusion This study provides new insights into changes in gene expression mediated by PARP-1 upon T cell activation. Pathway analysis of PARP-1 as a nuclear signalling molecule in T cells would be of relevance for the future development of new therapeutic approaches targeting PARP-1 in the acquired immune response. PMID:18412984

  20. Poly(ADP-ribose)polymerase-1 (PARP1) controls adipogenic gene expression and adipocyte function.

    PubMed

    Erener, Süheda; Hesse, Mareike; Kostadinova, Radina; Hottiger, Michael O

    2012-01-01

    Poly(ADP-ribose)polymerase-1 (PARP1) is a chromatin-associated enzyme that was described to affect chromatin compaction. Previous reports suggested a dynamic modulation of the chromatin landscape during adipocyte differentiation. We thus hypothesized that PARP1 plays an important transcriptional role in adipogenesis and metabolism and therefore used adipocyte development and function as a model to elucidate the molecular action of PARP1 in obesity-related diseases. Our results show that PARP1-dependent ADP-ribose polymer (PAR) formation increases during adipocyte development and, at late time points of adipogenesis, is involved in the sustained expression of PPARγ2 and of PPARγ2 target genes. During adipogenesis, PARP1 was recruited to PPARγ2 target genes such as CD36 or aP2 in a PAR-dependent manner. Our results also reveal a PAR-dependent decrease in repressory histone marks (e.g. H3K9me3) and an increase in stimulatory marks (e.g. H3K4me3) at the PPARγ2 promoter, suggesting that PARP1 may exert its regulatory function during adipogenesis by altering histone marks. Interestingly, activation of PARP1 enzymatic activity was prevented with a topoisomerase II inhibitor. These data hint at topoisomerase II-dependent, transient, site-specific double-strand DNA breaks as the cause for poly(ADP)-ribose formation, adipogenic gene expression, and adipocyte function. Together, our study identifies PARP1 as a critical regulator of PPARγ2-dependent gene expression with implications in adipocyte function and obesity-related disease models.

  1. Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity

    PubMed Central

    Duan, Yuntao; Gross, Robert A; Sheu, Shey-Shing

    2007-01-01

    Mitochondrial Ca2+ uptake and poly(ADP-ribose) polymerase-1 (PARP-1) activation are both required for glutamate-induced excitotoxic neuronal death. Since activation of the glutamate receptors can induce increased levels of reactive oxygen species (ROS), we investigated the relationship of mitochondrial Ca2+ uptake and ROS generation, and the possibility that ROS increase is a required signal for PARP-1 activation in cultured striatal neurons. Based on the spatial profile of NMDA-induced ROS generation, we found that only mitochondria showed a significant ROS increase within 30 min after NMDA receptor activation. This ROS increase was inhibited by the mitochondrial complex inhibitors rotenone and oligomycin, but not by the cytosolic phospholipase A2 or xanthine oxidase inhibitors. Mitochondrial ROS generation was also inhibited by both removal of Ca2+ from extracellular medium and blockage of mitochondrial Ca2+ uptake by either a mitochondrial uncoupler or a Ca2+ uniporter inhibitor. Furthermore, both DNA damage and PARP-1 activation induced by NMDA treatment was inhibited by blocking mitochondrial Ca2+ uptake or by antioxidants. Our results demonstrate that ROS production during the early stage of acute excitotoxicity derives primarily from mitochondria and is Ca2+-dependent. More importantly, the increase of mitochondrial ROS serves as a signal for PARP-1 activation, suggesting that concomitant mitochondrial Ca2+ uptake and PARP-1 activation constitute a unified mechanism for excitotoxic neuronal death. PMID:17947304

  2. ATM photoheliograph. [at a solar observatory

    NASA Technical Reports Server (NTRS)

    Prout, R. A.

    1975-01-01

    The design and fabrication are presented of a 65 cm photoheliograph functional verification unit (FVU) installed in a major solar observatory. The telescope is used in a daily program of solar observation while serving as a test bed for the development of instrumentation to be included in early space shuttle launched solar telescopes. The 65 cm FVU was designed to be mechanically compatible with the ATM spar/canister and would be adaptable to a second ATM flight utilizing the existing spar/canister configuration. An image motion compensation breadboard and a space-hardened, remotely tuned H alpha filter, as well as solar telescopes of different optical configurations or increased aperture are discussed.

  3. DNA double-strand breaks activate ATM independent of mitochondrial dysfunction in A549 cells.

    PubMed

    Kalifa, Lidza; Gewandter, Jennifer S; Staversky, Rhonda J; Sia, Elaine A; Brookes, Paul S; O'Reilly, Michael A

    2014-10-01

    Excessive nuclear or mitochondrial DNA damage can lead to mitochondrial dysfunction, decreased energy production, and increased generation of reactive oxygen species (ROS). Although numerous cell signaling pathways are activated when cells are injured, the ataxia telangiectasia mutant (ATM) protein has emerged as a major regulator of the response to both mitochondrial dysfunction and nuclear DNA double-strand breaks (DSBs). Because mitochondrial dysfunction is often a response to excessive DNA damage, it has been difficult to determine whether nuclear and/or mitochondrial DNA DSBs activate ATM independent of mitochondrial dysfunction. In this study, mitochondrial and nuclear DNA DSBs were generated in the A549 human lung adenocarcinoma cell line by infecting with retroviruses expressing the restriction endonuclease PstI fused to a mitochondrial targeting sequence (MTS) or nuclear localization sequence (NLS) and a hemagglutinin antigen epitope tag (HA). Expression of MTS-PstI-HA or NLS-PstI-HA activated the DNA damage response defined by phosphorylation of ATM, the tumor suppressor protein p53 (TP53), KRAB-associated protein (KAP)-1, and structural maintenance of chromosomes (SMC)-1. Phosphorylated ATM and SMC1 were detected in nuclear fractions, whereas phosphorylated TP53 and KAP1 were detected in both mitochondrial and nuclear fractions. PstI also enhanced expression of the cyclin-dependent kinase inhibitor p21 and inhibited cell growth. This response to DNA damage occurred in the absence of detectable mitochondrial dysfunction and excess production of ROS. These findings reveal that DNA DSBs are sufficient to activate ATM independent of mitochondrial dysfunction and suggest that the activated form of ATM and some of its substrates are restricted to the nuclear compartment, regardless of the site of DNA damage.

  4. SV40 utilizes ATM kinase activity to prevent non-homologous end joining of broken viral DNA replication products.

    PubMed

    Sowd, Gregory A; Mody, Dviti; Eggold, Joshua; Cortez, David; Friedman, Katherine L; Fanning, Ellen

    2014-12-01

    Simian virus 40 (SV40) and cellular DNA replication rely on host ATM and ATR DNA damage signaling kinases to facilitate DNA repair and elicit cell cycle arrest following DNA damage. During SV40 DNA replication, ATM kinase activity prevents concatemerization of the viral genome whereas ATR activity prevents accumulation of aberrant genomes resulting from breakage of a moving replication fork as it converges with a stalled fork. However, the repair pathways that ATM and ATR orchestrate to prevent these aberrant SV40 DNA replication products are unclear. Using two-dimensional gel electrophoresis and Southern blotting, we show that ATR kinase activity, but not DNA-PK(cs) kinase activity, facilitates some aspects of double strand break (DSB) repair when ATM is inhibited during SV40 infection. To clarify which repair factors associate with viral DNA replication centers, we examined the localization of DSB repair proteins in response to SV40 infection. Under normal conditions, viral replication centers exclusively associate with homology-directed repair (HDR) and do not colocalize with non-homologous end joining (NHEJ) factors. Following ATM inhibition, but not ATR inhibition, activated DNA-PK(cs) and KU70/80 accumulate at the viral replication centers while CtIP and BLM, proteins that initiate 5' to 3' end resection during HDR, become undetectable. Similar to what has been observed during cellular DSB repair in S phase, these data suggest that ATM kinase influences DSB repair pathway choice by preventing the recruitment of NHEJ factors to replicating viral DNA. These data may explain how ATM prevents concatemerization of the viral genome and promotes viral propagation. We suggest that inhibitors of DNA damage signaling and DNA repair could be used during infection to disrupt productive viral DNA replication.

  5. WWOX guards genome stability by activating ATM

    PubMed Central

    Hazan, Idit; Abu-Odeh, Mohammad; Hofmann, Thomas G; Aqeilan, Rami I

    2015-01-01

    Common fragile sites (CFSs) tend to break upon replication stress and have been suggested to be “hot spots” for genomic instability. Recent evidence, however, implies that in the wake of DNA damage, WW domain-containing oxidoreductase (WWOX, the gene product of the FRA16D fragile site), associates with ataxia telangiectasia-mutated (ATM) and regulates its activation to maintain genomic integrity. PMID:27308504

  6. Preservation of methane hydrate at 1 atm

    USGS Publications Warehouse

    Stern, L.A.; Circone, S.; Kirby, S.H.; Durham, W.B.

    2001-01-01

    A "pressure-release" method that enables reproducible bulk preservation of pure, porous, methane hydrate at conditions 50 to 75 K above its equilibrium T (193 K) at 1 atm is refined. The amount of hydrate preserved by this method appears to be greatly in excess of that reported in the previous citations, and is likely the result of a mechanism different from ice shielding.

  7. ATM Coastal Topography-Mississippi, 2001

    USGS Publications Warehouse

    Nayegandhi, Amar; Yates, Xan; Brock, John C.; Sallenger, A.H.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of the Mississippi coastline, from Lakeshore to Petit Bois Island, acquired September 9-10, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS

  8. ATM Coastal Topography-Alabama 2001

    USGS Publications Warehouse

    Nayegandhi, Amar; Yates, Xan; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of Lidar-derived first surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of the Alabama coastline, acquired October 3-4, 2001. The datasets are made available for use as a management tool to research scientists and natural resource managers. An innovative scanning Lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning Lidar system that measures high-resolution topography of the land surface, and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of Lidar data in an interactive or batch mode. Modules for pre-survey flight line definition, flight path plotting, Lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS is routinely used to create maps that

  9. Activation of ATM by DNA Damaging Agents

    DTIC Science & Technology

    2005-09-01

    serine 139. Pretreatment of cells with NAC partially, peroxide dismutase and glutathione peroxidase - 1 (37). This but significantly, attenuated the... Gy , concentrations of wortmannin (lanes 3-5) for 30 min prior to the addi- 2 h) (Fig. 4A). tion of 1 gm doxorubicin (lanes 2-5) and further incubation...AD Award Number: DAMD17-02- 1 -0318 TITLE: Activation of ATM by DNA Damaging Agents PRINCIPAL INVESTIGATOR: Ebba U. Kurz, Ph.D. Susan P. Lees-Miller

  10. Activation of ATM by DNA Damaging Agents

    DTIC Science & Technology

    2004-09-01

    all cases, observe a dependence on ATM for phosphorylation. These phosphorylation events are attenuated by pretreatment of cells with N-acetyl cysteine...Chemistry requested that I evaluate the effect of N-acetyl cysteine pretreatment on doxorubicin-induced phosphorylation of histone H2AX at serine 139. In...S33/35, T68) in response to doxorubicin treatment * I detennined that phosphorylation at these sites can be partially attenuated by pretreatment of

  11. Experiences with the AEROnet/PSCN ATM Prototype

    NASA Technical Reports Server (NTRS)

    Kurak, Richard S.; Lisotta, Anthony J.; McCabe, James D.; Nothaft, Alfred E.; Russell, Kelly R.; Lasinski, T. A. (Technical Monitor)

    1995-01-01

    This paper discusses the experience gained by the AEROnet/PSCN networking team in deploying a prototype Asynchronous Transfer Mode (ATM) based network as part of the wide-area network for the Numerical Aerodynamic Simulation (NAS) Program at NASA Ames Research Center. The objectives of this prototype were to test concepts in using ATM over wide-area Internet Protocol (IP) networks and measure end-to-end system performance. This testbed showed that end-to-end ATM over a DS3 reaches approximately 80% of the throughput achieved from a FDDI to DS3 network. The 20% reduction in through-put can be attributed to the overhead associated with running ATM. As a result, we conclude that if the loss in capacity due to ATM overhead is balanced by the reduction in cost of ATM services, as compared to dedicated circuits, then ATM can be a viable alternative.

  12. Intercalibrating and Validating Saphir and Atms Observations

    NASA Astrophysics Data System (ADS)

    Moradi, I.; Ferraro, R. R.

    2014-12-01

    We present the results of evaluating observations from microwave instruments aboard the Suomi National Polar-orbiting Partnership (NPP, ATMS instrument) and Megha-Tropiques (SAPHIR instrument) satellites. ATMS is a cross-track microwave sounder that currently flying on the Suomi National Polar-orbiting Partnership (S-NPP) satellite, launched in October 2011, which is in a Sun-synchronous orbit with the ascending equatorial crossing time at 01:30 a.m. Megha-Tropiques, launched in Nov 2011, is a low-inclination satellite meaning that the satellite only visits the tropical band between 30 S and 30 N. SAPHIR is a microwave humidity sounder with 6 channels operating at the frequencies close to the water vapor absorption line at 183 GHz. Megha-Tropiques revisits the tropical regions several times a day and provide a great capability for inter-calibrating the observations with the polar orbiting satellites. The study includes inter-comparison and inter-calibration of observations of similar channels from the two instruments, evaluation of the satellite data using high-quality radiosonde data from Atmospheric Radiation Measurement Program and GPS Radio Occultaion Observations from COSMIC mission, as well as geolocation error correction. The results of this study are valuable for generating climate data records from these instruments as well as for extending current climate data records from similar instruments such as AMSU-B and MHS to the ATMS and SAPHIR instruments.

  13. Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence.

    PubMed

    Nair, Raji R; Bagheri, Meisam; Saini, Deepak Kumar

    2015-01-15

    Cells exposed to genotoxic stress induce cellular senescence through a DNA damage response (DDR) pathway regulated by ATM kinase and reactive oxygen species (ROS). Here, we show that the regulatory roles for ATM kinase and ROS differ during induction and maintenance of cellular senescence. Cells treated with different genotoxic agents were analyzed using specific pathway markers and inhibitors to determine that ATM kinase activation is directly proportional to the dose of the genotoxic stress and that senescence initiation is not dependent on ROS or the p53 status of cells. Cells in which ROS was quenched still activated ATM and initiated the DDR when insulted, and progressed normally to senescence. By contrast, maintenance of a viable senescent state required the presence of ROS as well as activated ATM. Inhibition or removal of either of the components caused cell death in senescent cells, through a deregulated ATM-ROS axis. Overall, our work demonstrates existence of an intricate temporal hierarchy between genotoxic stress, DDR and ROS in cellular senescence. Our model reports the existence of different stages of cellular senescence with distinct regulatory networks.

  14. Isolation and characterization of Xenopus ATM (X-ATM): expression, localization, and complex formation during oogenesis and early development.

    PubMed

    Robertson, K; Hensey, C; Gautier, J

    1999-11-25

    ATM, the gene product mutated in Ataxia Telangiectasia (A-T) encodes a 350-kDa protein involved in the regulation of several cellular responses to DNA breaks. We used a degenerate PCR-based strategy to isolate a partial clone of X-ATM, the Xenopus homologue of human ATM. Sequence analysis and confirmed that the clone was most closely related to human ATM. Xenopus ATM protein (X-ATM) is 85% identical to human ATM within the kinase domain and 71% identical over the carboxyl-terminal half of the protein. Polyclonal antibodies raised against recombinant X-ATM are highly specific for the ATM protein and recognize a single polypeptide of 370-kDa in oocytes, embryos, egg extracts and a Xenopus cell line. We found that X-ATM was expressed maternally in eggs and as early as stage II pre-vitellogenic oocytes, and the protein and mRNA were present at relatively constant levels throughout development. Subcellular fractionation showed that the protein was nuclear in both the female and male germlines. The level of X-ATM protein did not change throughout the meiotic divisions or the synchronous mitotic cycles of cleavage stage embryos. In addition, we did not observe any change in the level or mobility of X-ATM protein following gamma-irradiation of embryos. Finally, we also demonstrated that X-ATM was present in a high molecular weight complex of approximately 500 kDa containing the X-ATM protein and other, as yet unidentified component(s).

  15. Linking ATM Promoter Methylation to Cell Cycle Protein Expression in Brain Tumor Patients: Cellular Molecular Triangle Correlation in ATM Territory.

    PubMed

    Mehdipour, P; Karami, F; Javan, Firouzeh; Mehrazin, M

    2015-08-01

    Ataxia telangiectasia mutated (ATM) is a key gene in DNA double-strand break (DSB), and therefore, most of its disabling genetic alterations play an important initiative role in many types of cancer. However, the exact role of ATM gene and its epigenetic alterations, especially promoter methylation in different grades of brain tumors, remains elusive. The current study was conducted to query possible correlations among methylation statue of ATM gene, ATM/ retinoblastoma (RB) protein expression, D1853N ATM polymorphism, telomere length (TL), and clinicopathological characteristics of various types of brain tumors. Isolated DNA from 30 fresh tissues was extracted from different types of brain tumors and two brain tissues from deceased normal healthy individuals. DNAs were treated with bisulfate sodium using DNA modification kit (Qiagen). Methylation-specific polymerase chain reaction (MSP-PCR) was implicated to determine the methylation status of treated DNA templates confirmed by promoter sequencing. Besides, the ATM and RB protein levels were determined by immunofluorescence (IF) assay using monoclonal mouse antihuman against ATM, P53, and RB proteins. To achieve an interactive correlation, the methylation data were statistically analyzed by considering TL and D1853N ATM polymorphism. More than 73% of the brain tumors were methylated in ATM gene promoter. There was strong correlation between ATM promoter methylation and its protein expression (p < 0.001). As a triangle, meaningful correlation was also found between methylated ATM promoter and ATM protein expression with D1853N ATM polymorphism (p = 0.01). ATM protein expression was not in line with RB protein expression while it was found to be significantly correlated with ATM promoter methylation (p = 0.01). There was significant correlation between TL neither with ATM promoter methylation nor with ATM protein expression nor with D1853N polymorphism. However, TL has shown strong correlation with patient's age and

  16. Double strand break repair by homologous recombination is regulated by cell cycle-independent signaling via ATM in human glioma cells.

    PubMed

    Golding, Sarah E; Rosenberg, Elizabeth; Khalil, Ashraf; McEwen, Alison; Holmes, Matthew; Neill, Steven; Povirk, Lawrence F; Valerie, Kristoffer

    2004-04-09

    To investigate double strand break (DSB) repair and signaling in human glioma cells, we stably transfected human U87 (ATM(+), p53(+)) glioma cells with a plasmid having a single I-SceI site within an inactive green fluorescent protein (GFP) expression cassette, allowing for the detection of homologous recombination repair (HRR) by GFP expression. HRR and nonhomologous end joining (NHEJ) were also determined by PCR. DSB repair was first detected at 12 h postinfection with an adenovirus expressing I-SceI with repair reaching plateau levels between 24 and 48 h. Within this time frame, NHEJ predominated over HRR in the range of 3-50-fold. To assess the involvement of ATM in DSB repair, we first examined whether ATM was associated with the DSB. Chromatin immunoprecipitation showed that ATM was present at the site of the DSB as early as 18 h postinfection. In cells treated with caffeine, an inhibitor of ATM, HRR was reduced, whereas NHEJ was not. In support of this finding, GFP flow cytometry demonstrated that caffeine reduced HRR by 90% under conditions when ATM kinase activity was inhibited. Dominant-negative ATM expressed from adenovirus inhibited HRR by 45%, also having little to no effect on NHEJ. Furthermore, HRR was inhibited by caffeine in serum-starved cells arrested in G(0)/G(1), suggesting that ATM is also important for HRR outside of the S and G(2) cell cycle phases. Altogether, these results demonstrate that HRR contributes substantially to DSB repair in human glioma cells, and, importantly, ATM plays a critical role in regulating HRR but not NHEJ throughout the cell cycle.

  17. Prognostic Significance of Nuclear Phospho-ATM Expression in Melanoma

    PubMed Central

    Bhandaru, Madhuri; Martinka, Magdalena; McElwee, Kevin J.; Rotte, Anand

    2015-01-01

    UV radiation induced genomic instability is one of the leading causes for melanoma. Phosphorylation of Ataxia Telangiectasia Mutated (ATM) is one of the initial events that follow DNA damage. Phospho-ATM (p-ATM) plays a key role in the activation of DNA repair and several oncogenic pathways as well as in the maintenance of genomic integrity. The present study was therefore performed to understand the significance of p-ATM in melanoma progression and to correlate it with patient prognosis. Tissue microarray and immunohistochemical analysis were employed to study the expression of p-ATM in melanoma patients. A total of 366 melanoma patients (230 primary melanoma and 136 metastatic melanoma) were used for the study. Chi-square test, Kaplan-Meier, univariate and multivariate Cox regression analysis were used to elucidate the prognostic significance of p-ATM expression. Results revealed that both loss of, and gain in, p-ATM expression were associated with progression of melanoma from normal nevi to metastatic melanoma. Patients whose samples showed negative or strong p-ATM staining had significantly worse 5-year survival compared to patients who had weak to moderate expression. Loss of p-ATM expression was associated with relatively better 5-year survival, but the corresponding 10-year survival curve almost overlapped with that of strong p-ATM expression. p-ATM expression was found to be an independent prognostic factor for 5-year but not for 10-year patient survival. In conclusion our findings show that loss of p-ATM expression and gain-in p-ATM expression are indicators of worse melanoma patient survival. PMID:26275218

  18. Prognostic Significance of Nuclear Phospho-ATM Expression in Melanoma.

    PubMed

    Bhandaru, Madhuri; Martinka, Magdalena; McElwee, Kevin J; Rotte, Anand

    2015-01-01

    UV radiation induced genomic instability is one of the leading causes for melanoma. Phosphorylation of Ataxia Telangiectasia Mutated (ATM) is one of the initial events that follow DNA damage. Phospho-ATM (p-ATM) plays a key role in the activation of DNA repair and several oncogenic pathways as well as in the maintenance of genomic integrity. The present study was therefore performed to understand the significance of p-ATM in melanoma progression and to correlate it with patient prognosis. Tissue microarray and immunohistochemical analysis were employed to study the expression of p-ATM in melanoma patients. A total of 366 melanoma patients (230 primary melanoma and 136 metastatic melanoma) were used for the study. Chi-square test, Kaplan-Meier, univariate and multivariate Cox regression analysis were used to elucidate the prognostic significance of p-ATM expression. Results revealed that both loss of, and gain in, p-ATM expression were associated with progression of melanoma from normal nevi to metastatic melanoma. Patients whose samples showed negative or strong p-ATM staining had significantly worse 5-year survival compared to patients who had weak to moderate expression. Loss of p-ATM expression was associated with relatively better 5-year survival, but the corresponding 10-year survival curve almost overlapped with that of strong p-ATM expression. p-ATM expression was found to be an independent prognostic factor for 5-year but not for 10-year patient survival. In conclusion our findings show that loss of p-ATM expression and gain-in p-ATM expression are indicators of worse melanoma patient survival.

  19. ATM Quality of Service Tests for Digitized Video Using ATM Over Satellite: Laboratory Tests

    NASA Technical Reports Server (NTRS)

    Ivancic, William D.; Brooks, David E.; Frantz, Brian D.

    1997-01-01

    A digitized video application was used to help determine minimum quality of service parameters for asynchronous transfer mode (ATM) over satellite. For these tests, binomially distributed and other errors were digitally inserted in an intermediate frequency link via a satellite modem and a commercial gaussian noise generator. In this paper, the relation- ship between the ATM cell error and cell loss parameter specifications is discussed with regard to this application. In addition, the video-encoding algorithms, test configurations, and results are presented in detail.

  20. Doxorubicin-induced necrosis is mediated by poly-(ADP-ribose) polymerase 1 (PARP1) but is independent of p53

    PubMed Central

    Shin, Hyeon-Jun; Kwon, Hyuk-Kwon; Lee, Jae-Hyeok; Gui, Xiangai; Achek, Asma; Kim, Jae-Ho; Choi, Sangdun

    2015-01-01

    Necrosis, unregulated cell death, is characterized by plasma membrane rupture as well as nuclear and cellular swelling. However, it has recently been reported that necrosis is a regulated form of cell death mediated by poly-(ADP-ribose) polymerase 1 (PARP1). PARP1 is thought to mediate necrosis by inducing DNA damage, although this remains unconfirmed. In this study, we examined the mechanisms of PARP1-mediated necrosis following doxorubicin (DOX)-induced DNA damage in human kidney proximal tubular (HK-2) cells. DOX initiated DNA damage response (DDR) and upregulated PARP1 and p53 expression, resulting in morphological changes similar to those observed during necrosis. Additionally, DOX induced mitochondrial hyper-activation, as evidenced by increased mitochondrial respiration and cytosolic ATP (cATP) production. However, DOX affected mitochondrial mass. DOX-induced DNA damage, cytosolic reactive oxygen species (cROS) generation, and mitochondrial hyper-activation decreased in cells with inhibited PARP1 expression, while generation of nitric oxide (NO) and mitochondrial ROS (mROS) remained unaffected. Moreover, DOX-induced DNA damage, cell cycle changes, and oxidative stress were not affected by p53 inhibition. These findings suggest that DNA damage induced necrosis through a PARP1-dependent and p53-independent pathway. PMID:26522181

  1. Multi-targeted organometallic ruthenium(II)-arene anticancer complexes bearing inhibitors of poly(ADP-ribose) polymerase-1: A strategy to improve cytotoxicity.

    PubMed

    Wang, Zhigang; Qian, Hui; Yiu, Shek-Man; Sun, Jianwei; Zhu, Guangyu

    2014-02-01

    Small-molecule inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have currently drawn much attention as promising chemotherapeutic drug candidates, and there is a need to develop more potent PARP inhibitors with improved bioavailability. Here we report a strategy to improve the cytotoxicity of PARP inhibitors by conjugation with organometallic ruthenium(II)-arene compounds. We also report a systematic study to reveal the mechanism of action of these ruthenium-PARP inhibitor conjugates. The complexes have been synthesized and characterized spectroscopically. The improved antiproliferative activity from the as-prepared complexes in four human cancer cell lines has indicated their potential for further development as antitumor drugs. Cellular uptake study reveals that the most active complex 3 easily entered into cells. Target validation assays show that the complexes inhibited PARP-1 slightly better than the original PARP inhibitors, that complex 3 strongly bound to DNA and inhibited transcription, and that this complex arrested the cell cycle at the G0/G1 stage. This type of information could shed light on the design of the next generation of more active ruthenium-PARP inhibitor conjugates.

  2. ATMS Snowfall Rate Product and Its Applications

    NASA Astrophysics Data System (ADS)

    Meng, H.; Kongoli, C.; Dong, J.; Wang, N. Y.; Ferraro, R. R.; Zavodsky, B.; Banghua Yan, B.

    2015-12-01

    A snowfall rate (SFR) algorithm has been developed for the Advanced Technology Microwave Sounder (ATMS) aboard S-NPP and future JPSS satellites. The product is based on the NOAA/NESDIS operational Microwave Humidity Sounder (MHS) SFR but with several key advancements. The algorithm has benefited from continuous development to improve accuracy and snowfall detection efficiency. The enhancements also expand the applicable temperature range for the algorithm and allow significantly more snowfall to be detected than the operational SFR. Another major improvement is the drastically reduced product latency by using Direct Broadcast (DB) data. The new developments have also been implemented in the MHS SFR to ensure product consistency across satellites. Currently, there are five satellites that carry either ATMS or MHS: S-NPP, NOAA-18/-19 and Metop-A/-B. The combined satellites deliver up to ten SFR estimates a day at any location over land in mid-latitudes. The product provides much needed winter precipitation estimates for applications such as weather forecasting and hydrology. Both ATMS and MHS SFR serve as input to a global precipitation analysis product, the NOAA/NCEP CMORPH-Snow. SFR is the sole satellite-based snowfall estimates in the blended product. In addition, ATMS and MHS SFR was assessed at several NWS Weather Forecast Offices (WFOs) and NESDIS/Satellite Analysis Branch (SAB) for its operational values in winter 2015. This is a joint effort among NASA/SPoRT, NOAA/NESDIS, University of Maryland/CICS, and the WFOs. The feedback from the assessment indicated that SFR provides useful information for snowfall forecast. It is especially valuable for areas with poor radar coverage and ground observations. The feedback also identified some limitations of the product such as inadequate detection of shallow snowfall. The algorithm developers will continue to improve product quality as well as developing SFR for new microwave sensors and over ocean in a project

  3. Traffic Management in ATM Networks Over Satellite Links

    NASA Technical Reports Server (NTRS)

    Goyal, Rohit; Jain, Raj; Goyal, Mukul; Fahmy, Sonia; Vandalore, Bobby; vonDeak, Thomas

    1999-01-01

    This report presents a survey of the traffic management Issues in the design and implementation of satellite Asynchronous Transfer Mode (ATM) networks. The report focuses on the efficient transport of Transmission Control Protocol (TCP) traffic over satellite ATM. First, a reference satellite ATM network architecture is presented along with an overview of the service categories available in ATM networks. A delay model for satellite networks and the major components of delay and delay variation are described. A survey of design options for TCP over Unspecified Bit Rate (UBR), Guaranteed Frame Rate (GFR) and Available Bit Rate (ABR) services in ATM is presented. The main focus is on traffic management issues. Several recommendations on the design options for efficiently carrying data services over satellite ATM networks are presented. Most of the results are based on experiments performed on Geosynchronous (GEO) latencies. Some results for Low Earth Orbits (LEO) and Medium Earth Orbit (MEO) latencies are also provided.

  4. Prevalence of deleterious ATM germline mutations in gastric cancer patients.

    PubMed

    Huang, Dong-Sheng; Tao, Hou-Quan; He, Xu-Jun; Long, Ming; Yu, Sheng; Xia, Ying-Jie; Wei, Zhang; Xiong, Zikai; Jones, Sian; He, Yiping; Yan, Hai; Wang, Xiaoyue

    2015-12-01

    Besides CDH1, few hereditary gastric cancer predisposition genes have been previously reported. In this study, we discovered two germline ATM mutations (p.Y1203fs and p.N1223S) in a Chinese family with a history of gastric cancer by screening 83 cancer susceptibility genes. Using a published exome sequencing dataset, we found deleterious germline mutations of ATM in 2.7% of 335 gastric cancer patients of different ethnic origins. The frequency of deleterious ATM mutations in gastric cancer patients is significantly higher than that in general population (p=0.0000435), suggesting an association of ATM mutations with gastric cancer predisposition. We also observed biallelic inactivation of ATM in tumors of two gastric cancer patients. Further evaluation of ATM mutations in hereditary gastric cancer will facilitate genetic testing and risk assessment.

  5. ATM and KAT5 safeguard replicating chromatin against formaldehyde damage.

    PubMed

    Ortega-Atienza, Sara; Wong, Victor C; DeLoughery, Zachary; Luczak, Michal W; Zhitkovich, Anatoly

    2016-01-08

    Many carcinogens damage both DNA and protein constituents of chromatin, and it is unclear how cells respond to this compound injury. We examined activation of the main DNA damage-responsive kinase ATM and formation of DNA double-strand breaks (DSB) by formaldehyde (FA) that forms histone adducts and replication-blocking DNA-protein crosslinks (DPC). We found that low FA doses caused a strong and rapid activation of ATM signaling in human cells, which was ATR-independent and restricted to S-phase. High FA doses inactivated ATM via its covalent dimerization and formation of larger crosslinks. FA-induced ATM signaling showed higher CHK2 phosphorylation but much lower phospho-KAP1 relative to DSB inducers. Replication blockage by DPC did not produce damaged forks or detectable amounts of DSB during the main wave of ATM activation, which did not require MRE11. Chromatin-monitoring KAT5 (Tip60) acetyltransferase was responsible for acetylation and activation of ATM by FA. KAT5 and ATM were equally important for triggering of intra-S-phase checkpoint and ATM signaling promoted recovery of normal human cells after low-dose FA. Our results revealed a major role of the KAT5-ATM axis in protection of replicating chromatin against damage by the endogenous carcinogen FA.

  6. Structural characterization of AtmS13, a putative sugar aminotransferase involved in indolocarbazole AT2433 aminopentose biosynthesis.

    PubMed

    Singh, Shanteri; Kim, Youngchang; Wang, Fengbin; Bigelow, Lance; Endres, Michael; Kharel, Madan K; Babnigg, Gyorgy; Bingman, Craig A; Joachimiak, Andrzej; Thorson, Jon S; Phillips, George N

    2015-08-01

    AT2433 from Actinomadura melliaura is an indolocarbazole antitumor antibiotic structurally distinguished by its unique aminodideoxypentose-containing disaccharide moiety. The corresponding sugar nucleotide-based biosynthetic pathway for this unusual sugar derives from comparative genomics where AtmS13 has been suggested as the contributing sugar aminotransferase (SAT). Determination of the AtmS13 X-ray structure at 1.50-Å resolution reveals it as a member of the aspartate aminotransferase fold type I (AAT-I). Structural comparisons of AtmS13 with homologous SATs that act upon similar substrates implicate potential active site residues that contribute to distinctions in sugar C5 (hexose vs. pentose) and/or sugar C2 (deoxy vs. hydroxyl) substrate specificity.

  7. BNL-NYSERNet ATM project report

    SciTech Connect

    O`Connor, M.; Peskin, A.; Rabinowitz, G.

    1997-07-01

    In 1994, Brookhaven National Laboratory (BNL) and NYSERNet, Incorporated embarked on a joint project to develop a prototype Asynchronous Transfer Mode (ATM) Regional Network testbed. This project was funded as a three-year effort under a Cooperative Research and Development Activity (CRADA) agreement between the parties, with half the funds being provided directly by the U.S. Department of Energy and the remainder as an in-kind contribution by NYSERNet. This report documents that effort as it comes to a close, providing an account of the original goals, the accomplishments of the projects, and the results as they might apply to the future. It is useful to remember that, when the collaboration discussions first began in 1993, it was far from certain that ATM would be the technology of choice for the then-next generation of the Internet. That, of course, has turned out to be the case, which in retrospect makes this experience particularly valuable. The investigators were not totally prescient, however, and the project changed during its duration to account for changes in technology, available infrastructure, and other circumstances.

  8. A quasi-quantitative dual multiplexed immunoblot method to simultaneously analyze ATM and H2AX Phosphorylation in human peripheral blood mononuclear cells.

    PubMed

    Bakkenist, Christopher J; Czambel, R Kenneth; Hershberger, Pamela A; Tawbi, Hussein; Beumer, Jan H; Schmitz, John C

    2015-01-01

    Pharmacologic inhibition of DNA repair may increase the efficacy of many cytotoxic cancer agents. Inhibitors of DNA repair enzymes including APE1, ATM, ATR, DNA-PK and PARP have been developed and the PARP inhibitor olaparib is the first-in-class approved in Europe and the USA for the treatment of advanced BRCA-mutated ovarian cancer. Sensitive pharmacodynamic (PD) biomarkers are needed to further evaluate the efficacy of inhibitors of DNA repair enzymes in clinical trials. ATM is a protein kinase that mediates cell-cycle checkpoint activation and DNA double-strand break repair. ATM kinase activation at DNA double-strand breaks (DSBs) is associated with intermolecular autophosphorylation on serine-1981. Exquisite sensitivity and high stoichiometry as well as facile extraction suggest that ATM serine-1981 phosphorylation may be a highly dynamic PD biomarker for both ATM kinase inhibitors and radiation- and chemotherapy-induced DSBs. Here we report the pre-clinical analytical validation and fit-for-purpose biomarker method validation of a quasi-quantitative dual multiplexed immunoblot method to simultaneously analyze ATM and H2AX phosphorylation in human peripheral blood mononuclear cells (PBMCs). We explore the dynamics of these phosphorylations in PBMCs exposed to chemotherapeutic agents and DNA repair inhibitors in vitro, and show that ATM serine-1981 phosphorylation is increased in PBMCs in sarcoma patients treated with DNA damaging chemotherapy.

  9. Reduced nicotinamide adenine dinucleotide fluorescence lifetime detected poly(adenosine-5'-diphosphate-ribose) polymerase-1-mediated cell death and therapeutic effect of pyruvate

    NASA Astrophysics Data System (ADS)

    Guo, Han-Wen; Wei, Yau-Huei; Wang, Hsing-Wen

    2011-06-01

    Noninvasive detection of cell death has the potential for definitive diagnosis and monitoring treatment outcomes in real time. Reduced nicotinamide adenine dinucleotide (NADH) fluorescence intensity has long been used as a noninvasive optical probe of metabolic states. NADH fluorescence lifetime has recently been studied for its potential as an alternative optical probe of cellular metabolic states and cell death. In this study, we investigated the potential using NADH fluorescence intensity and/or lifetime to detect poly(adenosine-5'-diphosphate-ribose) polymerase-1 (PARP-1)-mediated cell death in HeLa cells. We also examined if NADH signals respond to treatment by pyruvate. The mechanism of PARP-1-mediated cell death has been well studied that extensive PARP-1 activation leads to cytosolic nicotinamide adenine dinucleotide depletion resulting in glycolytic inhibition, mitochondrial failure, and death. Pyruvate could restore electron transport chain to prevent energy failure and death. Our results show that NADH fluorescence lifetime, not intensity, responded to PARP-1-mediated cell death and the rescue effect of pyruvate. This lifetime change of NADH fluorescence happened before the collapse of mitochondrial membrane potential and mitochondrial uncoupling. Together with our previous findings in staurosporine-induced cell death, we suggest that NADH fluorescence lifetime increase during cell death is mainly due to increased protein-protein interactions but not the intracellular NADH content.

  10. Differential and Concordant Roles for Poly(ADP-Ribose) Polymerase 1 and Poly(ADP-Ribose) in Regulating WRN and RECQL5 Activities

    PubMed Central

    Khadka, Prabhat; Hsu, Joseph K.; Veith, Sebastian; Tadokoro, Takashi; Shamanna, Raghavendra A.; Mangerich, Aswin; Croteau, Deborah L.

    2015-01-01

    Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) catalyzes the poly(ADP-ribosyl)ation (PARylation) of proteins, a posttranslational modification which forms the nucleic acid-like polymer PAR. PARP1 and PAR are integral players in the early DNA damage response, since PARylation orchestrates the recruitment of repair proteins to sites of damage. Human RecQ helicases are DNA unwinding proteins that are critical responders to DNA damage, but how their recruitment and activities are regulated by PARPs and PAR is poorly understood. Here we report that all human RecQ helicases interact with PAR noncovalently. Furthermore, we define the effects that PARP1, PARylated PARP1, and PAR have on RECQL5 and WRN, using both in vitro and in vivo assays. We show that PARylation is involved in the recruitment of RECQL5 and WRN to laser-induced DNA damage and that RECQL5 and WRN have differential responses to PARylated PARP1 and PAR. Furthermore, we show that the loss of RECQL5 or WRN resulted in increased sensitivity to PARP inhibition. In conclusion, our results demonstrate that PARP1 and PAR actively, and in some instances differentially, regulate the activities and cellular localization of RECQL5 and WRN, suggesting that PARylation acts as a fine-tuning mechanism to coordinate their functions in time and space during the genotoxic stress response. PMID:26391948

  11. Detecting ATM-Dependent Chromatin Modification in DNA Damage Response

    PubMed Central

    Udayakumar, Durga; Horikoshi, Nobuo; Mishra, Lope; Hunt, Clayton; Pandita, Tej K.

    2015-01-01

    Loss of function or mutation of the ataxia–telangiectasia mutated gene product (ATM) results in inherited genetic disorders characterized by neurodegeneration, immunodeficiency, and cancer. Ataxia-telangiectasia mutated (ATM) gene product belongs to the PI3K-like protein kinase (PIKKs) family and is functionally implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control, and telomere maintenance. The ATM protein kinase is primarily activated in response to DNA double strand breaks (DSBs), the most deleterious form of DNA damage produced by ionizing radiation (IR) or radiomimetic drugs. It is detected at DNA damage sites, where ATM autophosphorylation causes dissociation of the inactive homodimeric form to the activated monomeric form. Interestingly, heat shock can activate ATM independent of the presence of DNA strand breaks. ATM is an integral part of the sensory machinery that detects DSBs during meiosis, mitosis, or DNA breaks mediated by free radicals. These DNA lesions can trigger higher order chromatin reorganization fuelled by posttranslational modifications of histones and histone binding proteins. Our group, and others, have shown that ATM activation is tightly regulated by chromatin modifications. This review summarizes the multiple approaches used to discern the role of ATM and other associated proteins in chromatin modification in response to DNA damage. PMID:25827888

  12. Involvement of novel autophosphorylation sites in ATM activation.

    PubMed

    Kozlov, Sergei V; Graham, Mark E; Peng, Cheng; Chen, Philip; Robinson, Phillip J; Lavin, Martin F

    2006-08-09

    ATM kinase plays a central role in signaling DNA double-strand breaks to cell cycle checkpoints and to the DNA repair machinery. Although the exact mechanism of ATM activation remains unknown, efficient activation requires the Mre11 complex, autophosphorylation on S1981 and the involvement of protein phosphatases and acetylases. We report here the identification of several additional phosphorylation sites on ATM in response to DNA damage, including autophosphorylation on pS367 and pS1893. ATM autophosphorylates all these sites in vitro in response to DNA damage. Antibodies against phosphoserine 1893 revealed rapid and persistent phosphorylation at this site after in vivo activation of ATM kinase by ionizing radiation, paralleling that observed for S1981 phosphorylation. Phosphorylation was dependent on functional ATM and on the Mre11 complex. All three autophosphorylation sites are physiologically important parts of the DNA damage response, as phosphorylation site mutants (S367A, S1893A and S1981A) were each defective in ATM signaling in vivo and each failed to correct radiosensitivity, genome instability and cell cycle checkpoint defects in ataxia-telangiectasia cells. We conclude that there are at least three functionally important radiation-induced autophosphorylation events in ATM.

  13. Multimedia Applications in Heterogeneous Internet/ATM Environments.

    ERIC Educational Resources Information Center

    Wolf, Lars C.

    1999-01-01

    Discussion of multimedia systems focuses on interaction approaches for the quality of service (QoS) architectures developed for the Internet and for asynchronous transfer mode (ATM). Highlights include interactions, videoconferencing, video on demand, a comparison of the ATM and IntServ QoS architectures, interaction models, and subordination…

  14. ATM Technology Adoption in U.S. Campus Networking.

    ERIC Educational Resources Information Center

    Yao, Engui; Perry, John F.; Anderson, Larry S.; Brook, R. Dan; Hare, R. Dwight; Moore, Arnold J.; Xu, Xiaohe

    This study examined the relationships between ATM (asynchronous transfer mode) adoption in universities and four organizational variables: university size, type, finances, and information processing maturity. Another purpose of the study was to identify the current status of ATM adoption in campus networking. Subjects were university domain LAN…

  15. ATM LAN Emulation: Getting from Here to There.

    ERIC Educational Resources Information Center

    Learn, Larry L., Ed.

    1995-01-01

    Discusses current LAN (local area network) configuration and explains ATM (asynchronous transfer mode) as the future telecommunications transport. Highlights include LAN emulation, which enables the interconnection of legacy LANs and the new ATM environment; virtual LANs; broadcast servers; and standards. (LRW)

  16. ATM: The Key To Harnessing the Power of Networked Multimedia.

    ERIC Educational Resources Information Center

    Gross, Rod

    1996-01-01

    ATM (Asynchronous Transfer Mode) network technology handles the real-time continuous traffic flow necessary to support desktop multimedia applications. Describes network applications already used: desktop video collaboration, distance learning, and broadcasting video delivery. Examines the architecture of ATM technology, video delivery and sound…

  17. FPGA Based Reconfigurable ATM Switch Test Bed

    NASA Technical Reports Server (NTRS)

    Chu, Pong P.; Jones, Robert E.

    1998-01-01

    Various issues associated with "FPGA Based Reconfigurable ATM Switch Test Bed" are presented in viewgraph form. Specific topics include: 1) Network performance evaluation; 2) traditional approaches; 3) software simulation; 4) hardware emulation; 5) test bed highlights; 6) design environment; 7) test bed architecture; 8) abstract sheared-memory switch; 9) detailed switch diagram; 10) traffic generator; 11) data collection circuit and user interface; 12) initial results; and 13) the following conclusions: Advances in FPGA make hardware emulation feasible for performance evaluation, hardware emulation can provide several orders of magnitude speed-up over software simulation; due to the complexity of hardware synthesis process, development in emulation is much more difficult than simulation and requires knowledge in both networks and digital design.

  18. Aurora-A controls cancer cell radio- and chemoresistance via ATM/Chk2-mediated DNA repair networks.

    PubMed

    Sun, Huizhen; Wang, Yan; Wang, Ziliang; Meng, Jiao; Qi, Zihao; Yang, Gong

    2014-05-01

    High expression of Aurora kinase A (Aurora-A) has been found to confer cancer cell radio- and chemoresistance, however, the underlying mechanism is unclear. In this study, by using Aurora-A cDNA/shRNA or the specific inhibitor VX680, we show that Aurora-A upregulates cell proliferation, cell cycle progression, and anchorage-independent growth to enhance cell resistance to cisplatin and X-ray irradiation through dysregulation of DNA damage repair networks. Mechanistic studies showed that Aurora-A promoted the expression of ATM/Chk2, but suppressed the expression of BRCA1/2, ATR/Chk1, p53, pp53 (Ser15), H2AX, γH2AX (Ser319), and RAD51. Aurora-A inhibited the focus formation of γH2AX in response to ionizing irradiation. Treatment of cells overexpressing Aurora-A and ATM/Chk2 with the ATM specific inhibitor KU-55933 increased the cell sensitivity to cisplatin and irradiation through increasing the phosphorylation of p53 at Ser15 and inhibiting the expression of Chk2, γH2AX (Ser319), and RAD51. Further study revealed that BRCA1/2 counteracted the function of Aurora-A to suppress the expression of ATM/Chk2, but to activate the expression of ATR/Chk1, pp53, γH2AX, and RAD51, leading to the enhanced cell sensitivity to irradiation and cisplatin, which was also supported by the results from animal assays. Thus, our data provide strong evidences that Aurora-A and BRCA1/2 inversely control the sensitivity of cancer cells to radio- and chemotherapy through the ATM/Chk2-mediated DNA repair networks, indicating that the DNA repair molecules including ATM/Chk2 may be considered for the targeted therapy against cancers with overexpression of Aurora-A.

  19. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo.

    PubMed

    Vendetti, Frank P; Lau, Alan; Schamus, Sandra; Conrads, Thomas P; O'Connor, Mark J; Bakkenist, Christopher J

    2015-12-29

    ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.

  20. ATM Expression Predicts Veliparib and Irinotecan Sensitivity in Gastric Cancer by Mediating P53-Independent Regulation of Cell Cycle and Apoptosis.

    PubMed

    Subhash, Vinod Vijay; Tan, Shi Hui; Yeo, Mei Shi; Yan, Fui Leng; Peethala, Praveen C; Liem, Natalia; Krishnan, Vaidehi; Yong, Wei Peng

    2016-12-01

    Identification of synthetically lethal cellular targets and synergistic drug combinations is important in cancer chemotherapy as they help to overcome treatment resistance and increase efficacy. The Ataxia Telangiectasia Mutated (ATM) kinase is a nuclear protein that plays a major role in the initiation of DNA repair signaling and cell-cycle check points during DNA damage. Although ATM was shown to be associated with poor prognosis in gastric cancer, its implications as a predictive biomarker for cancer chemotherapy remain unexplored. The present study evaluated ATM-induced synthetic lethality and its role in sensitization of gastric cancer cells to PARP and TOP1 inhibitors, veliparib (ABT-888) and irinotecan (CPT-11), respectively. ATM expression was detected in a panel of gastric cell lines, and the IC50 against each inhibitors was determined. The combinatorial effect of ABT-888 and CPT-11 in gastric cancer cells was also determined both in vitro and in vivo ATM deficiency was found to be associated with enhanced sensitivity to ABT-888 and CPT-11 monotherapy, hence suggesting a mechanism of synthetic lethality. Cells with high ATM expression showed reduced sensitivity to monotherapy; however, they showed a higher therapeutic effect with ABT-888 and CPT-11 combinatorial therapy. Furthermore, ATM expression was shown to play a major role in cellular homeostasis by regulating cell-cycle progression and apoptosis in a P53-independent manner. The present study highlights the clinical utility of ATM expression as a predictive marker for sensitivity of gastric cancer cells to PARP and TOP1 inhibition and provides a deeper mechanistic insight into ATM-dependent regulation of cellular processes. Mol Cancer Ther; 15(12); 3087-96. ©2016 AACR.

  1. Studies of locomotor network neuroprotection by the selective poly(ADP-ribose) polymerase-1 inhibitor PJ-34 against excitotoxic injury to the rat spinal cord in vitro.

    PubMed

    Nasrabady, Sara E; Kuzhandaivel, Anujaianthi; Nistri, Andrea

    2011-06-01

    Delayed neuronal destruction after acute spinal injury is attributed to excitotoxicity mediated by hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) that induces 'parthanatos', namely a non-apoptotic cell death mechanism. With an in vitro model of excitotoxicity, we have previously observed parthanatos of rat spinal cord locomotor networks to be decreased by a broad spectrum PARP-1 inhibitor. The present study investigated whether the selective PARP-1 inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide.HCl (PJ-34) not only protected networks from kainate-evoked excitotoxicity, but also prevented loss of locomotor patterns recorded as fictive locomotion from lumbar (L) ventral roots (VRs) 24 h later. PJ-34 (60 μm) blocked PARP-1 activation and preserved dorsal, central and ventral gray matter with maintained reflex activity even after a large dose of kainate. Fictive locomotion could not, however, be restored by either electrical stimulation or bath-applied neurochemicals (N-methyl-D-aspartate plus 5-hydroxytryptamine). A low kainate concentration induced less histological damage that was widely prevented by PJ-34. Nonetheless, fictive locomotion was observed in just over 50% of preparations whose histological profile did not differ (except for the dorsal horn) from those lacking such a rhythm. Our data show that inhibition of PARP-1 could amply preserve spinal network histology after excitotoxicity, with return of locomotor patterns only when the excitotoxic stimulus was moderate. These results demonstrated divergence between histological and functional outcome, implying a narrow borderline between loss of fictive locomotion and neuronal preservation. Our data suggest that either damage of a few unidentified neurons or functional network inhibition was critical for ensuring locomotor cycles.

  2. Poly(ADP-Ribose) Polymerase 1–Sirtuin 1 Functional Interplay Regulates LPS-Mediated High Mobility Group Box 1 Secretion

    PubMed Central

    Walko, Thomas D; Di Caro, Valentina; Piganelli, Jon; Billiar, Timothy R; Clark, Robert SB; Aneja, Rajesh K

    2014-01-01

    Pathophysiological conditions that lead to the release of the prototypic damage-associated molecular pattern molecule high mobility group box 1 (HMGB1) also result in activation of poly(ADP-ribose) polymerase 1 (PARP1; now known as ADP-ribosyl transferase 1 [ARTD1]). Persistent activation of PARP1 promotes energy failure and cell death. The role of poly(ADP-ribosyl)ation in HMGB1 release has been explored previously; however, PARP1 is a versatile enzyme and performs several other functions including cross-talk with another nicotinamide adenine dinucleotide- (NAD+) dependent member of the Class III histone deacetylases (HDACs), sirtuin-1 (SIRT1). Previously, it has been shown that the hyperacetylation of HMGB1 is a seminal event prior to its secretion, a process that also is dependent on HDACs. Therefore, in this study, we seek to determine if PARP1 inhibition alters LPS-mediated HMGB1 hyperacetylation and subsequent secretion due to its effect on SIRT1. We demonstrate in an in vitro model that LPS treatment leads to hyperacetylated HMGB1 with concomitant reduction in nuclear HDAC activity. Treatment with PARP1 inhibitors mitigates the LPS-mediated reduction in nuclear HDAC activity and decreases HMGB1 acetylation. By utilizing an NAD+-based mechanism, PARP1 inhibition increases the activity of SIRT1. Consequently, there is an increased nuclear retention and decreased extracellular secretion of HMGB1. We also demonstrate that PARP1 physically interacts with SIRT1. Further confirmation of this data was obtained in a murine model of sepsis, that is, administration of PJ-34, a specific PARP1 inhibitor, led to decreased serum HMGB1 concentrations in mice subjected to cecal ligation and puncture (CLP) as compared with untreated mice. In conclusion, our study provides new insights in understanding the molecular mechanisms of HMGB1 secretion in sepsis. PMID:25517228

  3. Phosphorylation of Daxx by ATM Contributes to DNA Damage-Induced p53 Activation

    PubMed Central

    Cheng, Qian; Qu, Like; Brewer, Michael D.; Chen, Jiandong; Yang, Xiaolu

    2013-01-01

    p53 plays a central role in tumor suppression. It does so by inducing anti-proliferative processes as a response to various tumor-promoting stresses. p53 is regulated by the ubiquitin ligase Mdm2. The optimal function of Mdm2 requires Daxx, which stabilizes Mdm2 through the deubiquitinase Hausp/USP7 and also directly promotes Mdm2’s ubiquitin ligase activity towards p53. The Daxx-Mdm2 interaction is disrupted upon DNA damage. However, both the mechanisms and the consequence of the Daxx-Mdm2 dissociation are not understood. Here we show that upon DNA damage Daxx is phosphorylated in a manner that is dependent on ATM, a member of the PI 3-kinase family that orchestrates the DNA damage response. The main phosphorylation site of Daxx is identified to be Ser564, which is a direct target of ATM. Phosphorylation of endogenous Daxx at Ser564 occurs rapidly during the DNA damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of Daxx from Mdm2, stabilizes Mdm2, and inhibits DNA damage-induced p53 activation. These results suggest that phosphorylation of Daxx by ATM upon DNA damage disrupts the Daxx-Mdm2 interaction and facilitates p53 activation. PMID:23405218

  4. Deoxycytidine Kinase Augments ATM-Mediated DNA Repair and Contributes to Radiation Resistance

    PubMed Central

    Bunimovich, Yuri L.; Nair-Gill, Evan; Riedinger, Mireille; McCracken, Melissa N.; Cheng, Donghui; McLaughlin, Jami; Radu, Caius G.; Witte, Owen N.

    2014-01-01

    Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts its substrate specificity toward deoxycytidine, increases intracellular dCTP pools post IR, and enhances the rate of DNA repair. Mutation of a single serine 74 residue has profound effects on murine T and B lymphocyte development, suggesting that post-translational regulation of dCK may be important in maintaining genomic stability during hematopoiesis. Using [18F]-FAC, a dCK-specific positron emission tomography (PET) probe, we visualized and quantified dCK activation in tumor xenografts after IR, indicating that dCK activation could serve as a biomarker for ATM function and DNA damage response in vivo. In addition, dCK-deficient leukemia cell lines and murine embryonic fibroblasts exhibited increased sensitivity to IR, indicating that pharmacologic inhibition of dCK may be an effective radiosensitization strategy. PMID:25101980

  5. An Update on Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors: Opportunities and Challenges in Cancer Therapy.

    PubMed

    Wang, Ying-Qing; Wang, Ping-Yuan; Wang, Yu-Ting; Yang, Guang-Fu; Zhang, Ao; Miao, Ze-Hong

    2016-11-10

    Poly(ADP-ribose)polymerase-1 (PARP-1) is a critical DNA repair enzyme in the base excision repair pathway. Inhibitors of this enzyme comprise a new type of anticancer drug that selectively kills cancer cells by targeting homologous recombination repair defects. Since 2010, important advances have been achieved in PARP-1 inhibitors. Specifically, the approval of olaparib in 2014 for the treatment of ovarian cancer with BRCA mutations validated PARP-1 as an anticancer target and established its clinical importance in cancer therapy. Here, we provide an update on PARP-1 inhibitors, focusing on breakthroughs in their clinical applications and investigations into relevant mechanisms of action, biomarkers, and drug resistance. We also provide an update on the design strategies and the structural types of PARP-1 inhibitors. Opportunities and challenges in PARP-1 inhibitors for cancer therapy will be discussed based on the above advances.

  6. The Authenticated Tracking and Monitoring System (ATMS) concept

    SciTech Connect

    Schoeneman, J.L.

    1993-08-01

    The Authenticated Tracking and Monitoring System (ATMS) has been designed to address the need for global monitoring of the status and location of proliferation-sensitive items. Conceived to utilize the proposed Global Verification and Location System (GVLS) satellite link, ATMS could use the existing International Maritime Satellite commercial communication system until GVLS is operational. The ATMS concept uses sensor packs to monitor items and environmental conditions, collects a variety of events data through a sensor processing unit, and transmits the data to a satellite, which then sends data to ground stations. Authentication and encryption algorithms will be used to secure the data. A typical ATMS application would be to track and monitor the safety and security of a number of items in transit along a scheduled shipping route. This paper also discusses a possible proof-of-concept system demonstration.

  7. ATM/CHK/p53 Pathway Dependent Chemopreventive and Therapeutic Activity on Lung Cancer by Pterostilbene

    PubMed Central

    Lee, Hani; Kim, Yonghwan; Jeong, Ji Hye; Ryu, Jae-Ha

    2016-01-01

    Among the many stilbenoids found in a variety of berries, resveratrol and pterostilbene are of particular interest given their potential for use in cancer therapeutics and prevention. We purified four stilbenoids from R. undulatum and found that pterostilbene inhibits cancer cell proliferation more efficiently than rhapontigenin, piceatannol and resveratrol. To investigate the underlying mechanism of this superior action of pterostilbene on cancer cells, we utilized a reverse-phase protein array followed by bioinformatic analysis and found that the ATM/CHK pathway is modified by pterostilbene in a lung cancer cell line. Given that ATM/CHK signaling requires p53 for its biological effects, we hypothesized that p53 is required for the anticancer effect of pterostilbene. To test this hypothesis, we used two molecularly defined precancerous human bronchial epithelial cell lines, HBECR and HBECR/p53i, with normal p53 and suppressed p53 expression, respectively, to represent premalignant states of squamous lung carcinogenesis. Pterostilbene inhibited the cell cycle more efficiently in HBECR cells compared to HBECR/p53i cells, suggesting that the presence of p53 is required for the action of pterostilbene. Pterostilbene also activated ATM and CHK1/2, which are upstream of p53, in both cell lines, though pterostilbene-induced senescence was dependent on the presence of p53. Finally, pterostilbene more effectively inhibited p53-dependent cell proliferation compared to the other three stilbenoids. These results strongly support the potential chemopreventive effect of pterostilbene on p53-positive cells during early carcinogenesis. PMID:27612029

  8. ATM-Weather Integration Plan, Version 1.0

    DTIC Science & Technology

    2009-09-17

    identified in the previous step. 4. Serve as the subject matter expert ( SME ) for the ATM tool development team to assist in integration of the weather...serve as the SME for the ATM Tool development team to assist in interpretation and integration of the weather impacts and methodologies and to evaluate...impact point. Ceiling and visibility conditions may determine whether an airport should be operating under IFR or VFR, thereby impacting airport

  9. Global Analysis of ATM Polymorphism Reveals Significant Functional Constraint

    PubMed Central

    Thorstenson, Yvonne R.; Shen, Peidong; Tusher, Virginia G.; Wayne, Tierney L.; Davis, Ronald W.; Chu, Gilbert; Oefner, Peter J.

    2001-01-01

    ATM, the gene that is mutated in ataxia-telangiectasia, is associated with cerebellar degeneration, abnormal proliferation of small blood vessels, and cancer. These clinically important manifestations have stimulated interest in defining the sequence variation in the ATM gene. Therefore, we undertook a comprehensive survey of sequence variation in ATM in diverse human populations. The protein-encoding exons of the gene (9,168 bp) and the adjacent intron and untranslated sequences (14,661 bp) were analyzed in 93 individuals from seven major human populations. In addition, the coding sequence was analyzed in one chimpanzee, one gorilla, one orangutan, and one Old World monkey. In human ATM, 88 variant sites were discovered by denaturing high-performance liquid chromatography, which is 96%–100% sensitive for detection of DNA sequence variation. ATM was compared to 14 other autosomal genes for nucleotide diversity. The noncoding regions of ATM had diversity values comparable to other genes, but the coding regions had very low diversity, especially in the last 29% of the protein sequence. A test of the neutral evolution hypothesis, through use of the Hudson/Kreitman/Aguadé statistic, revealed that this region of the human ATM gene was significantly constrained relative to that of the orangutan, the Old World monkey, and the mouse, but not relative to that of the chimpanzee or the gorilla. ATM displayed extensive linkage disequilibrium, consistent with suppression of meiotic recombination at this locus. Seven haplotypes were defined. Two haplotypes accounted for 82% of all chromosomes analyzed in all major populations; two others carrying the same D126E missense polymorphism accounted for 33% of chromosomes in Africa but were never observed outside of Africa. The high frequency of this polymorphism may be due either to a population expansion within Africa or to selective pressure. PMID:11443540

  10. Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Reduce Reactive Gliosis and Improve Angiostatin Levels in Retina of Diabetic Rats.

    PubMed

    Guzyk, Mykhailo M; Tykhomyrov, Artem A; Nedzvetsky, Victor S; Prischepa, Irina V; Grinenko, Tatiana V; Yanitska, Lesya V; Kuchmerovska, Tamara M

    2016-10-01

    Diabetic retinopathy (DR) is a multifactorial disease characterized by reactive gliosis and disbalance of angiogenesis regulators, contributing to endothelial dysfunction and microvascular complications. This study was organized to elucidate whether poly(ADP-ribose) polymerase-1 (PARP-1) inhibition could attenuate diabetes-induced damage to macroglia and correct angiogenic disbalance in diabetic rat retina. After 8 weeks of streptozotocin (STZ)-induced diabetes, Wistar male rats were treated with PARP-1 inhibitors, nicotinamide (NAm) or 3-aminobenzamide (3-AB) (100 and 30 mg/kg/daily i.p., respectively), for 14 days. After the 10-weeks experiment period, retinas were undergone an immunohistochemical staining for glial fibrillary acidic protein (GFAP), while western blots were performed to evaluate effects of PAPR-1 inhibitors on the levels of PARP-1, poly(ADP-ribosyl)ated proteins (PARs), GFAP, and angiostatin isoforms. Diabetes induced significant up-regulation and activation of retinal PARP-1, reactive gliosis development, and GFAP overexpression compared to non-diabetic control. Moreover, extensive fragmentation of both PARP-1 and GFAP (hallmarks of apoptosis and macroglia reactivation, respectively) in diabetic retina was also observed. Levels of angiostatin isoforms were dramatically decreased in diabetic retina, sustaining aberrant pro-angiogenic condition. Both NAm and 3-AB markedly attenuated damage to macroglia, evidenced by down-regulation of PARP-1, PARs and total GFAP compared to diabetic non-treated group. PARP-1-inhibitory therapy prevented formation of PARP-1 and GFAP cleavage-derived products. In retinas of anti-PARP-treated diabetic animals, partial restoration of angiostatin's levels was shown. Therefore, PARP-1 inhibitors counteract diabetes-induced injuries and manifest retinoprotective effects, including attenuation of reactive gliosis and improvement of angiogenic status, thus, such agents could be considered as promising candidates for DR

  11. Expression of human poly (ADP-ribose) polymerase 1 in Saccharomyces cerevisiae: Effect on survival, homologous recombination and identification of genes involved in intracellular localization.

    PubMed

    La Ferla, Marco; Mercatanti, Alberto; Rocchi, Giulia; Lodovichi, Samuele; Cervelli, Tiziana; Pignata, Luca; Caligo, Maria Adelaide; Galli, Alvaro

    2015-04-01

    The poly (ADP-ribose) polymerase 1 (PARP-1) actively participates in a series of functions within the cell that include: mitosis, intracellular signaling, cell cycle regulation, transcription and DNA damage repair. Therefore, inhibition of PARP1 has a great potential for use in cancer therapy. As resistance to PARP inhibitors is starting to be observed in patients, thus the function of PARP-1 needs to be studied in depth in order to find new therapeutic targets. To gain more information on the PARP-1 activity, we expressed PARP-1 in yeast and investigated its effect on cell growth and UV induced homologous recombination. To identify candidate genes affecting PARP-1 activity and cellular localization, we also developed a yeast genome wide genetic screen. We found that PARP-1 strongly inhibited yeast growth, but when yeast was exposed to the PARP-1 inhibitor 6(5-H) phenantridinone (PHE), it recovered from the growth suppression. Moreover, we showed that PARP-1 produced PAR products in yeast and we demonstrated that PARP-1 reduced UV-induced homologous recombination. By genome wide screening, we identified 99 mutants that suppressed PARP-1 growth inhibition. Orthologues of human genes were found for 41 of these yeast genes. We determined whether the PARP-1 protein level was altered in strains which are deleted for the transcription regulator GAL3, the histone H1 gene HHO1, the HUL4 gene, the deubiquitination enzyme gene OTU1, the nuclear pore protein POM152 and the SNT1 that encodes for the Set3C subunit of the histone deacetylase complex. In these strains the PARP-1 level was roughly the same as in the wild type. PARP-1 localized in the nucleus more in the snt1Δ than in the wild type strain; after UV radiation, PARP-1 localized in the nucleus more in hho1 and pom152 deletion strains than in the wild type indicating that these functions may have a role on regulating PARP-1 level and activity in the nucleus.

  12. ATM kinase: Much more than a DNA damage responsive protein.

    PubMed

    Guleria, Ayushi; Chandna, Sudhir

    2016-03-01

    ATM, mutation of which causes Ataxia telangiectasia, has emerged as a cardinal multifunctional protein kinase during past two decades as evidenced by various studies from around the globe. Further to its well established and predominant role in DNA damage response, ATM has also been understood to help in maintaining overall functional integrity of cells; since its mutation, inactivation or deficiency results in a variety of pathological manifestations besides DNA damage. These include oxidative stress, metabolic syndrome, mitochondrial dysfunction as well as neurodegeneration. Recently, high throughput screening using proteomics, metabolomics and transcriptomic studies revealed several proteins which might be acting as substrates of ATM. Studies that can help in identifying effective regulatory controls within the ATM-mediated pathways/mechanisms can help in developing better therapeutics. In fact, more in-depth understanding of ATM-dependent cellular signals could also help in the treatment of variety of other disease conditions since these pathways seem to control many critical cellular functions. In this review, we have attempted to put together a detailed yet lucid picture of the present-day understanding of ATM's role in various pathophysiological conditions involving DNA damage and beyond.

  13. ATM controls meiotic double-strand-break formation.

    PubMed

    Lange, Julian; Pan, Jing; Cole, Francesca; Thelen, Michael P; Jasin, Maria; Keeney, Scott

    2011-10-16

    In many organisms, developmentally programmed double-strand breaks (DSBs) formed by the SPO11 transesterase initiate meiotic recombination, which promotes pairing and segregation of homologous chromosomes. Because every chromosome must receive a minimum number of DSBs, attention has focused on factors that support DSB formation. However, improperly repaired DSBs can cause meiotic arrest or mutation; thus, having too many DSBs is probably as deleterious as having too few. Only a small fraction of SPO11 protein ever makes a DSB in yeast or mouse and SPO11 and its accessory factors remain abundant long after most DSB formation ceases, implying the existence of mechanisms that restrain SPO11 activity to limit DSB numbers. Here we report that the number of meiotic DSBs in mouse is controlled by ATM, a kinase activated by DNA damage to trigger checkpoint signalling and promote DSB repair. Levels of SPO11-oligonucleotide complexes, by-products of meiotic DSB formation, are elevated at least tenfold in spermatocytes lacking ATM. Moreover, Atm mutation renders SPO11-oligonucleotide levels sensitive to genetic manipulations that modulate SPO11 protein levels. We propose that ATM restrains SPO11 via a negative feedback loop in which kinase activation by DSBs suppresses further DSB formation. Our findings explain previously puzzling phenotypes of Atm-null mice and provide a molecular basis for the gonadal dysgenesis observed in ataxia telangiectasia, the human syndrome caused by ATM deficiency.

  14. ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion.

    PubMed

    Chen, Wei-Ta; Ebelt, Nancy D; Stracker, Travis H; Xhemalce, Blerta; Van Den Berg, Carla L; Miller, Kyle M

    2015-06-01

    Ataxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression. Here we report a cancer-promoting role for ATM. ATM depletion in metastatic cancer cells reduced cell migration and invasion. Transcription analyses identified a gene network, including the chemokine IL-8, regulated by ATM. IL-8 expression required ATM and was regulated by oxidative stress. IL-8 was validated as an ATM target by its ability to rescue cell migration and invasion defects in ATM-depleted cells. Finally, ATM-depletion in human breast cancer cells reduced lung tumors in a mouse xenograft model and clinical data validated IL-8 in lung metastasis. These findings provide insights into how ATM activation by oxidative stress regulates IL-8 to sustain cell migration and invasion in cancer cells to promote metastatic potential. Thus, in addition to well-established roles in tumor suppression, these findings identify a role for ATM in tumor progression.

  15. Mobile phone signal exposure triggers a hormesis-like effect in Atm(+/+) and Atm(-/-) mouse embryonic fibroblasts.

    PubMed

    Sun, Chuan; Wei, Xiaoxia; Fei, Yue; Su, Liling; Zhao, Xinyuan; Chen, Guangdi; Xu, Zhengping

    2016-11-18

    Radiofrequency electromagnetic fields (RF-EMFs) have been classified by the International Agency for Research on Cancer as possible carcinogens to humans; however, this conclusion is based on limited epidemiological findings and lacks solid support from experimental studies. In particular, there are no consistent data regarding the genotoxicity of RF-EMFs. Ataxia telangiectasia mutated (ATM) is recognised as a chief guardian of genomic stability. To address the debate on whether RF-EMFs are genotoxic, we compared the effects of 1,800 MHz RF-EMF exposure on genomic DNA in mouse embryonic fibroblasts (MEFs) with proficient (Atm(+/+)) or deficient (Atm(-/-)) ATM. In Atm(+/+) MEFs, RF-EMF exposure for 1 h at an average special absorption rate of 4.0 W/kg induced significant DNA single-strand breaks (SSBs) and activated the SSB repair mechanism. This effect reduced the DNA damage to less than that of the background level after 36 hours of exposure. In the Atm(-/-) MEFs, the same RF-EMF exposure for 12 h induced both SSBs and double-strand breaks and activated the two repair processes, which also reduced the DNA damage to less than the control level after prolonged exposure. The observed phenomenon is similar to the hormesis of a toxic substance at a low dose. To the best of our knowledge, this study is the first to report a hormesis-like effect of an RF-EMF.

  16. Targeting Human Poly(ADP-Ribose) Polymerase-1 with Natural Medicines and Its Potential Applications in Ovarian Cancer Therapeutics.

    PubMed

    Song, Min; Li, Jun-Lan; Li, Xiao-Ping; Kan, Shi-Feng

    2015-09-07

    Targeting poly(ADP-ribose) polymerase-1 (PARP-1) has been established as an efficient therapeutics for advanced ovarian cancer. In this study, we describe an integrated procedure that combines virtual computer screening and an experimental enzyme assay to discover novel potent PARP-1 inhibitors from more than 130000 commercially available natural products. The protocol employed a stepwise strategy to fast exclude typical PARP-1 non-binders and then performing rigorous prediction to identify promising candidates with high potency against PARP-1. Consequently, eight natural products were hit and tested to determine their inhibitory activities against the PARP-1 catalytic domain. From these, four compounds, i.e., puerarin, phloretin, chlorogenic acid, and biochanin A, were found to have high or moderate potencies with inhibitory IC50 values of 6, 470, 25, and 86 nM, respectively. The values are comparable to that (IC50  = 1.94 nM) of the FDA-approved agent olaparib. Structural and energetic analyses of the modeled structures of the PARP-1 catalytic domain complexed with the newly identified inhibitors revealed a common binding mode in the complexes: the active site of PARP-1 is composed of a thin polar helix and a flat non-polar pocket; the inhibitors can form a number of hydrogen bonds and electrostatic forces with the helix, while tightly packing against the pocket to define chemical interactions.

  17. ExpandplusCrystal Structures of Poly(ADP-ribose) Polymerase-1 (PARP-1) Zinc Fingers Bound to DNA

    SciTech Connect

    M Langelier; J Planck; S Roy; J Pascal

    2011-12-31

    Poly(ADP-ribose) polymerase-1 (PARP-1) has two homologous zinc finger domains, Zn1 and Zn2, that bind to a variety of DNA structures to stimulate poly(ADP-ribose) synthesis activity and to mediate PARP-1 interaction with chromatin. The structural basis for interaction with DNA is unknown, which limits our understanding of PARP-1 regulation and involvement in DNA repair and transcription. Here, we have determined crystal structures for the individual Zn1 and Zn2 domains in complex with a DNA double strand break, providing the first views of PARP-1 zinc fingers bound to DNA. The Zn1-DNA and Zn2-DNA structures establish a novel, bipartite mode of sequence-independent DNA interaction that engages a continuous region of the phosphodiester backbone and the hydrophobic faces of exposed nucleotide bases. Biochemical and cell biological analysis indicate that the Zn1 and Zn2 domains perform distinct functions. The Zn2 domain exhibits high binding affinity to DNA compared with the Zn1 domain. However, the Zn1 domain is essential for DNA-dependent PARP-1 activity in vitro and in vivo, whereas the Zn2 domain is not strictly required. Structural differences between the Zn1-DNA and Zn2-DNA complexes, combined with mutational and structural analysis, indicate that a specialized region of the Zn1 domain is re-configured through the hydrophobic interaction with exposed nucleotide bases to initiate PARP-1 activation.

  18. Proteomic investigation of phosphorylation sites in poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase.

    PubMed

    Gagné, Jean-Philippe; Moreel, Xavier; Gagné, Pierre; Labelle, Yves; Droit, Arnaud; Chevalier-Paré, Mélissa; Bourassa, Sylvie; McDonald, Darin; Hendzel, Michael J; Prigent, Claude; Poirier, Guy G

    2009-02-01

    Phosphorylation is a very common post-translational modification event known to modulate a wide range of biological responses. Beyond the regulation of protein activity, the interrelation of phosphorylation with other post-translational mechanisms is responsible for the control of diverse signaling pathways. Several observations suggest that phosphorylation of poly(ADP-ribose) polymerase-1 (PARP-1) regulates its activity. There is also accumulating evidence to suggest the establishment of phosphorylation-dependent assembly of PARP-1-associated multiprotein complexes. Although it is relatively straightforward to demonstrate phosphorylation of a defined target, identification of the actual amino acids involved still represents a technical challenge for many laboratories. With the use of a combination of bioinformatics-based predictions tools for generic and kinase-specific phosphorylation sites, in vitro phosphorylation assays and mass spectrometry analysis, we investigated the phosphorylation profile of PARP-1 and poly(ADP-ribose) glycohydrolase (PARG), two major enzymes responsible for poly(ADP-ribose) turnover. Mass spectrometry analysis revealed the phosphorylation of several serine/threonine residues within important regulatory domains and motifs of both enzymes. With the use of in vivo microirradiation-induced DNA damage, we show that altered phosphorylation at specific sites can modify the dynamics of assembly and disassembly of PARP-1 at sites of DNA damage. By documenting and annotating a collection of known and newly identified phosphorylation sites, this targeted proteomics study significantly advances our understanding of the roles of phosphorylation in the regulation of PARP-1 and PARG.

  19. Postnatal Age Influences Hypoglycemia-induced Poly(ADP-ribose) Polymerase-1 Activation in the Brain Regions of Rats

    PubMed Central

    Rao, Raghavendra; Sperr, Dustin; Ennis, Kathleen; Tran, Phu

    2009-01-01

    Poly(ADP-ribose) polymerase-1 (PARP-1) overactivation plays a significant role in hypoglycemia-induced brain injury in adult rats. To determine the influence of postnatal age on PARP-1 activation, developing and adult male rats were subjected to acute hypoglycemia of equivalent severity and duration. The expression of PARP-1 and its downstream effectors, apoptosis inducing factor (Aifm1), caspase 3 (Casp3), NF-κB (Nfkb1) and bcl-2 (Bcl2), and cellular poly(ADP-ribose) (PAR) polymer expression was assessed in the cerebral cortex, hippocampus, striatum and hypothalamus at 0 h and 24 h post-hypoglycemia. Compared with the control group, PARP-1 expression increased in the cerebral cortex of adult rats 24 h post-hypoglycemia, but not at 0 h, and was accompanied by increased number of PAR-positive cells. The expression was not altered in other brain regions. Aifm1, Nfkb1, Casp3, and Bcl2 expression also increased in the cerebral cortex of adult rats 24 h post-hypoglycemia. Conversely, hypoglycemia did not alter PARP-1 expression and its downstream effectors in any brain region in developing rats. These data parallel the previously demonstrated pattern of hypoglycemia-induced brain injury and suggest that PARP-1 overactivation may determine age- and region-specific vulnerability during hypoglycemia. PMID:19687776

  20. Acyl-CoA-binding domain containing 3 modulates NAD+ metabolism through activating poly(ADP-ribose) polymerase 1.

    PubMed

    Chen, Yong; Bang, Sookhee; Park, Soohyun; Shi, Hanyuan; Kim, Sangwon F

    2015-07-15

    NAD(+) plays essential roles in cellular energy homoeostasis and redox state, functioning as a cofactor along the glycolysis and citric acid cycle pathways. Recent discoveries indicated that, through the NAD(+)-consuming enzymes, this molecule may also be involved in many other cellular and biological outcomes such as chromatin remodelling, gene transcription, genomic integrity, cell division, calcium signalling, circadian clock and pluripotency. Poly(ADP-ribose) polymerase 1 (PARP1) is such an enzyme and dysfunctional PARP1 has been linked with the onset and development of various human diseases, including cancer, aging, traumatic brain injury, atherosclerosis, diabetes and inflammation. In the present study, we showed that overexpressed acyl-CoA-binding domain containing 3 (ACBD3), a Golgi-bound protein, significantly reduced cellular NAD(+) content via enhancing PARP1's polymerase activity and enhancing auto-modification of the enzyme in a DNA damage-independent manner. We identified that extracellular signal-regulated kinase (ERK)1/2 as well as de novo fatty acid biosynthesis pathways are involved in ACBD3-mediated activation of PARP1. Importantly, oxidative stress-induced PARP1 activation is greatly attenuated by knocking down the ACBD3 gene. Taken together, these findings suggest that ACBD3 has prominent impacts on cellular NAD(+) metabolism via regulating PARP1 activation-dependent auto-modification and thus cell metabolism and function.

  1. Poly(ADP-ribose)polymerase 1 stimulates the AP-site cleavage activity of tyrosyl-DNA phosphodiesterase 1.

    PubMed

    Lebedeva, Natalia A; Anarbaev, Rashid O; Sukhanova, Maria; Vasil'eva, Inna A; Rechkunova, Nadejda I; Lavrik, Olga I

    2015-06-15

    The influence of poly(ADP-ribose)polymerase 1 (PARP1) on the apurinic/apyrimidinic (AP)-site cleavage activity of tyrosyl-DNA phosphodiesterase 1 (TDP1) and interaction of PARP1 and TDP1 were studied. The efficiency of single or clustered AP-site hydrolysis catalysed by TDP1 was estimated. It was shown that the efficiency of AP-site cleavage increases in the presence of an additional AP-site in the opposite DNA strand depending on its position. PARP1 stimulates TDP1; the stimulation effect was abolished in the presence of NAD(+). The interaction of these two proteins was characterized quantitatively by measuring the dissociation constant for the TDP1-PARP1 complex using fluorescently-labelled proteins. The distance between the N-termini of the proteins within the complex was estimated using FRET. The data obtained suggest that PARP1 and TDP1 bind in an antiparallel orientation; the N-terminus of the former protein interacts with the C-terminal domain of the latter. The functional significance of PARP1 and TDP1 interaction in the process of DNA repair was demonstrated for the first time.

  2. Snowfall Rate Retrieval using NPP ATMS Passive Microwave Measurements

    NASA Technical Reports Server (NTRS)

    Meng, Huan; Ferraro, Ralph; Kongoli, Cezar; Wang, Nai-Yu; Dong, Jun; Zavodsky, Bradley; Yan, Banghua; Zhao, Limin

    2014-01-01

    Passive microwave measurements at certain high frequencies are sensitive to the scattering effect of snow particles and can be utilized to retrieve snowfall properties. Some of the microwave sensors with snowfall sensitive channels are Advanced Microwave Sounding Unit (AMSU), Microwave Humidity Sounder (MHS) and Advance Technology Microwave Sounder (ATMS). ATMS is the follow-on sensor to AMSU and MHS. Currently, an AMSU and MHS based land snowfall rate (SFR) product is running operationally at NOAA/NESDIS. Based on the AMSU/MHS SFR, an ATMS SFR algorithm has been developed recently. The algorithm performs retrieval in three steps: snowfall detection, retrieval of cloud properties, and estimation of snow particle terminal velocity and snowfall rate. The snowfall detection component utilizes principal component analysis and a logistic regression model. The model employs a combination of temperature and water vapor sounding channels to detect the scattering signal from falling snow and derive the probability of snowfall (Kongoli et al., 2014). In addition, a set of NWP model based filters is also employed to improve the accuracy of snowfall detection. Cloud properties are retrieved using an inversion method with an iteration algorithm and a two-stream radiative transfer model (Yan et al., 2008). A method developed by Heymsfield and Westbrook (2010) is adopted to calculate snow particle terminal velocity. Finally, snowfall rate is computed by numerically solving a complex integral. The ATMS SFR product is validated against radar and gauge snowfall data and shows that the ATMS algorithm outperforms the AMSU/MHS SFR.

  3. Assessment of asynchronous transfer mode (ATM) networks for regional teleradiology

    NASA Astrophysics Data System (ADS)

    Duerinckx, Andre J.; Hayrapetian, Alek S.; Valentino, Daniel J.; Grant, Edward G.; Rahbar, Darius; Kiszonas, Mike; Franco, Ricky; Shimabuku, Guy H.; Hagan, Girish T.; Melany, Michelle; Narin, Sherelle L.; Ragavendra, Nagesh

    1996-05-01

    The purpose of this study was to assess the effect of ATM network capabilities on the clinical practice of regional teleradiology, by providing immediate interactive radiology consultations between subspecialists and general radiologists at affiliated academic institutions. PACS installed at three affiliated hospitals (UCLA Medical Center, West LA VAMC and UCLA Olive-View Medical Centers) were connected via an ATM network. Two commercial PACS (Agfa) systems, one at the VAMC and one in an ultrasound outpatient clinic at UCLA were connected via ATM switches (Newbridge, Inc.) and a Santa Monica GTE central office switch. We evaluated this initial system configuration and measured image transfer performance, including memory-to-memory, disk-to-disk, disk-to-archive with and without DICOM protocols. Although the memory-to-memory data rate was 25 Mbps, the average remote disk-to-disk image transfer performance, using DICOM 3.0 communications protocols on SUN SPARCstation 10 servers, was 3 to 5 Mbps. Using these capabilities, timely interactive subspecialty consultations between radiologists was successfully performed while both were at different physical locations. We present the use of ATM technology in a realistic clinical environment and evaluate its impact on patient care and clinical teaching within the radiology departments of 2 institutions. Image communications over a regional PACS using an ATM network can allow interactive consultations between different subspecialist and general radiologists or other specialized radiologist spread over three different medical centers.

  4. The intronic splicing code: multiple factors involved in ATM pseudoexon definition.

    PubMed

    Dhir, Ashish; Buratti, Emanuele; van Santen, Maria A; Lührmann, Reinhard; Baralle, Francisco E

    2010-02-17

    Abundance of pseudo splice sites in introns can potentially give rise to innumerable pseudoexons, outnumbering the real ones. Nonetheless, these are efficiently ignored by the splicing machinery, a process yet to be understood completely. Although numerous 5' splice site-like sequences functioning as splicing silencers have been found to be enriched in predicted human pseudoexons, the lack of active pseudoexons pose a fundamental challenge to how these U1snRNP-binding sites function in splicing inhibition. Here, we address this issue by focusing on a previously described pathological ATM pseudoexon whose inhibition is mediated by U1snRNP binding at intronic splicing processing element (ISPE), composed of a consensus donor splice site. Spliceosomal complex assembly demonstrates inefficient A complex formation when ISPE is intact, implying U1snRNP-mediated unproductive U2snRNP recruitment. Furthermore, interaction of SF2/ASF with its motif seems to be dependent on RNA structure and U1snRNP interaction. Our results suggest a complex combinatorial interplay of RNA structure and trans-acting factors in determining the splicing outcome and contribute to understanding the intronic splicing code for the ATM pseudoexon.

  5. Homeostatic regulation of meiotic DSB formation by ATM/ATR

    SciTech Connect

    Cooper, Tim J.; Wardell, Kayleigh; Garcia, Valerie; Neale, Matthew J.

    2014-11-15

    Ataxia–telangiectasia mutated (ATM) and RAD3-related (ATR) are widely known as being central players in the mitotic DNA damage response (DDR), mounting responses to DNA double-strand breaks (DSBs) and single-stranded DNA (ssDNA) respectively. The DDR signalling cascade couples cell cycle control to damage-sensing and repair processes in order to prevent untimely cell cycle progression while damage still persists [1]. Both ATM/ATR are, however, also emerging as essential factors in the process of meiosis; a specialised cell cycle programme responsible for the formation of haploid gametes via two sequential nuclear divisions. Central to achieving accurate meiotic chromosome segregation is the introduction of numerous DSBs spread across the genome by the evolutionarily conserved enzyme, Spo11. This review seeks to explore and address how cells utilise ATM/ATR pathways to regulate Spo11-DSB formation, establish DSB homeostasis and ensure meiosis is completed unperturbed.

  6. Homeostatic regulation of meiotic DSB formation by ATM/ATR.

    PubMed

    Cooper, Tim J; Wardell, Kayleigh; Garcia, Valerie; Neale, Matthew J

    2014-11-15

    Ataxia-telangiectasia mutated (ATM) and RAD3-related (ATR) are widely known as being central players in the mitotic DNA damage response (DDR), mounting responses to DNA double-strand breaks (DSBs) and single-stranded DNA (ssDNA) respectively. The DDR signalling cascade couples cell cycle control to damage-sensing and repair processes in order to prevent untimely cell cycle progression while damage still persists [1]. Both ATM/ATR are, however, also emerging as essential factors in the process of meiosis; a specialised cell cycle programme responsible for the formation of haploid gametes via two sequential nuclear divisions. Central to achieving accurate meiotic chromosome segregation is the introduction of numerous DSBs spread across the genome by the evolutionarily conserved enzyme, Spo11. This review seeks to explore and address how cells utilise ATM/ATR pathways to regulate Spo11-DSB formation, establish DSB homeostasis and ensure meiosis is completed unperturbed.

  7. Poly (ADP-ribose) polymerase-1 inhibitor, 3-aminobenzamide pretreatment ameliorates lipopolysaccharide-induced neurobehavioral and neurochemical anomalies in mice.

    PubMed

    Sriram, Chandra Shaker; Jangra, Ashok; Gurjar, Satendra Singh; Hussain, Md Iftikar; Borah, Probodh; Lahkar, Mangala; Mohan, Pritam; Bezbaruah, Babul Kumar

    2015-06-01

    Poly (ADP-ribose) polymerase-1 (PARP-1) functions at the center of cellular stress and sways the immune system at several key points, thus modulates inflammatory diseases. The antiinflammatory properties of PARP-1 inhibitors have been demonstrated ameliorating effect in various neuroinflammatory disorders. It has been reported that there is a close relationship between the inflammatory processes and major depressive disorder. In the present study, we have elucidated the role of oxidative-nitrosative stress-PARP-1 pathway in lipopolysaccharide (LPS)-induced neurobehavioral and neurochemical alterations in mice. 3-Aminobenzamide (10 and 30mg/kg) and imipramine (10 and 30mg/kg) were administered once daily for 14days. Mice were challenged with LPS (1mg/kg, i.p.) 30min after drug administration on the 14th day. The mRNA expression level of PARP-1 (12h after LPS injection) in the hippocampus was measured through quantitative real-time PCR. All the behavioral and biochemical parameters were assessed at 24h after LPS injection. The expression level of PARP-1mRNA was found significantly up-regulated in the hippocampus at 12h after LPS administration. Results showed that the LPS-challenged mice exhibited an increase in immobility time seen in forced swimming test and tail suspension test. LPS increased the levels of proinflammatory cytokines and oxido-nitrosative stress parameters in the hippocampus. However, pretreatment with 3-aminobenzamide (30mg/kg) significantly reversed the LPS-induced alterations in behavioral parameters, proinflammatory cytokines, oxidative-nitrosative stress and PARP-1 mRNA levels. Imipramine failed to prevent the up-regulation of PARP-1 induced by LPS administration. Our results emphasized that oxidative-nitrosative stress-PARP-1 cascade can play a key role in LPS-induced neurobehavioral and neurochemical anomalies.

  8. Transition in Survival From Low-Dose Hyper-Radiosensitivity to Increased Radioresistance Is Independent of Activation of ATM SER1981 Activity

    SciTech Connect

    Krueger, Sarah A.; Collis, Spencer J.; Joiner, Michael C.; Wilson, George D.; Marples, Brian

    2007-11-15

    Purpose: The molecular basis of low-dose hyper-radiosensitivity (HRS) is only partially understood. The aim of this study was to define the roles of ataxia telangiectasia mutated (ATM) activity and the downstream ATM-dependent G{sub 2}-phase cell cycle checkpoint in overcoming HRS and triggering radiation resistance. Methods and Materials: Survival was measured using a high-resolution clonogenic assay. ATM Ser1981 activation was measured by Western blotting. The role of ATM was determined in survival experiments after molecular (siRNA) and chemical (0.4 mM caffeine) inhibition and chemical (20 {mu}g/mL chloroquine, 15 {mu}M genistein) activation 4-6 h before irradiation. Checkpoint responsiveness was assessed in eight cell lines of differing HRS status using flow cytometry to quantify the progression of irradiated (0-2 Gy) G{sub 2}-phase cells entering mitosis, using histone H3 phosphorylation analysis. Results: The dose-response pattern of ATM activation was concordant with the transition from HRS to radioresistance. However, ATM activation did not play a primary role in initiating increased radioresistance. Rather, a relationship was discovered between the function of the downstream ATM-dependent early G{sub 2}-phase checkpoint and the prevalence and overcoming of HRS. Four cell lines that exhibited HRS failed to show low-dose (<0.3-Gy) checkpoint function. In contrast, four HRS-negative cell lines exhibited immediate cell cycle arrest for the entire 0-2-Gy dose range. Conclusion: Overcoming HRS is reliant on the function of the early G{sub 2}-phase checkpoint. These data suggest that clinical exploitation of HRS could be achieved by combining radiotherapy with chemotherapeutic agents that modulate this cell cycle checkpoint.

  9. The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells

    PubMed Central

    Tomasella, Andrea; Picco, Raffaella; Ciotti, Sonia; Sgorbissa, Andrea; Bianchi, Elisa; Manfredini, Rossella; Benedetti, Fabio; Trimarco, Valentina; Frezzato, Federica; Trentin, Livio; Semenzato, Gianpietro; Delia, Domenico; Brancolini, Claudio

    2016-01-01

    Relapse after treatment is a common and unresolved problem for patients suffering of the B-cell chronic lymphocytic leukemia (B-CLL). Here we investigated the ability of the isopeptidase inhibitor 2cPE to trigger apoptosis in leukemia cells in comparison with bortezomib, another inhibitor of the ubiquitin-proteasome system (UPS). Both inhibitors trigger apoptosis in CLL B cells and gene expression profiles studies denoted how a substantial part of genes up-regulated by these compounds are elements of adaptive responses, aimed to sustain cell survival. 2cPE treatment elicits the up-regulation of chaperones, proteasomal subunits and elements of the anti-oxidant response. Selective inhibition of these responses augments apoptosis in response to 2cPE treatment. We have also observed that the product of the ataxia telangiectasia mutated gene (ATM) is activated in 2cPE treated cells. Stimulation of ATM signaling is possibly dependent on the alteration of the redox homeostasis. Importantly ATM inhibition, mutations or down-modulation increase cell death in response to 2cPE. Overall this work suggests that 2cPE could offer new opportunities for the treatment of B-CLL. PMID:27259251

  10. Skylab ATM/S-056 X-ray event analyzer observations versus solar flare activity: An event compilation. [tables (data)

    NASA Technical Reports Server (NTRS)

    Wilson, R. M.

    1977-01-01

    An event compilation is presented which correlates ATM/S-056 X-ray event analyzer solar observations with solar flare activity. Approximately 1,070 h of pulse height analyzed X-ray proportional counter data were obtained with the X-ray event analyzer during Skylab. During its operation, 449 flares (including 343 flare peaks) were observed. Seventy events of peak X-ray emission or = Cl were simultaneously observed by ground based telescopes, SOLRAD 9 and/or Vela, and the X-ray event analyzer. These events were observed from preflare through flare rise to peak and through flare decline.

  11. Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2

    PubMed Central

    Inoue, Satoshi; Li, Wanda Y.; Tseng, Alan; Beerman, Isabel; Elia, Andrew J.; Bendall, Sean C.; Lemonnier, François; Kron, Ken J.; Cescon, David W.; Hao, Zhenyue; Lind, Evan F.; Takayama, Naoya; Planello, Aline C.; Shen, Shu Yi; Shih, Alan H.; Larsen, Dana M.; Li, Qinxi; Snow, Bryan E.; Wakeham, Andrew; Haight, Jillian; Gorrini, Chiara; Bassi, Christian; Thu, Kelsie L.; Murakami, Kiichi; Elford, Alisha R.; Ueda, Takeshi; Straley, Kimberly; Yen, Katharine E.; Melino, Gerry; Cimmino, Luisa; Aifantis, Iannis; Levine, Ross L.; De Carvalho, Daniel D.; Lupien, Mathieu; Rossi, Derrick J.; Nolan, Garry P.; Cairns, Rob A.; Mak, Tak W.

    2016-01-01

    SUMMARY Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSC), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia. PMID:27424808

  12. Characterization of spent fuel approved testing material: ATM-106

    SciTech Connect

    Guenther, R.J.; Blahnik, D.E.; Campbell, T.K.; Jenquin, U.P.; Mendel, J.E.; Thornhill, C.K.

    1988-10-01

    The characterization data obtained to date are described for Approved Testing Material (ATM)-106 spent fuel from Assembly BT03 of pressurized-water reactor Calvert Cliffs No. 1. This report is one in a series being prepared by the Materials Characterization Center at Pacific Northwest Laboratory on spent fuel ATMs. The ATMs are receiving extensive examinations to provide a source of well- characterized spent fuel for testing in the US Department of Energy Office of Civilian Radioactive Waste Management (OCWRM) program. ATM-106 consists of 20 full-length irradiated fuel rods with rod-average burnups of about 3700 GJ/kgM (43 MWd/kgM) and expected fission gas release of /approximately/10%. Characterization data include (1) as-fabricated fuel design, irradiation history, and subsequent storage and handling; (2) isotopic gamma scans; (3) fission gas analyses; (4) ceramography of the fuel and metallography of the cladding; (5) calculated nuclide inventories and radioactivities in the fuel and cladding; and (6) radiochemical analyses of the fuel and cladding. Additional analyses of the fuel rod are being conducted and will be included in planned revisions of this report. 12 refs., 110 figs., 81 tabs.

  13. The ATM signaling network in development and disease

    PubMed Central

    Stracker, Travis H.; Roig, Ignasi; Knobel, Philip A.; Marjanović, Marko

    2013-01-01

    The DNA damage response (DDR) rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence (Jackson and Bartek, 2009). DNA double-strand breaks (DSBs) represent one of the most cytotoxic DNA lesions and defects in their metabolism underlie many human hereditary diseases characterized by genomic instability (Stracker and Petrini, 2011; McKinnon, 2012). Patients with hereditary defects in the DDR display defects in development, particularly affecting the central nervous system, the immune system and the germline, as well as aberrant metabolic regulation and cancer predisposition. Central to the DDR to DSBs is the ataxia-telangiectasia mutated (ATM) kinase, a master controller of signal transduction. Understanding how ATM signaling regulates various aspects of the DDR and its roles in vivo is critical for our understanding of human disease, its diagnosis and its treatment. This review will describe the general roles of ATM signaling and highlight some recent advances that have shed light on the diverse roles of ATM and related proteins in human disease. PMID:23532176

  14. NPP ATMS Prelaunch Performance Assessment and Sensor Data Record Validation

    DTIC Science & Technology

    2011-04-29

    Joint Airborne IASI Yalidation Experiment (JAlYEx 2007, Houston, TX). Radiance differences between the NAST-M sensor and the Advanced Microwave...34Evaluation OfCRIS/ATMS Proxy RadianceslRetrievais With IASI Retrievals, ECMWF Analysis and RAOB Measurements," IEEE Proc. IGARSS, July, 20 I O. G. A

  15. Profiling of UV-induced ATM/ATR signaling pathways

    PubMed Central

    Stokes, Matthew P.; Rush, John; MacNeill, Joan; Ren, Jian Min; Sprott, Kam; Nardone, Julie; Yang, Vicky; Beausoleil, Sean A.; Gygi, Steven P.; Livingstone, Mark; Zhang, Hui; Polakiewicz, Roberto D.; Comb, Michael J.

    2007-01-01

    To ensure survival in the face of genomic insult, cells have evolved complex mechanisms to respond to DNA damage, termed the DNA damage checkpoint. The serine/threonine kinases ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) activate checkpoint signaling by phosphorylating substrate proteins at SQ/TQ motifs. Although some ATM/ATR substrates (Chk1, p53) have been identified, the lack of a more complete list of substrates limits current understanding of checkpoint pathways. Here, we use immunoaffinity phosphopeptide isolation coupled with mass spectrometry to identify 570 sites phosphorylated in UV-damaged cells, 498 of which are previously undescribed. Semiquantitative analysis yielded 24 known and 192 previously uncharacterized sites differentially phosphorylated upon UV damage, some of which were confirmed by SILAC, Western blotting, and immunoprecipitation/Western blotting. ATR-specific phosphorylation was investigated by using a Seckel syndrome (ATR mutant) cell line. Together, these results provide a rich resource for further deciphering ATM/ATR signaling and the pathways mediating the DNA damage response. PMID:18077418

  16. Characterization of spent fuel approved testing material: ATM-103

    SciTech Connect

    Guenther, R.J.; Blahnik, D.E.; Campbell, T.K.; Jenquin, U.P.; Mendel, J.E.; Thomas, L.E.; Thornhill, C.K.

    1988-04-01

    The characterization data obtained to date are described for Approved Testing Material (ATM)-103, which is spent fuel from Assembly D101 of pressurized-water reactor Calvert Cliffs, No. 1. This report is one in a series being written by the Materials Characterization Center (MCC) at Pacific Northwest Laboratory (PNL) on spent fuel ATMs. The ATMs are receiving extensive examinations to provide a source of well-characterized spent fuel for testing in the US nuclear waste repository program. ATM-103 consists of 176 full-length irradiated fuel rods with rod-average burnups of about 2600 GJ/kgM (30 MWd/kgM) and less than 1% fission gas release. Characterization data include 1) as-fabricated fuel design, irradiation history, and subsequent storage and handling; 2) isotopic gamma scans; 3) fission gas analyses; 4) ceramography of the fuel and metallography of the cladding; 5) special fuels studies involving analytical transmission electron microscopy (AEM); 6) calculated nuclide inventories and radioactivities in the fuel and cladding; and 7) radiochemical analyses of the fuel and cladding. Additional analyses of the fuel are being conducted and will be included in planned revisions of this report. 10 refs., 103 figs., 63 tabs.

  17. U-View: Student Access to Information Using ATMs.

    ERIC Educational Resources Information Center

    Springfield, John J.

    1990-01-01

    A discussion of Boston College's system allowing students to display and print their campus records at automated teller machines (ATMs) around the institution looks at the system's evolution, current operations, human factors affecting system design and operation, shared responsibility, campus acceptance, future enhancements, and cost…

  18. ATM facilitates mouse gammaherpesvirus reactivation from myeloid cells during chronic infection.

    PubMed

    Kulinski, Joseph M; Darrah, Eric J; Broniowska, Katarzyna A; Mboko, Wadzanai P; Mounce, Bryan C; Malherbe, Laurent P; Corbett, John A; Gauld, Stephen B; Tarakanova, Vera L

    2015-09-01

    Gammaherpesviruses are cancer-associated pathogens that establish life-long infection in most adults. Insufficiency of Ataxia-Telangiectasia mutated (ATM) kinase leads to a poor control of chronic gammaherpesvirus infection via an unknown mechanism that likely involves a suboptimal antiviral response. In contrast to the phenotype in the intact host, ATM facilitates gammaherpesvirus reactivation and replication in vitro. We hypothesized that ATM mediates both pro- and antiviral activities to regulate chronic gammaherpesvirus infection in an immunocompetent host. To test the proposed proviral activity of ATM in vivo, we generated mice with ATM deficiency limited to myeloid cells. Myeloid-specific ATM deficiency attenuated gammaherpesvirus infection during the establishment of viral latency. The results of our study uncover a proviral role of ATM in the context of gammaherpesvirus infection in vivo and support a model where ATM combines pro- and antiviral functions to facilitate both gammaherpesvirus-specific T cell immune response and viral reactivation in vivo.

  19. The Relationships between Selected Organizational Variables and ATM Technology Adoption in Campus Networking.

    ERIC Educational Resources Information Center

    Yao, Engui

    1998-01-01

    Determines the relationships between ATM (Asynchronous Transfer Mode) adoption and four organizational variables: university size, type, finances, and information-processing maturity. Identifies the current status of ATM adoption in campus networking in the United States. Contains 33 references. (DDR)

  20. ATM is required for rapid degradation of cyclin D1 in response to {gamma}-irradiation

    SciTech Connect

    Choo, Dong Wan; Baek, Hye Jung; Motoyama, Noboru; Cho, Kwan Ho; Kim, Hye Sun; Kim, Sang Soo

    2009-01-23

    The cellular response to DNA damage induced by {gamma}-irradiation activates cell-cycle arrest to permit DNA repair and to prevent replication. Cyclin D1 is the key molecule for transition between the G1 and S phases of the cell-cycle, and amplification or overexpression of cyclin D1 plays pivotal roles in the development of several human cancers. To study the regulation of cyclin D1 in the DNA-damaged condition, we analyzed the proteolytic regulation of cyclin D1 expression upon {gamma}-irradiation. Upon {gamma}-irradiation, a rapid reduction in cyclin D1 levels was observed prior to p53 stabilization, indicating that the stability of cyclin D1 is controlled in a p53-independent manner. Further analysis revealed that irradiation facilitated ubiquitination of cyclin D1 and that a proteasome inhibitor blocked cyclin D1 degradation under the same conditions. Interestingly, after mutation of threonine residue 286 of cyclin D1, which is reported to be the GSK-3{beta} phosphorylation site, the mutant protein showed resistance to irradiation-induced proteolysis although inhibitors of GSK-3{beta} failed to prevent cyclin D1 degradation. Rather, ATM inhibition markedly prevented cyclin D1 degradation induced by {gamma}-irradiation. Our data indicate that communication between ATM and cyclin D1 may be required for maintenance of genomic integrity achieved by rapid arrest of the cell-cycle, and that disruption of this crosstalk may increase susceptibility to cancer.

  1. AIF-mediated caspase-independent necroptosis requires ATM and DNA-PK-induced histone H2AX Ser139 phosphorylation

    PubMed Central

    Baritaud, M; Cabon, L; Delavallée, L; Galán-Malo, P; Gilles, M-E; Brunelle-Navas, M-N; Susin, S A

    2012-01-01

    The alkylating DNA-damage agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) induces a form of caspase-independent necroptosis implicating the mitochondrial flavoprotein apoptosis-inducing factor (AIF). Following the activation of PARP-1 (poly(ADP-ribose) polymerase-1), calpains, BID (BH3 interacting domain death agonist), and BAX (Bcl-2-associated X protein), the apoptogenic form of AIF (tAIF) is translocated to the nucleus where, associated with Ser139-phosphorylated histone H2AX (γH2AX), it creates a DNA-degrading complex that provokes chromatinolysis and cell death by necroptosis. The generation of γH2AX is crucial for this form of cell death, as mutation of H2AX Ser139 to Ala or genetic ablation of H2AX abolish both chromatinolysis and necroptosis. On the contrary, reintroduction of H2AX-wt or the phosphomimetic H2AX mutant (H2AX-S139E) into H2AX−/− cells resensitizes to MNNG-triggered necroptosis. Employing a pharmacological approach and gene knockout cells, we also demonstrate in this paper that the phosphatidylinositol-3-OH kinase-related kinases (PIKKs) ATM (ataxia telangiectasia mutated) and DNA-dependent protein kinase (DNA-PK) mediate γH2AX generation and, consequently, MNNG-induced necroptosis. By contrast, H2AX phosphorylation is not regulated by ATR or other H2AX-related kinases, such as JNK. Interestingly, ATM and DNA-PK phosphorylate H2AX at Ser139 in a synergistic manner with different kinetics of activation. Early after MNNG treatment, ATM generates γH2AX. Further, DNA-PK contributes to H2AX Ser139 phosphorylation. In revealing the pivotal role of PIKKs in MNNG-induced cell death, our data uncover a milestone in the mechanisms regulating AIF-mediated caspase-independent necroptosis. PMID:22972376

  2. Application of Computer Simulation to Teach ATM Access to Individuals with Intellectual Disabilities

    ERIC Educational Resources Information Center

    Davies, Daniel K.; Stock, Steven E.; Wehmeyer, Michael L.

    2003-01-01

    This study investigates use of computer simulation for teaching ATM use to adults with intellectual disabilities. ATM-SIM is a computer-based trainer used for teaching individuals with intellectual disabilities how to use an automated teller machine (ATM) to access their personal bank accounts. In the pilot evaluation, a prototype system was…

  3. Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics

    PubMed Central

    Luczak, Michal W.; Green, Samantha E.; Zhitkovich, Anatoly

    2015-01-01

    Background Carcinogenic hexavalent chromium [Cr(VI)] requires cellular reduction to generate DNA damage. Metabolism of Cr(VI) by its principal reducer ascorbate (Asc) lacks a Cr(V) intermediate, which is abundant in reactions with a minor reducing agent, glutathione. Cultured cells are widely used in mechanistic studies of Cr(VI) toxicity; however, they typically contain < 1% of normal Asc levels. Asc deficiency is also expected to diminish protection against reactive oxygen species. Objectives We assessed how the presence of Asc in cells affects their stress signaling and survival responses to chromate. Methods We investigated the effects of Asc restoration in human lung H460 cells and normal human lung fibroblasts on the activation and functional role of ATM kinase, which controls DNA damage responses involving several hundreds of proteins. Results Treatment of standard cultures with Cr(VI) strongly activated ATM, as indicated by its automodification at Ser1981 and by phosphorylation of checkpoint kinase 2 (CHK2) and chromatin/transcription regulator KRAB-associated protein 1 (KAP1). Confirming the importance of activated ATM, its inhibition impaired replication recovery and clonogenic survival. In contrast, fully Asc-restored cells lacked ATM activation by Cr(VI), and ATM silencing produced no significant effects on p53 stabilization, apoptosis, replication recovery, or clonogenic survival. Dose dependence studies found a close correlation between ATM activation and the extent of Cr(VI) reduction by glutathione. Conclusions Asc restoration in cultured cells dramatically altered their stress responses to Cr(VI) by preventing activation of the oxidant-sensitive ATM network. We suggest that toxicogenomic and other cell response-based approaches likely underestimate Cr(VI) genotoxicity when standard ATM-activating carcinogens are used as references. Citation Luczak MW, Green SE, Zhitkovich A. 2016. Different ATM signaling in response to chromium(VI) metabolism via

  4. Chromosomal damage and micronucleus induction by MP-124, a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor: Evidence for a non-DNA-reactive mode of action.

    PubMed

    Yamamura, Eiji; Muto, Shigeharu; Yamada, Katsuya; Sato, Yuko; Iwase, Yumiko; Uno, Yoshifumi

    2015-04-01

    MP-124, a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor that competes with the binding of the PARP substrate nicotinamide adenine dinucleotide (NAD), is being developed as a neuroprotective agent against acute ischemic stroke. MP-124 increased structural chromosomal aberration in CHL/IU cells, but showed negative results in the bacterial reverse mutation test, and the rat bone marrow micronucleus (MN) and the rat liver unscheduled DNA synthesis tests after the intravenous bolus injection. Thus, MP-124 did not appear to be direct-acting mutagen. Since, PARP-1 is a key enzyme in DNA repair, the effect of continuous PARP-1 inhibition by MP-124 was further examined in the rat MN test under 24-h intravenous infusion, and an increase in micronucleated immature erythrocytes (MNIE) was observed. The increase was clearly reduced by co-treatment with nicotinic acid, which resulted in increased intracellular NAD levels. This is consistent with the established activity of MP-124 as a competitive inhibitor of PARP and provides strong evidence that the DNA-damaging effect that leads to the increase in MNIE is a secondary effect of PARP-1 inhibition. This mechanism is expected to result in a threshold for the induction of MNIE by MP-124, and allows for the establishment of a safe margin of exposure for the therapeutic use of MP-124.

  5. Targeting the kinase activities of ATR and ATM exhibits therapeutic potential in a mouse model of MLL-rearranged AML

    PubMed Central

    Lafarga, Vanesa; Anton, Marta Elena; Tubbs, Anthony; Chen, Hua Tang; Ergan, Aysegul; Anderson, Rhonda; Bhandoola, Avinash; Pike, Kurt G.; Barlaam, Bernard; Cadogan, Elaine; Wang, Xi; Pierce, Andrew J.; Hubbard, Chad; Armstrong, Scott A.; Nussenzweig, André; Fernandez-Capetillo, Oscar

    2016-01-01

    Among the various subtypes of Acute Myeloid Leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies due to an attenuated response by p53, which induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AMLMLL cells (with an MLL-ENL fusion and a constitutively active N-RAS) independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AMLMLL and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AMLMLL mice. Collectively, these data indicated that ATR and ATM inhibition represent potential alternative therapeutic strategies for the treatment of AML, especially MLL-driven leukemias. PMID:27625305

  6. Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.

    PubMed

    Morgado-Palacin, Isabel; Day, Amanda; Murga, Matilde; Lafarga, Vanesa; Anton, Marta Elena; Tubbs, Anthony; Chen, Hua-Tang; Ergan, Aysegul; Anderson, Rhonda; Bhandoola, Avinash; Pike, Kurt G; Barlaam, Bernard; Cadogan, Elaine; Wang, Xi; Pierce, Andrew J; Hubbard, Chad; Armstrong, Scott A; Nussenzweig, André; Fernandez-Capetillo, Oscar

    2016-09-13

    Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias.

  7. Alpha particles induce pan-nuclear phosphorylation of H2AX in primary human lymphocytes mediated through ATM.

    PubMed

    Horn, Simon; Brady, Darren; Prise, Kevin

    2015-10-01

    The use of high linear energy transfer radiations in the form of carbon ions in heavy ion beam lines or alpha particles in new radionuclide treatments has increased substantially over the past decade and will continue to do so due to the favourable dose distributions they can offer versus conventional therapies. Previously it has been shown that exposure to heavy ions induces pan-nuclear phosphorylation of several DNA repair proteins such as H2AX and ATM in vitro. Here we describe similar effects of alpha particles on ex vivo irradiated primary human peripheral blood lymphocytes. Following alpha particle irradiation pan-nuclear phosphorylation of H2AX and ATM, but not DNA-PK and 53BP1, was observed throughout the nucleus. Inhibition of ATM, but not DNA-PK, resulted in the loss of pan-nuclear phosphorylation of H2AX in alpha particle irradiated lymphocytes. Pan-nuclear gamma-H2AX signal was rapidly lost over 24h at a much greater rate than foci loss. Surprisingly, pan-nuclear gamma-H2AX intensity was not dependent on the number of alpha particle induced double strand breaks, rather the number of alpha particles which had traversed the cell nucleus. This distinct fluence dependent damage signature of particle radiation is important in both the fields of radioprotection and clinical oncology in determining radionuclide biological dosimetry and may be indicative of patient response to new radionuclide cancer therapies.

  8. Digital Coin Business Model Using the Coin ATM

    NASA Astrophysics Data System (ADS)

    Jung, Won-Gyo; Park, Sang-Sung; Shin, Young-Geun; Jang, Dong-Sik

    2009-08-01

    Because about 83.6 billion won worth coins are not collected annually, 35 billion won of government money is being wasted for producing new coins in Korea. In order to improve unnecessary government money leakage, we now have to develop a proper way of managing small valued money such as coins. We have already developed the coin ATM to solve such problem in the previous study. In this study, we proposed business model, which enables users to deposit or consume such small amount of money with the coin ATM. The proposed business model has advantages that enable to connect various payment system and is efficient to consume such small amount of money. This business model improves not only the way of managing small valued money but also the way of consuming small valued money. Furthermore, our business model can contribute to activating circulation of coins as well as preventing leakage of government money.

  9. ATM solar array in-flight performance analysis

    NASA Technical Reports Server (NTRS)

    Thornton, J. P.; Crabtree, L. W.

    1974-01-01

    The physical and electrical characteristics of the Apollo Telescope Mount (ATM) solar array are described and in-flight performance data are analyzed and compared with predicted results. Two solar cell module configurations were used. Type I module consists of 228 2 x 6 cm solar cells with two cells in parallel and 114 cells in series. Type II modules contain 684 2 x 2 cm cells with six cells in parallel and 114 cells in series. A different interconnection scheme was used for each type. Panels using type II modules with mesh interconnect system performed marginally better than those using type I module with loop interconnect system. The average degradation rate for the ATM array was 8.2% for a 271-day mission.

  10. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.

    PubMed

    Wang, Chen; Jette, Nicholas; Moussienko, Daniel; Bebb, D Gwyn; Lees-Miller, Susan P

    2017-02-06

    The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor.

  11. ATM Coastal Topography-Texas, 2001: UTM Zone 15

    USGS Publications Warehouse

    Klipp, Emily S.; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Yates, Xan; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of a portion of the Texas coastline within UTM zone 15, from Matagorda Peninsula to Galveston Island, acquired October 12-13, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant

  12. ATM Coastal Topography-Florida 2001: Western Panhandle

    USGS Publications Warehouse

    Yates, Xan; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of Lidar-derived first surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of the western Florida panhandle coastline, acquired October 2-4 and 7-10, 2001. The datasets are made available for use as a management tool to research scientists and natural resource managers. An innovative scanning Lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning Lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of Lidar data in an interactive or batch mode. Modules for presurvey flight line definition, flight path plotting, Lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS is routinely used

  13. ATM Coastal Topography-Texas, 2001: UTM Zone 14

    USGS Publications Warehouse

    Klipp, Emily S.; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Yates, Xan; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of a portion of the Texas coastline within UTM zone 14, acquired October 12-13, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS is used

  14. ATM Coastal Topography-Florida 2001: Eastern Panhandle

    USGS Publications Warehouse

    Yates, Xan; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Bonisteel, Jamie M.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of Lidar-derived first surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of the eastern Florida panhandle coastline, acquired October 2, 2001. The datasets are made available for use as a management tool to research scientists and natural resource managers. An innovative scanning Lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning Lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of Lidar data in an interactive or batch mode. Modules for presurvey flight line definition, flight path plotting, Lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last significant return within each waveform. ALPS is routinely used to create

  15. The effect of algorithm-agile encryption on ATM quality of service

    SciTech Connect

    Sholander, P.; Tarman, T.; Pierson, L.; Hutchinson, R.

    1997-04-01

    Asynchronous Transfer Mode (ATM) users often open multiple ATM Virtual Circuits (VCs) to multiple ATM users on multiple ATM networks. Each network and user may implement a different encryption policy. Hence ATM users may need shared, flexible hardware-based 3encryption that supports multiple encryption algorithms for multiple concurrent ATM users and VCs. An algorithm-agile encryption architecture, that uses multiple, parallel encryption-pipelines, is proposed. That algorithm-agile encryptor`s effect on the ATM Quality of Service (QoS) metrics, such as Cell Transfer Delay (CTD) and Cell Delay Variation (CDV), is analyzed. Bounds on the maximum CDV and the CDV`s probability density are derived.

  16. Final report for the protocol extensions for ATM Security Laboratory Directed Research and Development Project

    SciTech Connect

    Tarman, T.D.; Pierson, L.G.; Brenkosh, J.P.

    1996-03-01

    This is the summary report for the Protocol Extensions for Asynchronous Transfer Mode project, funded under Sandia`s Laboratory Directed Research and Development program. During this one-year effort, techniques were examined for integrating security enhancements within standard ATM protocols, and mechanisms were developed to validate these techniques and to provide a basic set of ATM security assurances. Based on our experience during this project, recommendations were presented to the ATM Forum (a world-wide consortium of ATM product developers, service providers, and users) to assist with the development of security-related enhancements to their ATM specifications. As a result of this project, Sandia has taken a leading role in the formation of the ATM Forum`s Security Working Group, and has gained valuable alliances and leading-edge experience with emerging ATM security technologies and protocols.

  17. Transputer-based architecture for ATM LAN protocol testing

    NASA Astrophysics Data System (ADS)

    Di Concetto, M.; Crocetti, P.; Marino, G.; Merli, E.; Pavesi, M.; Zizza, F.

    1993-10-01

    Local Area Networks (LANs) have completed two generations of development (Ethernet and Token Ring the first, and FDDI and DQDB the second); the large volumes of traffic involved in the emerging multimedia applications, however, lead towards a third generation of LANs. This generation must provide real-time capabilities needed by new services and solve the problems of interworking with ATM-based B-ISDN. Moreover the possibility to vary the subscribed bandwidth with the B-ISDN will be given to the LAN interfaces. This paper focuses on an architecture for protocol testing of a Dynamic Bandwidth Allocation Protocol inserted in a LAN environment based on ATM technology. In fact, the technology of the third LAN generation will be the Asynchronous Transfer Mode solving every interface problem with the public B-ISDN. A testing and debugging environment which checks the implementation of the Dynamic Bandwidth Allocation Protocol at the interface host/LAN- ATM is discussed. The main concepts of the overall system architecture are analyzed, evidencing both software and hardware issues.

  18. DHPLC Screening of ATM Gene in Italian Patients Affected by Ataxia-Telangiectasia: Fourteen Novel ATM Mutations

    PubMed Central

    Magliozzi, Monia; Piane, Maria; Torrente, Isabella; Sinibaldi, Lorenzo; Rizzo, Giovanni; Savio, Camilla; Lulli, Patrizia; De Luca, Alessandro; Dallapiccola, Bruno; Chessa, Luciana

    2006-01-01

    The gene for ataxia-telangiectasia (A-T:MIM:#208900), ATM, spans about 150~kb of genomic DNA and is composed of 62 coding exons. ATM mutations are found along the entire coding sequence of the gene, without evidence of mutational hot spots. Using DNA as the starting material, we used denaturing high performance liquid chromatography (DHPLC) technique to search for ATM gene mutations. Initially, DHPLC was validated in a retrospective study of 16 positive control samples that included 19 known mutations; 100% of mutations were detected. Subsequently, DHPLC was used to screen for mutations a cohort of 22 patients with the classical form of A-T. A total of 27 different mutations were identified on 38 of the 44 alleles, corresponding to a 86% detection rate. Fourteen of the mutations were novel. In addition, 15 different variants and polymorphisms of unknown functional significance were found. The high incidence of new and individual A-T mutations in our cohort of patients demonstrates marked mutational heterogeneity of A-T in Italy and corroborate the efficiency of DHPLC as a method for the mutation screening of A-T patients. PMID:17124347

  19. Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice.

    PubMed

    Pietzner, J; Merscher, B M; Baer, P C; Duecker, R P; Eickmeier, O; Fußbroich, D; Bader, P; Del Turco, D; Henschler, R; Zielen, S; Schubert, R

    2016-04-01

    Ataxia telangiectasia is a genetic instability syndrome characterized by neurodegeneration, immunodeficiency, severe bronchial complications, hypersensitivity to radiotherapy and an elevated risk of malignancies. Repopulation with ATM-competent bone marrow-derived cells (BMDCs) significantly prolonged the lifespan and improved the phenotype of Atm-deficient mice. The aim of the present study was to promote BMDC engraftment after bone marrow transplantation using low-dose irradiation (IR) as a co-conditioning strategy. Atm-deficient mice were transplanted with green fluorescent protein-expressing, ATM-positive BMDCs using a clinically relevant non-myeloablative host-conditioning regimen together with TBI (0.2-2.0 Gy). IR significantly improved the engraftment of BMDCs into the bone marrow, blood, spleen and lung in a dose-dependent manner, but not into the cerebellum. However, with increasing doses, IR lethality increased even after low-dose IR. Analysis of the bronchoalveolar lavage fluid and lung histochemistry revealed a significant enhancement in the number of inflammatory cells and oxidative damage. A delay in the resolution of γ-H2AX-expression points to an insufficient double-strand break repair capacity following IR with 0.5 Gy in Atm-deficient splenocytes. Our results demonstrate that even low-dose IR results in ATM activation. In the absence of ATM, low-dose IR leads to increased inflammation, oxidative stress and lethality in the Atm-deficient mouse model.

  20. ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2).

    PubMed

    Jiang, Y; Chen, H-C; Su, X; Thompson, P A; Liu, X; Do, K-A; Wierda, W; Keating, M J; Plunkett, W

    2016-09-02

    Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22-23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.

  1. Downregulation of ATM Gene and Protein Expression in Canine Mammary Tumors.

    PubMed

    Raposo-Ferreira, T M M; Bueno, R C; Terra, E M; Avante, M L; Tinucci-Costa, M; Carvalho, M; Cassali, G D; Linde, S D; Rogatto, S R; Laufer-Amorim, R

    2016-11-01

    The ataxia telangiectasia mutated (ATM) gene encodes a protein associated with DNA damage repair and maintenance of genomic integrity. In women, ATM transcript and protein downregulation have been reported in sporadic breast carcinomas, and the absence of ATM protein expression has been associated with poor prognosis. The aim of this study was to evaluate ATM gene and protein expression in canine mammary tumors and their association with clinical outcome. ATM gene and protein expression was evaluated by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively, in normal mammary gland samples (n = 10), benign mammary tumors (n = 11), nonmetastatic mammary carcinomas (n = 19), and metastatic mammary carcinomas (n = 11). Lower ATM transcript levels were detected in benign mammary tumors and carcinomas compared with normal mammary glands (P = .011). Similarly, lower ATM protein expression was observed in benign tumors (P = .0003), nonmetastatic mammary carcinomas (P < .0001), and the primary sites of metastatic carcinomas (P < .0001) compared with normal mammary glands. No significant differences in ATM gene or protein levels were detected among benign tumors and nonmetastatic and metastatic mammary carcinomas (P > .05). The levels of ATM gene or protein expression were not significantly associated with clinical and pathological features or with survival. Similar to human breast cancer, the data in this study suggest that ATM gene and protein downregulation is involved in canine mammary gland tumorigenesis.

  2. Discovery and Structure–Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors

    PubMed Central

    2015-01-01

    Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66–68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (−)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors. PMID:24922587

  3. Enhanced radiation-induced cytotoxic effect by 2-ME in glioma cells is mediated by induction of cell cycle arrest and DNA damage via activation of ATM pathways.

    PubMed

    Zou, Huichao; Zhao, Shiguang; Zhang, Jianhua; Lv, Gongwei; Zhang, Xu; Yu, Hongwei; Wang, Huibo; Wang, Ligang

    2007-12-14

    Glioblastoma multiform is the most common malignant primary brain tumor in adults, but there remains no effective therapeutic approach. 2-methoxyestradiol (2-ME), which is a naturally occurring metabolite of 17beta-estradiol, was shown to enhance radiotherapeutic effect in certain tumors; however, whether 2-ME can also enhance the sensitivity of glioma cells to radiotherapy remains unknown. The present study, therefore, was to address this issue using two human glioma cell lines (T98G and U251MG). These cells were irradiated with and without 2-ME and then clonogenic assay, apoptosis assay, DNA damage, and cell cycle change were examined. Results showed that 2-ME significantly enhances radiation-induced cell death in both glioma cells, shown by decreasing cell viability and increasing apoptotic cell death. No such radiosensitizing effect was observed if cells pre-treated with Estrodiol, suggesting the specifically radiosensitizing effect of 2-ME rather than a general effect of estrodials. The enhanced radio-cytotoxic effect in glioma cells by 2-ME was found to be associated with its enhancement of G(2)/M arrest and DNA damage, and phosphorylated ATM protein kinases as well as cell cycle checkpoint protein Chk2. Furthermore, inhibition of ATM by ATM inhibitor abolished 2-ME-activated Chk2 and enhanced radio-cytotoxic effects. These results suggest that 2-ME enhancement of the sensitivity of glioma cell lines to radiotherapy is mediated by induction of G2/M cell cycle arrest and increased DNA damage via activation of ATM kinases.

  4. Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors

    PubMed Central

    Yamamoto, Kenta; Wang, Jiguang; Sprinzen, Lisa; Xu, Jun; Haddock, Christopher J; Li, Chen; Lee, Brian J; Loredan, Denis G; Jiang, Wenxia; Vindigni, Alessandro; Wang, Dong; Rabadan, Raul; Zha, Shan

    2016-01-01

    Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (AtmKD/-) is more oncogenic than loss of ATM (Atm-/-) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate AtmKD/-, but not Atm-proficientor Atm-/- leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy. DOI: http://dx.doi.org/10.7554/eLife.14709.001 PMID:27304073

  5. Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors.

    PubMed

    Yamamoto, Kenta; Wang, Jiguang; Sprinzen, Lisa; Xu, Jun; Haddock, Christopher J; Li, Chen; Lee, Brian J; Loredan, Denis G; Jiang, Wenxia; Vindigni, Alessandro; Wang, Dong; Rabadan, Raul; Zha, Shan

    2016-06-15

    Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (Atm(KD/-)) is more oncogenic than loss of ATM (Atm(-/-)) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate Atm(KD/-), but not Atm-proficientor Atm(-/-) leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy.

  6. ER-Dependent Ca++-mediated Cytosolic ROS as an Effector for Induction of Mitochondrial Apoptotic and ATM-JNK Signal Pathways in Gallic Acid-treated Human Oral Cancer Cells.

    PubMed

    Lu, Yao-Cheng; Lin, Meng-Liang; Su, Hong-Lin; Chen, Shih-Shun

    2016-02-01

    Release of calcium (Ca(++)) from the endoplasmic reticulum (ER) has been proposed to be involved in induction of apoptosis by oxidative stress. Using inhibitor of ER Ca(++) release dantrolene and inhibitor of mitochondrial Ca(++) uptake Ru-360, we demonstrated that Ca(++) release from the ER was associated with generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, and apoptosis of human oral cancer (OC) cells induced by gallic acid (GA). Small interfering RNA-mediated suppression of protein kinase RNA-like endoplasmic reticulum kinase inhibited tunicamycin-induced induction of 78 kDa glucose-regulated protein, C/EBP homologous protein, pro-caspase-12 cleavage, cytosolic Ca(++) increase and apoptosis, but did not attenuate the increase in cytosolic Ca(++) level and apoptosis induced by GA. Ataxia telangiectasia mutated (ATM)-mediated c-Jun N-terminal kinase (JNK) phosphorylation and apoptosis by GA was blocked by dantrolene. The specificity of ROS-mediated ATM-JNK activation was confirmed by treatment with N-acetylcysteine, a ROS scavenger. Blockade of ATM activation by specific inhibitor KU55933, short hairpin RNA, or kinase-dead ATM overexpression suppressed JNK phosphorylation but did not completely inhibit cytosolic ROS production, mitochondrial cytochrome c release, pro-caspase-3 cleavage, and apoptosis induced by GA. Taken together, these results indicate that GA induces OC cell apoptosis by inducing the activation of mitochondrial apoptotic and ATM-JNK signal pathways, likely through ER Ca(++)-mediated ROS production.

  7. Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM and ATR

    PubMed Central

    Liu, Qingsong; Xu, Chunxiao; Kirubakaran, Sivapriya; Zhang, Xin; Hur, Wooyoung; Liu, Yan; Kwiatkowski, Nicholas P.; Wang, Jinhua; Westover, Kenneth D.; Gao, Peng; Ercan, Dalia; Niepel, Mario; Thoreen, Carson C.; Kang, Seong A.; Patricelli, Matthew P.; Wang, Yuchuan; Tupper, Tanya; Altabef, Abigail; Kawamura, Hidemasa; Held, Kathryn D.; Chou, Danny M.; Elledge, Stephen J.; Janne, Pasi A.; Wong, Kwok-Kin; Sabatini, David M.; Gray, Nathanael S.

    2013-01-01

    mTOR is a highly conserved serine/threonine protein kinase that serves as a central regulator of cell growth, survival and autophagy. Deregulation of the PI3K/Akt/mTOR signaling pathway occurs commonly in cancer and numerous inhibitors targeting the ATP-binding site of these kinases are currently undergoing clinical evaluation. Here we report the characterization of Torin2, a second generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. Torin2 inhibited mTORC1-dependent T389 phosphorylation on S6K (RPS6KB1) with an EC50 of 250 pM with approximately 800-fold selectivity for cellular mTOR versus PI3K. Torin2 also exhibited potent biochemical and cellular activity against PIKK family kinases including ATM (EC50 28 nM), ATR (EC50 35 nM) and DNA-PK (EC50 118 nM) (PRKDC), the inhibition of which sensitized cells to Irradiation. Similar to the earlier generation compound Torin1 and in contrast to other reported mTOR inhibitors, Torin2 inhibited mTOR kinase and mTORC1 signaling activities in a sustained manner suggestive of a slow dissociation from the kinase. Cancer cell treatment with Torin2 for 24 hours resulted in a prolonged block in negative feedback and consequent T308 phosphorylation on Akt. These effects were associated with strong growth inhibition in vitro. Single agent treatment with Torin2 in vivo did not yield significant efficacy against KRAS-driven lung tumors, but the combination of Torin2 with MEK inhibitor AZD6244 yielded a significant growth inhibition. Taken together, our findings establish Torin2 as a strong candidate for clinical evaluation in a broad number of oncological settings where mTOR signaling has a pathogenic role. PMID:23436801

  8. RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress

    PubMed Central

    Kanu, Nnennaya; Zhang, Tianyi; Burrell, Rebecca A.; Chakraborty, Atanu; Cronshaw, Janet; Da Costa, Clive; Grönroos, Eva; Pemberton, Helen N.; Anderton, Emma; Gonzalez, Laure; Sabbioneda, Simone; Ulrich, Helle D.; Swanton, Charles; Behrens, Axel

    2015-01-01

    The DNA replication machinery invariably encounters obstacles that slow replication fork progression, and threaten to prevent complete replication and faithful segregation of sister chromatids. The resulting replication stress activates ATR, the major kinase involved in resolving impaired DNA replication. In addition, replication stress also activates the related kinase ATM, which is required to prevent mitotic segregation errors. However, the molecular mechanism of ATM activation by replication stress is not defined. Here we show that monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA), a marker of stalled replication forks, interacts with the ATM cofactor ATMIN via WRN interacting protein 1 (WRNIP1). ATMIN, WRNIP1 and RAD18, the E3 ligase responsible for PCNA monoubiquitination, are specifically required for ATM signalling and 53BP1 focus formation induced by replication stress, not ionising radiation. Thus, WRNIP1 connects PCNA monoubiquitination with ATMIN/ATM to activate ATM signalling in response to replication stress and contribute to the maintenance of genomic stability. PMID:26549024

  9. Development of the Advanced Technology Microwave Sounder (ATMS) for NPOESS C1

    NASA Astrophysics Data System (ADS)

    Brann, C.; Kunkee, D.

    2008-12-01

    The National Polar-orbiting Operational Environmental Satellite System's Advanced Technology Microwave Sounder (ATMS) is planned for flight on the first NPOESS mission (C1) in 2013. The C1 ATMS will be the second instrument of the ATMS series and will provide along with the companion Cross-track Infrared Sounder (CrIS), atmospheric temperature and moisture profiles for NPOESS. The first flight of the ATMS is scheduled in 2010 on the NPOESS Preparatory Project (NPP) satellite, which is an early instrument risk reduction component of the NPOESS mission. This poster will focus on the development of the ATMS for C1 including aspects of the sensor calibration, antenna beam and RF characteristics and scanning. New design aspects of the C1 ATMS, required primarily by parts obsolescence, will also be addressed in this poster.

  10. Pilot Performance on New ATM Operations: Maintaining In-Trail Separation and Arrival Sequencing

    NASA Technical Reports Server (NTRS)

    Pritchett, Amy R.; Yankosky, L. J.; Johnson, Walter (Technical Monitor)

    1999-01-01

    Cockpit Display of Traffic Information (CDTI) may enable new Air Traffic Management (ATM) operations. However, CDTI is not the only source of traffic information in the cockpit; ATM procedures may provide information, implicitly and explicitly, about other aircraft. An experiment investigated pilot ability to perform two new ATM operations - maintaining in-trail separation from another aircraft and sequencing into an arrival stream. In the experiment, pilots were provided different amounts of information from displays and procedures. The results are described.

  11. Design Issues for Traffic Management for the ATM UBR + Service for TCP Over Satellite Networks

    NASA Technical Reports Server (NTRS)

    Jain, Raj

    1999-01-01

    This project was a comprehensive research program for developing techniques for improving the performance of Internet protocols over Asynchronous Transfer Mode (ATM) based satellite networks. Among the service categories provided by ATM networks, the most commonly used category for data traffic is the unspecified bit rate (UBR) service. UBR allows sources to send data into the network without any feedback control. The project resulted in the numerous ATM Forum contributions and papers.

  12. Reaction test revealed impaired performance at 6.0 atm abs but not at 1.9 atm abs in professional divers.

    PubMed

    Tikkinen, Janne; Parkkola, Kai; Siimes, Martti A

    2013-01-01

    In order to evaluate the effects of ambient pressure on reaction and movement times we investigated 60 professional divers by a computerized test (Reaction Test). The experiments were carried out four times in a hyperbaric chamber: prior to pressure, at 6.0 and 1.9 atm abs and after decompression. Reaction time varied from 202 to 443 milliseconds (275 +/- 42 ms), but the individual levels remained similar. The reaction time increased between precompression and 6.0 atm abs (p < 0.05), decreased between 6.0 and 1.9 atm abs (p < 0.05) and remained at the original level at 1.9 and 1.0 atm abs after decompression. Ten divers had an increase of more than 1SD in the reaction time at 6.0 atm abs. The number of mistakes was small and not influenced by elevation of pressure. Further, the movement time remained unchanged throughout the experiment. We conclude that the response time increases due to ambient pressure and the increase in simple reaction time is detectable in professional divers at 6.0 atm not at 1.9 atm abs. At the same time accuracy stays constant. We speculate that our findings are caused by nitrogen narcosis in some divers.

  13. ATM Quality of Service Parameters at 45 Mbps Using a Satellite Emulator: Laboratory Measurements

    NASA Technical Reports Server (NTRS)

    Ivancic, William D.; Bobinsky, Eric A.

    1997-01-01

    Results of 45-Mbps DS3 intermediate-frequency loopback measurements of asynchronous transfer mode (ATM) quality of service parameters (cell error ratio and cell loss ratio) are presented. These tests, which were conducted at the NASA Lewis Research Center in support of satellite-ATM interoperability research, represent initial efforts to quantify the minimum parameters for stringent ATM applications, such as MPEG-1 and MPEG-2 video transmission. Portions of these results were originally presented to the International Telecommunications Union's ITU-R Working Party 4B in February 1996 in support of their Draft Preliminary Recommendation on the Transmission of ATM Traffic via Satellite.

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

    SciTech Connect

    Takubo, Keiyo . E-mail: keiyot@gmail.com; Hirao, Atsushi; Ohmura, Masako; Azuma, Masaki; Arai, Fumio; Nagamatsu, Go; Suda, Toshio . E-mail: sudato@sc.itc.keio.ac.jp

    2006-12-29

    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{sup 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{sup 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{sup Ink4a}-mediated senescence.

  15. Results from CrIS/ATMS Obtained Using an "AIRS Version-6 Like" Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena

    2015-01-01

    A main objective of AIRS/AMSU on EOS is to provide accurate sounding products that are used to generate climate data sets. Suomi NPP carries CrIS/ATMS that were designed as follow-ons to AIRS/AMSU. Our objective is to generate a long term climate data set of products derived from CrIS/ATMS to serve as a continuation of the AIRS/AMSU products. We have modified an improved version of the operational AIRS Version-6 retrieval algorithm for use with CrIS/ATMS. CrIS/ATMS products are of very good quality, and are comparable to, and consistent with, those of AIRS.

  16. ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts.

    PubMed

    Qi, Yongmei; Qiu, Qian; Gu, Xueyan; Tian, Yihong; Zhang, Yingmei

    2016-04-19

    The ATM (ataxia telangiectasia mutated) protein has recently been proposed to play critical roles in the response to mitochondrial dysfunction by initiating mitophagy. Here, we have used ATM-proficient GM00637 cells and ATM-deficient GM05849 cells to investigate the mitophagic effect of spermidine and to elucidate the role of ATM in spermdine-induced mitophagy. Our results indicate that spermidine induces mitophagy by eliciting mitochondrial depolarization, which triggers the formation of mitophagosomes and mitolysosomes, thereby promoting the accumulation of PINK1 and translocation of Parkin to damaged mitochondria, finally leading to the decreased mitochondrial mass in GM00637 cells. However, in GM05849 cells or GM00637 cells pretreated with the ATM kinase inhibitor KU55933, the expression of full-length PINK1 and the translocation of Parkin are blocked, and the colocalization of Parkin with either LC3 or PINK1 is disrupted. These results suggest that ATM drives the initiation of the mitophagic cascade. Our study demonstrates that spermidine induces mitophagy through ATM-dependent activation of the PINK1/Parkin pathway. These findings underscore the importance of a mitophagy regulatory network of ATM and PINK1/Parkin and elucidate a novel mechanism by which ATM influences spermidine-induced mitophagy.

  17. Achieving High Throughput for Data Transfer over ATM Networks

    NASA Technical Reports Server (NTRS)

    Johnson, Marjory J.; Townsend, Jeffrey N.

    1996-01-01

    File-transfer rates for ftp are often reported to be relatively slow, compared to the raw bandwidth available in emerging gigabit networks. While a major bottleneck is disk I/O, protocol issues impact performance as well. Ftp was developed and optimized for use over the TCP/IP protocol stack of the Internet. However, TCP has been shown to run inefficiently over ATM. In an effort to maximize network throughput, data-transfer protocols can be developed to run over UDP or directly over IP, rather than over TCP. If error-free transmission is required, techniques for achieving reliable transmission can be included as part of the transfer protocol. However, selected image-processing applications can tolerate a low level of errors in images that are transmitted over a network. In this paper we report on experimental work to develop a high-throughput protocol for unreliable data transfer over ATM networks. We attempt to maximize throughput by keeping the communications pipe full, but still keep packet loss under five percent. We use the Bay Area Gigabit Network Testbed as our experimental platform.

  18. Functional studies on the ATM intronic splicing processing element.

    PubMed

    Lewandowska, Marzena A; Stuani, Cristiana; Parvizpur, Alireza; Baralle, Francisco E; Pagani, Franco

    2005-01-01

    In disease-associated genes, the understanding of the functional significance of deep intronic nucleotide variants may represent a difficult challenge. We have previously reported a new disease-causing mechanism that involves an intronic splicing processing element (ISPE) in ATM, composed of adjacent consensus 5' and 3' splice sites. A GTAA deletion within ISPE maintains potential adjacent splice sites, disrupts a non-canonical U1 snRNP interaction and activates an aberrant exon. In this paper, we demonstrate that binding of U1 snRNA through complementarity within a approximately 40 nt window downstream of the ISPE prevents aberrant splicing. By selective mutagenesis at the adjacent consensus ISPE splice sites, we show that this effect is not due to a resplicing process occurring at the ISPE. Functional comparison of the ATM mouse counterpart and evaluation of the pre-mRNA splicing intermediates derived from affected cell lines and hybrid minigene assays indicate that U1 snRNP binding at the ISPE interferes with the cryptic acceptor site. Activation of this site results in a stringent 5'-3' order of intron sequence removal around the cryptic exon. Artificial U1 snRNA loading by complementarity to heterologous exonic sequences represents a potential therapeutic method to prevent the usage of an aberrant CFTR cryptic exon. Our results suggest that ISPE-like intronic elements binding U1 snRNPs may regulate correct intron processing.

  19. Functional studies on the ATM intronic splicing processing element

    PubMed Central

    Lewandowska, Marzena A.; Stuani, Cristiana; Parvizpur, Alireza; Baralle, Francisco E.; Pagani, Franco

    2005-01-01

    In disease-associated genes, the understanding of the functional significance of deep intronic nucleotide variants may represent a difficult challenge. We have previously reported a new disease-causing mechanism that involves an intronic splicing processing element (ISPE) in ATM, composed of adjacent consensus 5′ and 3′ splice sites. A GTAA deletion within ISPE maintains potential adjacent splice sites, disrupts a non-canonical U1 snRNP interaction and activates an aberrant exon. In this paper, we demonstrate that binding of U1 snRNA through complementarity within a ∼40 nt window downstream of the ISPE prevents aberrant splicing. By selective mutagenesis at the adjacent consensus ISPE splice sites, we show that this effect is not due to a resplicing process occurring at the ISPE. Functional comparison of the ATM mouse counterpart and evaluation of the pre-mRNA splicing intermediates derived from affected cell lines and hybrid minigene assays indicate that U1 snRNP binding at the ISPE interferes with the cryptic acceptor site. Activation of this site results in a stringent 5′–3′ order of intron sequence removal around the cryptic exon. Artificial U1 snRNA loading by complementarity to heterologous exonic sequences represents a potential therapeutic method to prevent the usage of an aberrant CFTR cryptic exon. Our results suggest that ISPE-like intronic elements binding U1 snRNPs may regulate correct intron processing. PMID:16030351

  20. Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses.

    PubMed

    Kobayashi, Junya; Saito, Yuichiro; Okui, Michiyo; Miwa, Noriko; Komatsu, Kenshi

    2015-04-01

    Ataxia telangiectasia (AT) is caused by a mutation in the ataxia-telangiectasia-mutated (ATM) gene; the condition is associated with hyper-radiosensitivity, abnormal cell-cycle checkpoints, and genomic instability. AT patients also show cerebellar ataxia, possibly due to reactive oxygen species (ROS) sensitivity in neural cells. The ATM protein is a key regulator of the DNA damage response. Recently, several AT-like disorders have been reported. The genes responsible for them are predicted to encode proteins that interact with ATM in the DNA-damage response. Ataxia with oculomotor apraxia types 1-3 (AOA1, 2, and 3) result in a neurodegenerative and cellular phenotype similar to AT; however, the basis of this phenotypic similarity is unclear. Here, we show that the cells of AOA3 patients display aberrant ATM-dependent phosphorylation and apoptosis following γ-irradiation. The ATM-dependent response to H2O2 treatment was abrogated in AOA3 cells. Furthermore, AOA3 cells had reduced ATM activity. Our results suggest that the attenuated ATM-related response is caused by an increase in endogenous ROS in AOA3 cells. Pretreatment of cells with pyocyanin, which induces endogenous ROS production, abolished the ATM-dependent response. Moreover, AOA3 cells had decreased homologous recombination (HR) activity, and pyocyanin pretreatment reduced HR activity in HeLa cells. These results indicate that excess endogenous ROS represses the ATM-dependent cellular response and HR repair in AOA3 cells. Since the ATM-dependent cell-cycle checkpoint is an important block to carcinogenesis, such inactivation of ATM may lead to tumorigenesis as well as neurodegeneration.

  1. Design and synthesis of N-substituted indazole-3-carboxamides as poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors(†).

    PubMed

    Patel, Maulik R; Pandya, Kashyap G; Lau-Cam, Cesar A; Singh, Satyakam; Pino, Maria A; Billack, Blase; Degenhardt, Kurt; Talele, Tanaji T

    2012-04-01

    A group of novel N-1-substituted indazole-3-carboxamide derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy was applied to a weakly active unsubstituted 1H-indazole-3-carboxamide 2, by introducing a three carbon linker between 1H-indazole-3-carboxamide and different heterocycles, and led to compounds 4 [1-(3-(piperidine-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) =36μm] and 5 [1-(3-(2,3-dioxoindolin-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) = 6.8μm]. Compound 5 was evaluated in rats for its protective action against diabetes induced by a treatment with streptozotocin, a known diabetogenic agent. In addition to preserving the ability of the pancreas to secrete insulin, compound 5 was also able to attenuate the ensuing hyperglycemic response to a significant extent.

  2. ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes.

    PubMed

    Liu, Na; Stoica, George; Yan, Mingshan; Scofield, Virginia L; Qiang, Wenan; Lynn, William S; Wong, Paul K Y

    2005-12-01

    ATM kinase, the product of the ataxia telangiectasia mutated (Atm) gene, is activated by genomic damage. ATM plays a crucial role in cell growth and development. Here we report that primary astrocytes isolated from ATM-deficient mice grow slowly, become senescent, and die in culture. However, before reaching senescence, these primary Atm(-/-) astrocytes, like Atm(-/-) lymphocytes, show increased spontaneous DNA synthesis. These astrocytes also show markers of oxidative stress and endoplasmic reticulum (ER) stress, including increased levels of heat shock proteins (HSP70 and GRP78), malondialdehyde adducts, Cu/Zn superoxide dismutase, procaspase 12 cleavage, and redox-sensitive phosphorylation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). In addition, HSP70 and ERK1/2 phosphorylation are upregulated in the cerebella of ATM-deficient mice. This increase in ERK1/2 phosphorylation is seen primarily in cerebellar astrocytes, or Bergmann glia, near degenerating Purkinje cells. ERK1/2 activation and astrogliosis are also found in other parts of the brain, for example, the cortex. We conclude that ATM deficiency induces intrinsic growth defects, oxidative stress, ER stress, and ERKs activation in astrocytes.

  3. Conditional abrogation of Atm in osteoclasts extends osteoclast lifespan and results in reduced bone mass

    PubMed Central

    Hirozane, Toru; Tohmonda, Takahide; Yoda, Masaki; Shimoda, Masayuki; Kanai, Yae; Matsumoto, Morio; Morioka, Hideo; Nakamura, Masaya; Horiuchi, Keisuke

    2016-01-01

    Ataxia-telangiectasia mutated (ATM) kinase is a central component involved in the signal transduction of the DNA damage response (DDR) and thus plays a critical role in the maintenance of genomic integrity. Although the primary functions of ATM are associated with the DDR, emerging data suggest that ATM has many additional roles that are not directly related to the DDR, including the regulation of oxidative stress signaling, insulin sensitivity, mitochondrial homeostasis, and lymphocyte development. Patients and mice lacking ATM exhibit growth retardation and lower bone mass; however, the mechanisms underlying the skeletal defects are not fully understood. In the present study, we generated mutant mice in which ATM is specifically inactivated in osteoclasts. The mutant mice did not exhibit apparent developmental defects but showed reduced bone mass due to increased osteoclastic bone resorption. Osteoclasts lacking ATM were more resistant to apoptosis and showed a prolonged lifespan compared to the controls. Notably, the inactivation of ATM in osteoclasts resulted in enhanced NF-κB signaling and an increase in the expression of NF-κB-targeted genes. The present study reveals a novel function for ATM in regulating bone metabolism by suppressing the lifespan of osteoclasts and osteoclast-mediated bone resorption. PMID:27677594

  4. A Framework for Applying Asynchronous Transfer Mode (ATM) Technology to Command, Control and Communications Systems

    DTIC Science & Technology

    1994-06-01

    available they can be implemented in ATM LANs by using different reserved signaling channels ( Biagioni , Cooper, and Sansom, 1993, p. 35). An argument...conference, San Francisco, California, 12-14 April 1994. Biagioni , E., Cooper, E. and Sansom, R., "Designing a Practical ATM LAN", IEEE Network, v. 7, March

  5. The effects of mobile ATM switches on PNNI peer group operation

    SciTech Connect

    Martinez, L.; Sholander, P.; Tolendino, L.

    1997-04-01

    This contribution discusses why, and how, mobile networks and mobile switches might be discussed during Phase 1 of the WATM standards process. Next, it reviews mobile routers within Mobile IP. That IP mobility architecture may not apply to the proposed mobile ATM switches. Finally, it discusses problems with PNNI peer group formation and operation when mobile ATM switches are present.

  6. ATM protein is located on presynaptic vesicles and its deficit leads to failures in synaptic plasticity.

    PubMed

    Vail, Graham; Cheng, Aifang; Han, Yu Ray; Zhao, Teng; Du, Shengwang; Loy, Michael M T; Herrup, Karl; Plummer, Mark R

    2016-07-01

    Ataxia telangiectasia is a multisystemic disorder that includes a devastating neurodegeneration phenotype. The ATM (ataxia-telangiectasia mutated) protein is well-known for its role in the DNA damage response, yet ATM is also found in association with cytoplasmic vesicular structures: endosomes and lysosomes, as well as neuronal synaptic vesicles. In keeping with this latter association, electrical stimulation of the Schaffer collateral pathway in hippocampal slices from ATM-deficient mice does not elicit normal long-term potentiation (LTP). The current study was undertaken to assess the nature of this deficit. Theta burst-induced LTP was reduced in Atm(-/-) animals, with the reduction most pronounced at burst stimuli that included 6 or greater trains. To assess whether the deficit was associated with a pre- or postsynaptic failure, we analyzed paired-pulse facilitation and found that it too was significantly reduced in Atm(-/-) mice. This indicates a deficit in presynaptic function. As further evidence that these synaptic effects of ATM deficiency were presynaptic, we used stochastic optical reconstruction microscopy. Three-dimensional reconstruction revealed that ATM is significantly more closely associated with Piccolo (a presynaptic marker) than with Homer1 (a postsynaptic marker). These results underline how, in addition to its nuclear functions, ATM plays an important functional role in the neuronal synapse where it participates in the regulation of presynaptic vesicle physiology.

  7. Neurons in Vulnerable Regions of the Alzheimer's Disease Brain Display Reduced ATM Signaling.

    PubMed

    Shen, Xuting; Chen, Jianmin; Li, Jiali; Kofler, Julia; Herrup, Karl

    2016-01-01

    Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer's disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function-nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity-appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals.

  8. Conditional abrogation of Atm in osteoclasts extends osteoclast lifespan and results in reduced bone mass.

    PubMed

    Hirozane, Toru; Tohmonda, Takahide; Yoda, Masaki; Shimoda, Masayuki; Kanai, Yae; Matsumoto, Morio; Morioka, Hideo; Nakamura, Masaya; Horiuchi, Keisuke

    2016-09-28

    Ataxia-telangiectasia mutated (ATM) kinase is a central component involved in the signal transduction of the DNA damage response (DDR) and thus plays a critical role in the maintenance of genomic integrity. Although the primary functions of ATM are associated with the DDR, emerging data suggest that ATM has many additional roles that are not directly related to the DDR, including the regulation of oxidative stress signaling, insulin sensitivity, mitochondrial homeostasis, and lymphocyte development. Patients and mice lacking ATM exhibit growth retardation and lower bone mass; however, the mechanisms underlying the skeletal defects are not fully understood. In the present study, we generated mutant mice in which ATM is specifically inactivated in osteoclasts. The mutant mice did not exhibit apparent developmental defects but showed reduced bone mass due to increased osteoclastic bone resorption. Osteoclasts lacking ATM were more resistant to apoptosis and showed a prolonged lifespan compared to the controls. Notably, the inactivation of ATM in osteoclasts resulted in enhanced NF-κB signaling and an increase in the expression of NF-κB-targeted genes. The present study reveals a novel function for ATM in regulating bone metabolism by suppressing the lifespan of osteoclasts and osteoclast-mediated bone resorption.

  9. Mitochondria are required for ATM activation by extranuclear oxidative stress in cultured human hepatoblastoma cell line Hep G2 cells

    SciTech Connect

    Morita, Akinori; Tanimoto, Keiji; Murakami, Tomoki; Morinaga, Takeshi; Hosoi, Yoshio

    2014-01-24

    Highlights: • Oxidative ATM activation can occur in the absence of nuclear DNA damage response. • The oxidized Hep G2 cells were subjected to subcellular fractionation. • The obtained results suggest that the ATM activation occurs in mitochondria. • ATM failed to respond to oxidative stress in mitochondria-depleted Hep G2 cells. • Mitochondria are required for the oxidative activation of ATM. - Abstract: Ataxia–telangiectasia mutated (ATM) is a serine/threonine protein kinase that plays a central role in DNA damage response (DDR). A recent study reported that oxidized ATM can be active in the absence of DDR. However, the issue of where ATM is activated by oxidative stress remains unclear. Regarding the localization of ATM, two possible locations, namely, mitochondria and peroxisomes are possible. We report herein that ATM can be activated when exposed to hydrogen peroxide without inducing nuclear DDR in Hep G2 cells, and the oxidized cells could be subjected to subcellular fractionation. The first detergent-based fractionation experiment revealed that active, phosphorylated ATM was located in the second fraction, which also contained both mitochondria and peroxisomes. An alternative fractionation method involving homogenization and differential centrifugation, which permits the light membrane fraction containing peroxisomes to be produced, but not mitochondria, revealed that the light membrane fraction contained only traces of ATM. In contrast, the heavy membrane fraction, which mainly contained mitochondrial components, was enriched in ATM and active ATM, suggesting that the oxidative activation of ATM occurs in mitochondria and not in peroxisomes. In Rho 0-Hep G2 cells, which lack mitochondrial DNA and functional mitochondria, ATM failed to respond to hydrogen peroxide, indicating that mitochondria are required for the oxidative activation of ATM. These findings strongly suggest that ATM can be activated in response to oxidative stress in mitochondria

  10. Wide-area ATM networking for large-scale MPPs

    SciTech Connect

    Papadopoulos, P.M.; Geist, G.A. II

    1997-04-01

    This paper presents early experiences with using high-speed ATM interfaces to connect multiple Intel Paragons on both local and wide area networks. The testbed includes the 1024 and 512 node Paragons running the OSF operating system at Oak Ridge National Laboratory and the 1840 node Paragon running the Puma operating system at Sandia National Laboratories. The experimental OC-12 (622 Mbits/sec) interfaces are built by GigaNet and provide a proprietary API for sending AAL-5 encapsulated packets. PVM is used as the massaging infrastructure and significant modifications have been made to use the GigaNet API, operate in the Puma environment, and attain acceptable performance over local networks. These modifications are described along with a discussion of roadblocks to networking MPPs with high-performance interfaces. Our early prototype utilizes approximately 25 percent of an OC-12 circuit and 80 percent of an OC-3 circuit in send plus acknowledgment ping-pong tests.

  11. Analysis of components from drip tests with ATM-10 glass

    SciTech Connect

    Fortner, J.A.; Bates, J.K.; Gerding, T.J.

    1996-09-01

    Waste package assemblies consisting of actinide-doped West Valley ATM-10 reference glass and sensitized 304L stainless steel have been reacted with simulated repository groundwater using the Unsaturated Test Method. Analyses of surface corrosion and reaction products resulting from tests that were terminated at scheduled intervals between 13 and 52 weeks are reported. Analyses reveal complex interactions between the groundwater, the sensitized stainless steel waste form holder, and the glass. Alteration phases form that consist mainly of smectite clay, brockite, and an amorphous thorium iron titanium silicate, the latter two incorporating thorium, uranium, and possibly transuranics. The results from the terminated tests, combined with data from tests that are still ongoing, will help determine the suitability of glass waste forms in the proposed high-level repository at the Yucca Mountain Site.

  12. Wireless optical communication for FDDI, fast Ethernet, and ATM connectivity

    NASA Astrophysics Data System (ADS)

    Medved, David B.; Azancot, Yossi

    1995-09-01

    The bandwidth limitations of spread spectrum RF technology are easily removed by use of optical carriers. A variety of wireless connectivity system applications have been achieved using IR LED (not laser) at data rates up to 125 Mbps and with low frequency corners below 100 Kbps. By use of the UWINTM principle it is possible to achieve wireless communications which are protocol independent. Thus, an urgent installation which must serve today as an Ethernet or Token Ring wireless connection in the future can be used at FDDI, Fast Ethernet, 100 VG Anylan or ATM without any modification to the original installation. In this paper we describe three separate applications of this principle where there are significant trade-offs between range and angular coverage.

  13. Bidirectional coupling of splicing and ATM signaling in response to transcription-blocking DNA damage

    PubMed Central

    Tresini, Maria; Marteijn, Jurgen A.; Vermeulen, Wim

    2016-01-01

    ABSTRACT In response to DNA damage cells activate intricate protein networks to ensure genomic fidelity and tissue homeostasis. DNA damage response signaling pathways coordinate these networks and determine cellular fates, in part, by modulating RNA metabolism. Here we discuss a replication-independent pathway activated by transcription-blocking DNA lesions, which utilizes the ATM signaling kinase to regulate spliceosome function in a reciprocal manner. We present a model according to which, displacement of co-transcriptional spliceosomes from lesion-arrested RNA polymerases, culminates in R-loop formation and non-canonical ATM activation. ATM signals in a feed-forward fashion to further impede spliceosome organization and regulates UV-induced gene expression and alternative splicing genome-wide. This reciprocal coupling between ATM and the spliceosome highlights the importance of ATM signaling in the cellular response to transcription-blocking lesions and supports a key role of the splicing machinery in this process. PMID:26913497

  14. New mutations in the ATM gene and clinical data of 25 AT patients.

    PubMed

    Demuth, Ilja; Dutrannoy, Véronique; Marques, Wilson; Neitzel, Heidemarie; Schindler, Detlev; Dimova, Petja S; Chrzanowska, Krystyna H; Bojinova, Veneta; Gregorek, Hanna; Graul-Neumann, Luitgard M; von Moers, Arpad; Schulze, Ilka; Nicke, Marion; Bora, Elcin; Cankaya, Tufan; Oláh, Éva; Kiss, Csongor; Bessenyei, Beáta; Szakszon, Katalin; Gruber-Sedlmayr, Ursula; Kroisel, Peter Michael; Sodia, Sigrun; Goecke, Timm O; Dörk, Thilo; Digweed, Martin; Sperling, Karl; de Sá, Joaquim; Lourenco, Charles Marques; Varon, Raymonda

    2011-11-01

    Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T>C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.

  15. The effects of Atm haploinsufficiency on mutation rate in the mouse germ line and somatic tissue.

    PubMed

    Ahuja, Akshay K; Barber, Ruth C; Hardwick, Robert J; Weil, Michael M; Genik, Paula C; Brenner, David J; Dubrova, Yuri E

    2008-09-01

    Using single-molecule polymerase chain reaction, the frequency of spontaneous and radiation-induced mutation at an expanded simple tandem repeat (ESTR) locus was studied in DNA samples extracted from sperm and bone marrow of Atm knockout (Atm(+/-)) heterozygous male mice. The frequency of spontaneous mutation in sperm and bone marrow in Atm(+/-) males did not significantly differ from that in wild-type BALB/c mice. Acute exposure to 1 Gy of gamma-rays did not affect ESTR mutation frequency in bone marrow and resulted in similar increases in sperm samples taken from Atm(+/-) and BALB/c males. Taken together, these results suggest that the Atm haploinsufficiency analysed in our study does not affect spontaneous and radiation-induced ESTR mutation frequency in mice.

  16. Feedback regulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 via ATM/Chk2 pathway contributes to the resistance of MCF-7 breast cancer cells to cisplatin.

    PubMed

    Lv, Juan; Qian, Ying; Ni, Xiaoyan; Xu, Xiuping; Dong, Xuejun

    2017-03-01

    The methyl methanesulfonate and ultraviolet-sensitive gene clone 81 protein is a structure-specific nuclease that plays important roles in DNA replication and repair. Knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 has been found to sensitize cancer cells to chemotherapy. However, the underlying molecular mechanism is not well understood. We found that methyl methanesulfonate and ultraviolet-sensitive gene clone 81 was upregulated and the ATM/Chk2 pathway was activated at the same time when MCF-7 cells were treated with cisplatin. By using lentivirus targeting methyl methanesulfonate and ultraviolet-sensitive gene clone 81 gene, we showed that knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 enhanced cell apoptosis and inhibited cell proliferation in MCF-7 cells under cisplatin treatment. Abrogation of ATM/Chk2 pathway inhibited cell viability in MCF-7 cells in response to cisplatin. Importantly, we revealed that ATM/Chk2 was required for the upregulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 resulted in inactivation of ATM/Chk2 pathway in response to cisplatin. Meanwhile, knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 activated the p53/Bcl-2 pathway in response to cisplatin. These data suggest that the ATM/Chk2 may promote the repair of DNA damage caused by cisplatin by sustaining methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and the double-strand breaks generated by methyl methanesulfonate and ultraviolet-sensitive gene clone 81 may activate the ATM/Chk2 pathway in turn, which provide a novel mechanism of how methyl methanesulfonate and ultraviolet-sensitive gene clone 81 modulates DNA damage response and repair.

  17. DNA damage checkpoint kinase ATM regulates germination and maintains genome stability in seeds.

    PubMed

    Waterworth, Wanda M; Footitt, Steven; Bray, Clifford M; Finch-Savage, William E; West, Christopher E

    2016-08-23

    Genome integrity is crucial for cellular survival and the faithful transmission of genetic information. The eukaryotic cellular response to DNA damage is orchestrated by the DNA damage checkpoint kinases ATAXIA TELANGIECTASIA MUTATED (ATM) and ATM AND RAD3-RELATED (ATR). Here we identify important physiological roles for these sensor kinases in control of seed germination. We demonstrate that double-strand breaks (DSBs) are rate-limiting for germination. We identify that desiccation tolerant seeds exhibit a striking transcriptional DSB damage response during germination, indicative of high levels of genotoxic stress, which is induced following maturation drying and quiescence. Mutant atr and atm seeds are highly resistant to aging, establishing ATM and ATR as determinants of seed viability. In response to aging, ATM delays germination, whereas atm mutant seeds germinate with extensive chromosomal abnormalities. This identifies ATM as a major factor that controls germination in aged seeds, integrating progression through germination with surveillance of genome integrity. Mechanistically, ATM functions through control of DNA replication in imbibing seeds. ATM signaling is mediated by transcriptional control of the cell cycle inhibitor SIAMESE-RELATED 5, an essential factor required for the aging-induced delay to germination. In the soil seed bank, seeds exhibit increased transcript levels of ATM and ATR, with changes in dormancy and germination potential modulated by environmental signals, including temperature and soil moisture. Collectively, our findings reveal physiological functions for these sensor kinases in linking genome integrity to germination, thereby influencing seed quality, crucial for plant survival in the natural environment and sustainable crop production.

  18. ATM-Dependent Hyper-Radiosensitivity in Mammalian Cells Irradiated by Heavy Ions

    SciTech Connect

    Xue Lian; Yu Dong Furusawa, Yoshiya; Cao Jianping; Okayasu, Ryuichi; Fan Saijun

    2009-09-01

    Purpose: Low-dose hyper-radiosensitivity (HRS) and the later appearing radioresistance (termed induced radioresistance [IRR]) was mainly studied in low linear energy transfer (LET) radiation with survival observation. The aim of this study was to find out whether equivalent hypersensitivity occurred in high LET radiation, and the roles of ataxia telangiectasia mutated (ATM) kinase. Methods and Materials: Survival and mutation were measured by clonogenic assay and HPRT mutation assay. ATM Ser1981 activation was detected by Western blotting and immunofluorescent staining. Pretreatment of specific ATM inhibitor (10 {mu}M KU55933) and activator (20 {mu}g/mL chloroquine) before carbon radiation were adopted to explore the involvement of ATM. The roles of ATM were also investigated in its G2/M checkpoint function with histone H3 phosphorylation analysis and flow cytometric assay, and DNA double strand break (DSB) repair function measured using {gamma}-H2AX foci assay. Results: HRS/IRR was observed with survival and mutation in normal human skin fibroblast cells by carbon ions, while impaired in cells with intrinsic ATM deficiency or normal cells modified with specific ATM activator or inhibitor before irradiation. The dose-response pattern of ATM kinase activation was concordant with the transition from HRS to IRR. The ATM-dependent 'early' G2 checkpoint arrest and DNA DSB repair efficiency could explain the difference between HRS and IRR. Conclusions: These data demonstrate that the HRS/IRR by carbon ion radiation is an ATM-dependent phenomenon in the cellular response to DNA damage.

  19. Drug repurposing screen identifies lestaurtinib amplifies the ability of the poly (ADP-ribose) polymerase 1 inhibitor AG14361 to kill breast cancer associated gene-1 mutant and wild type breast cancer cells

    PubMed Central

    2014-01-01

    Introduction Breast cancer is a devastating disease that results in approximately 40,000 deaths each year in the USA. Current drug screening and chemopreventatitive methods are suboptimal, due in part to the poor specificity of compounds for cancer cells. Poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARPi)-mediated therapy is a promising approach for familial breast cancers caused by mutations of breast cancer-associated gene-1 and -2 (BRCA1/2), yet drug resistance frequently occurs during the treatment. Moreover, PARPis exhibit very little effect on cancers that are proficient for DNA repair and clinical efficacy for PARPis as single-agent therapies has yet to be illustrated. Methods Using a quantitative high-throughput screening approach, we screened a library containing 2,816 drugs, most of which are approved for human or animal use by the Food and Drug Administration (FDA) or other countries, to identify compounds that sensitize breast cancer cells to PARPi. After initial screening, we performed further cellular and molecular analysis on lestaurtinib, which is an orally bioavailable multikinase inhibitor and has been used in clinical trials for myeloproliferative disorders and acute myelogenous leukemia. Results Our study indicated that lestaurtinib is highly potent against breast cancers as a mono-treatment agent. It also strongly enhanced the activity of the potent PARPi AG14361 on breast cancer cell growth both in vitro and in vivo conditions. The inhibition of cancer growth is measured by increased apoptosis and reduced cell proliferation. Consistent with this, the treatment results in activation of caspase 3/7, and accumulation of cells in the G2 phase of the cell cycle, irrespective of their BRCA1 status. Finally, we demonstrated that AG14361 inhibits NF-κB signaling, which is further enhanced by lestaurtinib treatment. Conclusions Lestaurtinib amplifies the ability of the PARP1 inhibitor AG14361 to kill BRCA1 mutant and wild-type breast cancer

  20. Galiellalactone induces cell cycle arrest and apoptosis through the ATM/ATR pathway in prostate cancer cells.

    PubMed

    García, Víctor; Lara-Chica, Maribel; Cantarero, Irene; Sterner, Olov; Calzado, Marco A; Muñoz, Eduardo

    2016-01-26

    Galiellalactone (GL) is a fungal metabolite that presents antitumor activities on prostate cancer in vitro and in vivo. In this study we show that GL induced cell cycle arrest in G2/M phase, caspase-dependent apoptosis and also affected the microtubule organization and migration ability in DU145 cells. GL did not induce double strand DNA break but activated the ATR and ATM-mediated DNA damage response (DDR) inducing CHK1, H2AX phosphorylation (fH2AX) and CDC25C downregulation. Inhibition of the ATM/ATR activation with caffeine reverted GL-induced G2/M cell cycle arrest, apoptosis and DNA damage measured by fH2AX. In contrast, UCN-01, a CHK1 inhibitor, prevented GL-induced cell cycle arrest but enhanced apoptosis in DU145 cells. Furthermore, we found that GL did not increase the levels of intracellular ROS, but the antioxidant N-acetylcysteine (NAC) completely prevented the effects of GL on fH2AX, G2/M cell cycle arrest and apoptosis. In contrast to NAC, other antioxidants such as ambroxol and EGCG did not interfere with the activity of GL on cell cycle. GL significantly suppressed DU145 xenograft growth in vivo and induced the expression of fH2AX in the tumors. These findings identify for the first time that GL activates DDR in prostate cancer.

  1. An Activation Threshold Model for Response Inhibition

    PubMed Central

    MacDonald, Hayley J.; McMorland, Angus J. C.; Stinear, Cathy M.; Coxon, James P.; Byblow, Winston D.

    2017-01-01

    Reactive response inhibition (RI) is the cancellation of a prepared response when it is no longer appropriate. Selectivity of RI can be examined by cueing the cancellation of one component of a prepared multi-component response. This substantially delays execution of other components. There is debate regarding whether this response delay is due to a selective neural mechanism. Here we propose a computational activation threshold model (ATM) and test it against a classical “horse-race” model using behavioural and neurophysiological data from partial RI experiments. The models comprise both facilitatory and inhibitory processes that compete upstream of motor output regions. Summary statistics (means and standard deviations) of predicted muscular and neurophysiological data were fit in both models to equivalent experimental measures by minimizing a Pearson Chi-square statistic. The ATM best captured behavioural and neurophysiological dynamics of partial RI. The ATM demonstrated that the observed modulation of corticomotor excitability during partial RI can be explained by nonselective inhibition of the prepared response. The inhibition raised the activation threshold to a level that could not be reached by the original response. This was necessarily followed by an additional phase of facilitation representing a secondary activation process in order to reach the new inhibition threshold and initiate the executed component of the response. The ATM offers a mechanistic description of the neural events underlying RI, in which partial movement cancellation results from a nonselective inhibitory event followed by subsequent initiation of a new response. The ATM provides a framework for considering and exploring the neuroanatomical constraints that underlie RI. PMID:28085907

  2. Assessment of p53 and ATM functionality in chronic lymphocytic leukemia by multiplex ligation-dependent probe amplification.

    PubMed

    te Raa, G D; Moerland, P D; Leeksma, A C; Derks, I A; Yigittop, H; Laddach, N; Loden-van Straaten, M; Navrkalova, V; Trbusek, M; Luijks, D M; Zenz, T; Skowronska, A; Hoogendoorn, M; Stankovic, T; van Oers, M H; Eldering, E; Kater, A P

    2015-08-06

    The ATM-p53 DNA-damage response (DDR) pathway has a crucial role in chemoresistance in CLL, as indicated by the adverse prognostic impact of genetic aberrations of TP53 and ATM. Identifying and distinguishing TP53 and ATM functional defects has become relevant as epigenetic and posttranscriptional dysregulation of the ATM/p53 axis is increasingly being recognized as the underlying cause of chemoresistance. Also, specific treatments sensitizing TP53- or ATM-deficient CLL cells are emerging. We therefore developed a new ATM-p53 functional assay with the aim to (i) identify and (ii) distinguish abnormalities of TP53 versus ATM and (iii) enable the identification of additional defects in the ATM-p53 pathway. Reversed transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was used to measure ATM and/or p53-dependent genes at the RNA level following DNA damage using irradiation. Here, we showed that this assay is able to identify and distinguish three subgroups of CLL tumors (i.e., TP53-defective, ATM-defective and WT) and is also able to detect additional samples with a defective DDR, without molecular aberrations in TP53 and/or ATM. These findings make the ATM-p53 RT-MLPA functional assay a promising prognostic tool for predicting treatment responses in CLL.

  3. ATM mediates oxidative stress-induced dephosphorylation of DNA ligase IIIalpha.

    PubMed

    Dong, Zhiwan; Tomkinson, Alan E

    2006-01-01

    Among the three mammalian genes encoding DNA ligases, only the LIG3 gene does not have a homolog in lower eukaryotes. In somatic mammalian cells, the nuclear form of DNA ligase IIIalpha forms a stable complex with the DNA repair protein XRCC1 that is also found only in higher eukaryotes. Recent studies have shown that XRCC1 participates in S phase-specific DNA repair pathways independently of DNA ligase IIIalpha and is constitutively phosphorylated by casein kinase II. In this study we demonstrate that DNA ligase IIIalpha, unlike XRCC1, is phosphorylated in a cell cycle-dependent manner. Specifically, DNA ligase IIIalpha is phosphorylated on Ser123 by the cell division cycle kinase Cdk2 beginning early in S phase and continuing into M phase. Interestingly, treatment of S phase cells with agents that cause oxygen free radicals induces the dephosphorylation of DNA ligase IIIalpha. This oxidative stress-induced dephosphorylation of DNA ligase IIIalpha is dependent upon the ATM (ataxia-telangiectasia mutated) kinase and appears to involve inhibition of Cdk2 and probably activation of a phosphatase.

  4. ATM mediates oxidative stress-induced dephosphorylation of DNA ligase IIIα

    PubMed Central

    Dong, Zhiwan; Tomkinson, Alan E.

    2006-01-01

    Among the three mammalian genes encoding DNA ligases, only the LIG3 gene does not have a homolog in lower eukaryotes. In somatic mammalian cells, the nuclear form of DNA ligase IIIα forms a stable complex with the DNA repair protein XRCC1 that is also found only in higher eukaryotes. Recent studies have shown that XRCC1 participates in S phase-specific DNA repair pathways independently of DNA ligase IIIα and is constitutively phosphorylated by casein kinase II. In this study we demonstrate that DNA ligase IIIα, unlike XRCC1, is phosphorylated in a cell cycle-dependent manner. Specifically, DNA ligase IIIα is phosphorylated on Ser123 by the cell division cycle kinase Cdk2 beginning early in S phase and continuing into M phase. Interestingly, treatment of S phase cells with agents that cause oxygen free radicals induces the dephosphorylation of DNA ligase IIIα. This oxidative stress-induced dephosphorylation of DNA ligase IIIα is dependent upon the ATM (ataxia-telangiectasia mutated) kinase and appears to involve inhibition of Cdk2 and probably activation of a phosphatase. PMID:17040896

  5. ATM participates in the regulation of viability and cell cycle via ellipticine in bladder cancer

    PubMed Central

    Tao, Shuixiang; Meng, Shuai; Zheng, Xiangyi; Xie, Liping

    2017-01-01

    Ellipticine, an alkaloid isolated from Apocyanaceae plants, has been demonstrated to exhibit antitumor activity in several cancers. However, the effect and the mechanisms underlying its action have not been investigated in human bladder cancer cells. The aim of the present study was to investigate the effect and mechanism of ellipticine on the behavior of T-24 bladder cancer cells. T-24 cells were treated with varying concentrations and durations of ellipticine. Cell viability was evaluated by Cell Counting Kit-8 assay. Cell motility was analyzed by Transwell migration assay. Flow cytometry, reverse transcription-quantitative polymerase chain reaction and western blot analyses were performed to detect the cell cycle and signaling pathways involved. The results demonstrated that ellipticine suppressed proliferation and inhibited the migration ability of T-24 bladder cancer cells in a dose- and time-dependent manner, and resulted in G2/M cell cycle arrest. The mechanism of this action was demonstrated to be due to ellipticine-triggered activation of the ATM serine/threonine kinase pathway. These data therefore suggest that ellipticine may be effective towards treating human bladder cancer. PMID:28138703

  6. Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism.

    PubMed

    Mandriota, Stefano J; Valentijn, Linda J; Lesne, Laurence; Betts, David R; Marino, Denis; Boudal-Khoshbeen, Mary; London, Wendy B; Rougemont, Anne-Laure; Attiyeh, Edward F; Maris, John M; Hogarty, Michael D; Koster, Jan; Molenaar, Jan J; Versteeg, Rogier; Ansari, Marc; Gumy-Pause, Fabienne

    2015-07-30

    Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma.

  7. Role of ataxia-telangiectasia mutated (ATM) in porcine oocyte in vitro maturation.

    PubMed

    Lin, Zi-Li; Kim, Nam-Hyung

    2015-06-01

    Ataxia-telangiectasia mutated (ATM) is critical for the DNA damage response, cell cycle checkpoints, and apoptosis. Significant effort has focused on elucidating the relationship between ATM and other nuclear signal transducers; however, little is known about the connection between ATM and oocyte meiotic maturation. We investigated the function of ATM in porcine oocytes. ATM was expressed at all stages of oocyte maturation and localized predominantly in the nucleus. Furthermore, the ATM-specific inhibitor KU-55933 blocked porcine oocyte maturation, reducing the percentages of oocytes that underwent germinal vesicle breakdown (GVBD) and first polar body extrusion. KU-55933 also decreased the expression of DNA damage-related genes (breast cancer 1, budding uninhibited by benzimidazoles 1, and P53) and reduced the mRNA and protein levels of AKT and other cell cycle-regulated genes that are predominantly expressed during G2/M phase, including bone morphogenetic protein 15, growth differentiation factor 9, cell division cycle protein 2, cyclinB1, and AKT. KU-55933 treatment decreased the developmental potential of blastocysts following parthenogenetic activation and increased the level of apoptosis. Together, these data suggested that ATM influenced the meiotic and cytoplasmic maturation of porcine oocytes, potentially by decreasing their sensitivity to DNA strand breaks, stimulating the AKT pathway, and/or altering the expression of other maternal genes.

  8. ATM-dependent phosphorylation of MEF2D promotes neuronal survival after DNA damage.

    PubMed

    Chan, Shing Fai; Sances, Sam; Brill, Laurence M; Okamoto, Shu-Ichi; Zaidi, Rameez; McKercher, Scott R; Akhtar, Mohd W; Nakanishi, Nobuki; Lipton, Stuart A

    2014-03-26

    Mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a kinase critical for the normal DNA damage response, cause the neurodegenerative disorder ataxia-telangiectasia (AT). The substrates of ATM in the brain are poorly understood. Here we demonstrate that ATM phosphorylates and activates the transcription factor myocyte enhancer factor 2D (MEF2D), which plays a critical role in promoting survival of cerebellar granule cells. ATM associates with MEF2D after DNA damage and phosphorylates the transcription factor at four ATM consensus sites. Knockdown of endogenous MEF2D with a short-hairpin RNA (shRNA) increases sensitivity to etoposide-induced DNA damage and neuronal cell death. Interestingly, substitution of endogenous MEF2D with an shRNA-resistant phosphomimetic MEF2D mutant protects cerebellar granule cells from cell death after DNA damage, whereas an shRNA-resistant nonphosphorylatable MEF2D mutant does not. In vivo, cerebella in Mef2d knock-out mice manifest increased susceptibility to DNA damage. Together, our results show that MEF2D is a substrate for phosphorylation by ATM, thus promoting survival in response to DNA damage. Moreover, dysregulation of the ATM-MEF2D pathway may contribute to neurodegeneration in AT.

  9. Integrated Service Provisioning in an Ipv6 over ATM Research Network

    SciTech Connect

    Eli Dart; Helen Chen; Jerry Friesen; Jim Brandt; Jim Hutchins; Perry Robertson

    1999-02-01

    During the past few years, the worldwide Internet has grown at a phenomenal rate, which has spurred the proposal of innovative network technologies to support the fast, efficient and low-latency transport of a wide spectrum of multimedia traffic types. Existing network infrastructures have been plagued by their inability to provide for real-time application traffic as well as their general lack of resources and resilience to congestion. This work proposes to address these issues by implementing a prototype high-speed network infrastructure consisting of Internet Protocol Version 6 (IPv6) on top of an Asynchronous Transfer Mode (ATM) transport medium. Since ATM is connection-oriented whereas IP uses a connection-less paradigm, the efficient integration of IPv6 over ATM is especially challenging and has generated much interest in the research community. We propose, in collaboration with an industry partner, to implement IPv6 over ATM using a unique approach that integrates IP over fast A TM hardware while still preserving IP's connection-less paradigm. This is achieved by replacing ATM's control software with IP's routing code and by caching IP's forwarding decisions in ATM's VPI/VCI translation tables. Prototype ''VR'' and distributed-parallel-computing applications will also be developed to exercise the realtime capability of our IPv6 over ATM network.

  10. Function of the ATR N-terminal domain revealed by an ATM/ATR chimera

    SciTech Connect

    Chen Xinping; Zhao Runxiang; Glick, Gloria G.; Cortez, David . E-mail: david.cortez@vanderbilt.edu

    2007-05-01

    The ATM and ATR kinases function at the apex of checkpoint signaling pathways. These kinases share significant sequence similarity, phosphorylate many of the same substrates, and have overlapping roles in initiating cell cycle checkpoints. However, they sense DNA damage through distinct mechanisms. ATR primarily senses single stranded DNA (ssDNA) through its interaction with ATRIP, and ATM senses double strand breaks through its interaction with Nbs1. We determined that the N-terminus of ATR contains a domain that binds ATRIP. Attaching this domain to ATM allowed the fusion protein (ATM*) to bind ATRIP and associate with RPA-coated ssDNA. ATM* also gained the ability to localize efficiently to stalled replication forks as well as double strand breaks. Despite having normal kinase activity when tested in vitro and being phosphorylated on S1981 in vivo, ATM* is defective in checkpoint signaling and does not complement cellular deficiencies in either ATM or ATR. These data indicate that the N-terminus of ATR is sufficient to bind ATRIP and to promote localization to sites of replication stress.

  11. Biophysical Characterization of the Iron in Mitochondria from Atm1p-depleted Saccharomyces cerevisiae

    PubMed Central

    Miao, Ren; Kim, Hansoo; Koppolu, Uma Mahendra Kumar; Ellis, E. Ann; Scott, Robert A.; Lindahl, Paul A.

    2009-01-01

    Atm1p is an ABC transporter localized in the mitochondrial inner membrane; it functions to export an unknown species into the cytosol and is involved in cellular iron metabolism. Depletion or deletion of Atm1p causes Fe accumulation in mitochondria and a defect in cytosolic Fe/S cluster assembly, but reportedly not a defect in mitochondrial Fe/S cluster assembly. In this study the nature of the accumulated Fe was examined using Mössbauer spectroscopy, EPR, electronic absorption spectroscopy, X-ray absorption spectroscopy, and electron microscopy. The Fe that accumulated in aerobically grown cells was in the form of Fe(III) phosphate nanoparticles similar to that which accumulates in yeast frataxin Yfh1p-deleted or yeast ferredoxin Yah1p-depleted cells. Relative to WT mitochondria, Fe/S cluster and heme levels in Atm1p-depleted mitochondria from aerobic cells were significantly diminished. Atm1p-depletion also caused a build-up of nonheme Fe(II) ions in the mitochondria and an increase in oxidative damage. Atm1p-depleted mitochondria isolated from anaerobically grown cells exhibited WT levels of Fe/S clusters and hemes, and they did not hyper-accumulate Fe. Atm1p-depleted cells lacked Leu1p activity, regardless of whether they were grown aerobically or anaerobically. These results indicate that Atm1p does not participate in mitochondrial Fe/S cluster assembly, and that the species exported by Atm1p is required for cytosolic Fe/S cluster assembly. The Fe/S cluster defect and the Fe-accumulation phenotype, resulting from the depletion of Atm1p in aerobic cells (but not in anaerobic cells), may be secondary effects that are observed only when cells are exposed to oxygen during growth. Reactive oxygen species generated under these conditions might degrade iron-sulfur clusters and lower heme levels in the organelle. PMID:19761223

  12. Antitumor Activity of Americanin A Isolated from the Seeds of Phytolacca americana by Regulating the ATM/ATR Signaling Pathway and the Skp2-p27 Axis in Human Colon Cancer Cells.

    PubMed

    Jung, Cholomi; Hong, Ji-Young; Bae, Song Yi; Kang, Sam Sik; Park, Hyen Joo; Lee, Sang Kook

    2015-12-24

    The antiproliferative and antitumor activities of americanin A (1), a neolignan isolated from the seeds of Phytolacca americana, were investigated in human colon cancer cells. Compound 1 inhibited the proliferation of HCT116 human colon cancer cells both in vitro and in vivo. The induction of G2/M cell-cycle arrest by 1 was concomitant with regulation of the ataxia telangiectasia-mutated/ATM and Rad3-related (ATM/ATR) signaling pathway. Treatment with 1 activated ATM and ATR, initiating the subsequent signal transduction cascades that include checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2), and tumor suppressor p53. Another line of evidence underlined the significance of 1 in regulation of the S phase kinase-associated protein 2 (Skp2)-p27 axis. Compound 1 targeted selectively Skp2 for degradation and thereby stabilized p27. Therefore, compound 1 suppressed the activity of cyclin B1 and its partner cell division cycle 2 (cdc2) to prevent entry into mitosis. Furthermore, prolonged treatment with 1 induced apoptosis by producing excessive reactive oxygen species. The intraperitoneal administration of 1 inhibited the growth of HCT116 tumor xenografts in nude mice without any overt toxicity. Modulation of the ATM/ATR signaling pathway and the Skp2-p27 axis might be plausible mechanisms of action for the antiproliferative and antitumor activities of 1 in human colon cancer cells.

  13. Exposure to chronic hyperglycemic conditions results in Ras-related C3 botulinum toxin substrate 1 (Rac1)-mediated activation of p53 and ATM kinase in pancreatic β-cells.

    PubMed

    Sidarala, Vaibhav; Kowluru, Anjaneyulu

    2017-02-21

    Chronic hyperglycemia (HG) promotes pancreatic islet dysfunction which leads to the onset of T2DM. This study is aimed at defining regulatory roles of Rac1, a small G-protein, in the activation of p53 and ATM kinase in pancreatic β-cells, under the duress of HG conditions. We report significant stimulatory effects of HG (20 mM; 24 h) on p53 activation in INS-1 832/13 cells, normal rodent and human islets. Pharmacological inhibition of Rac1 (EHT1864 or NSC23766) significantly suppressed HG-induced p53 activation in INS-1 832/13 cells and rat islets, suggesting novel roles for this small G-protein in the activation of p53. Inhibition of Rac1 geranylgeranylation with simvastatin or GGTI-2147, significantly attenuated HG-induced p53 activation, suggesting requisite roles for this signaling step in HG-mediated effects on β-cells. HG-induced p53 activation was also suppressed by SB203580, a known inhibitor of p38MAPK. Additionally, we observed increased activation of ATM kinase under HG conditions, which was blocked in presence of EHT1864. Furthermore, pharmacological inhibition of ATM kinase (KU55933) reduced activation of ATM kinase, but not p53, suggesting that HG-mediated activation of p53 and ATM could represent independent pro-apoptotic events. In conclusion, these data indicate that sustained activation of Rac1-p38MAPK signaling axis leads to activation of p53 leading to β-cell dysfunction under the duress of chronic hyperglycemic conditions.

  14. CATCOM catalyst 5 atm 1000 hour aging study using No. 2 fuel oil

    NASA Technical Reports Server (NTRS)

    Osgerby, I. T.; Olson, B. A.; Lee, H. C.

    1980-01-01

    The durability of the CATCOM catalyst for use in catalytically supported thermal combustion has been demonstrated at 5 atm, complementing a previous 1000 hour durability study at 1 atm. Both of these studies were conducted at about 640 K air preheat temperature at a reference velocity of about 14 m/s; the adiabatic flame temperature of the fuel/air mixture was about 1530 K. The catalyst proved to be capable of low emissions operations after 1000 hours of diesel fuel aging. However, more severe deactivation occurred in the 5 atm test; this was attributed to a loss in kinetic (ignition) activity.

  15. Infiltrating mast cells increase prostate cancer chemotherapy and radiotherapy resistances via modulation of p38/p53/p21 and ATM signals.

    PubMed

    Xie, Hongjun; Li, Chong; Dang, Qiang; Chang, Luke S; Li, Lei

    2016-01-12

    Early studies indicated that mast cells in prostate tumor microenvironment might influence prostate cancer (PCa) progression. Their impacts to PCa therapy, however, remained unclear. Here we found PCa could recruit more mast cells than normal prostate epithelial cells then alter PCa chemotherapy and radiotherapy sensitivity, leading to PCa more resistant to these therapies. Mechanism dissection revealed that infiltrated mast cells could increase p21 expression via modulation of p38/p53 signals, and interrupting p38-p53 signals via siRNAs of p53 or p21 could reverse mast cell-induced docetaxel chemotherapy resistance of PCa. Furthermore, recruited mast cells could also increase the phosphorylation of ATM at ser-1981 site, and inhibition of ATM activity could reverse mast cell-induced radiotherapy resistance. The in vivo mouse model with xenografted PCa C4-2 cells co-cultured with mast cells also confirmed that mast cells could increase PCa chemotherapy resistance via activating p38/p53/p21 signaling. Together, our results provide a new mechanism showing infiltrated mast cells could alter PCa chemotherapy and radiotherapy sensitivity via modulating the p38/p53/p21 signaling and phosphorylation of ATM. Targeting this newly identified signaling may help us better suppress PCa chemotherapy and radiotherapy resistance.

  16. Endogenous short RNAs generated by Dicer 2 and RNA-dependent RNA polymerase 1 regulate mRNAs in the basal fungus Mucor circinelloides

    SciTech Connect

    Grigoriev, Igor; Nicolas, Francisco; Moxon, Simon; Haro, Juan de; Calo, Silvia; Torres-Martinez, Santiago; Moulton, Vincent; Ruiz-Vazquez, Rosa; Dalmay, Tamas

    2011-09-01

    Endogenous short RNAs (esRNAs) play diverse roles in eukaryotes and usually are produced from double-stranded RNA (dsRNA) by Dicer. esRNAs are grouped into different classes based on biogenesis and function but not all classes are present in all three eukaryotic kingdoms. The esRNA register of fungi is poorly described compared to other eukaryotes and it is not clear what esRNA classes are present in this kingdom and whether they regulate the expression of protein coding genes. However, evidence that some dicer mutant fungi display altered phenotypes suggests that esRNAs play an important role in fungi. Here, we show that the basal fungus Mucor circinelloides produces new classes of esRNAs that map to exons and regulate the expression of many protein coding genes. The largest class of these exonic-siRNAs (ex-siRNAs) are generated by RNA-dependent RNA Polymerase 1 (RdRP1) and dicer-like 2 (DCL2) and target the mRNAs of protein coding genes from which they were produced. Our results expand the range of esRNAs in eukaryotes and reveal a new role for esRNAs in fungi

  17. The 3′–5′ DNA Exonuclease TREX1 Directly Interacts with Poly(ADP-ribose) Polymerase-1 (PARP1) during the DNA Damage Response*

    PubMed Central

    Miyazaki, Takuya; Kim, Yong-Soo; Yoon, Jeongheon; Wang, Hongsheng; Suzuki, Teruhiko; Morse, Herbert C.

    2014-01-01

    The main function of the 3′–5′ DNA exonuclease TREX1 is to digest cytosolic single-stranded DNA to prevent activation of cell-intrinsic responses to immunostimulatory DNA. TREX1 translocates to the nucleus following DNA damage with its nuclear activities being less well defined. Although mutations in human TREX1 have been linked to autoimmune/inflammatory diseases, the mechanisms contributing to the pathogenesis of these diseases remain incompletely understood. Here, using mass spectrometry and co-immunoprecipitation assays and in vivo overexpression models, we show that TREX1 interacts with poly(ADP-ribose) polymerase-1 (PARP1), a nuclear enzyme involved in the DNA damage response. Two zinc finger domains at the amino terminus of PARP1 were required for the interaction with TREX1 that occurs after nuclear translocation of TREX1 in response to DNA damage. Functional studies suggested that TREX1 may contribute to stabilization of PARP1 levels in the DNA damage response and its activity. These results provide new insights into the mechanisms of single-stranded DNA repair following DNA damage and alterations induced by gene mutations. PMID:25278026

  18. Apurinic/apyrimidinic (AP) site recognition by the 5'-dRP/AP lyase in poly(ADP-ribose) polymerase-1 (PARP-1).

    PubMed

    Khodyreva, S N; Prasad, R; Ilina, E S; Sukhanova, M V; Kutuzov, M M; Liu, Y; Hou, E W; Wilson, S H; Lavrik, O I

    2010-12-21

    The capacity of human poly(ADP-ribose) polymerase-1 (PARP-1) to interact with intact apurinic/apyrimidinic (AP) sites in DNA has been demonstrated. In cell extracts, sodium borohydride reduction of the PARP-1/AP site DNA complex resulted in covalent cross-linking of PARP-1 to DNA; the identity of cross-linked PARP-1 was confirmed by mass spectrometry. Using purified human PARP-1, the specificity of PARP-1 binding to AP site-containing DNA was confirmed in competition binding experiments. PARP-1 was only weakly activated to conduct poly(ADP-ribose) synthesis upon binding to AP site-containing DNA, but was strongly activated for poly(ADP-ribose) synthesis upon strand incision by AP endonuclease 1 (APE1). By virtue of its binding to AP sites, PARP-1 could be poised for its role in base excision repair, pending DNA strand incision by APE1 or the 5'-dRP/AP lyase activity in PARP-1.

  19. Video transmission on ATM networks. Ph.D. Thesis

    NASA Technical Reports Server (NTRS)

    Chen, Yun-Chung

    1993-01-01

    The broadband integrated services digital network (B-ISDN) is expected to provide high-speed and flexible multimedia applications. Multimedia includes data, graphics, image, voice, and video. Asynchronous transfer mode (ATM) is the adopted transport techniques for B-ISDN and has the potential for providing a more efficient and integrated environment for multimedia. It is believed that most broadband applications will make heavy use of visual information. The prospect of wide spread use of image and video communication has led to interest in coding algorithms for reducing bandwidth requirements and improving image quality. The major results of a study on the bridging of network transmission performance and video coding are: Using two representative video sequences, several video source models are developed. The fitness of these models are validated through the use of statistical tests and network queuing performance. A dual leaky bucket algorithm is proposed as an effective network policing function. The concept of the dual leaky bucket algorithm can be applied to a prioritized coding approach to achieve transmission efficiency. A mapping of the performance/control parameters at the network level into equivalent parameters at the video coding level is developed. Based on that, a complete set of principles for the design of video codecs for network transmission is proposed.

  20. MAC protocol for an ATM-based SuperPON

    NASA Astrophysics Data System (ADS)

    Angelopoulos, John D.; Koulouris, John; Fragoulopoulos, Stratos K.

    1996-11-01

    Developments in optical amplifiers and the tendency towards fewer and larger switching stages made feasible and desirable the concept of SuperPONs with a range of 100km. Up to 15000 residential customers can share the SuperPON on a TDMA basis lowering the cost of access to B-ISDN services. Tree PONs require a MAC protocol to arbitrate the access to upstream slots among the competing customer ATM cells in a dynamic and efficient way. The protocol presented in this work combines different access mechanisms according to service quality requirements. All bursty traffic is manipulated transparently using a reservation approach with closed loop control so as to handle the unpredictability of arrivals. In contrast, voice, N-ISDN and other delay sensitive services are provided with unsolicited access permits. In addition, composite cells offered quasi- synchronous permits are used to support STM legacy traffic without echo-cancellers. So, ABR traffic which is delay tolerant and more cost sensitive, can and should be concentrated with full exploitation of multiplexing gain prospects. The permit distribution algorithm focuses on cell spacing, control of CDV, almost jitter free access for synchronous traffic and efficiency for ABR traffic.

  1. NASA's ATM Technology Demonstration-1: Integrated Concept of Arrival Operations

    NASA Technical Reports Server (NTRS)

    Baxley, Brian T.; Swenson, Harry N.; Prevot, Thomas; Callantine, Todd J.

    2012-01-01

    This paper describes operations and procedures envisioned for NASA s Air Traffic Management (ATM) Technology Demonstration #1 (ATD-1). The ATD-1 Concept of Operations (ConOps) demonstration will integrate three NASA technologies to achieve high throughput, fuel-efficient arrival operations into busy terminal airspace. They are Traffic Management Advisor with Terminal Metering (TMA-TM) for precise time-based schedules to the runway and points within the terminal area, Controller-Managed Spacing (CMS) decision support tools for terminal controllers to better manage aircraft delay using speed control, and Flight deck Interval Management (FIM) avionics and flight crew procedures to conduct airborne spacing operations. The ATD-1 concept provides de-conflicted and efficient operations of multiple arrival streams of aircraft, passing through multiple merge points, from top-of-descent (TOD) to touchdown. It also enables aircraft to conduct Optimized Profile Descents (OPDs) from en route altitude to the runway, using primarily speed control to maintain separation and schedule. The ATD-1 project is currently addressing the challenges of integrating the three technologies, and implantation into an operational environment. Goals of the ATD-1 demonstration include increasing the throughput of high-density airports, reducing controller workload, increasing efficiency of arrival operations and the frequency of trajectory-based operations, and promoting aircraft ADS-B equipage.

  2. ATM traffic-policing and traffic-shaping measurements

    NASA Astrophysics Data System (ADS)

    Pugaczewski, Jack T.; Sanderson, Dave; Hoffman, David W.

    1997-10-01

    ATM (Asynchronous Transfer Mode) defines several Quality of Service (QoS) levels such as CBR (Constant Bit Rate) and VBR (Variable Bit Rate). Each service has parameters that are associated with its performance characteristic. The parameters used for specifying CBR service are Peak Cell Rate (PCR) and Cell Delay Variation Tolerance (CDVTOL). The parameters used for specifying VBR service are PCR, SCR (Sustainable Cell Rate), and BT (Burst Tolerance). The network takes responsibility for monitoring and policing the traffic of each VCC/VPC at the ingress of the network. The CPE needs to traffic shape at the ingress of the network in order to meet the contracted QoS requirements. Measurement procedures and tools are required in order to provide a means of tuning the CPE and network service to meet the customer's end-to-end QoS expectations. The following paper describes how the Generic Cell Rate Algorithm variables can be adjusted to provide acceptable levels of QoS in a mixed VBR, and CBR environment. In addition, the paper examines a methodology for measuring the performance of VBR and CBR services. The authors uses this information to build a QoS measurement tool.

  3. Anomalous preservation of pure methane hydrate at 1 atm

    USGS Publications Warehouse

    Stern, L.A.; Circone, S.; Kirby, S.H.; Durham, W.B.

    2001-01-01

    Direct measurement of decomposition rates of pure, polycrystalline methane hydrate reveals a thermal regime where methane hydrate metastably `preserves' in bulk by as much as 75 K above its nominal equilibrium temperature (193 K at 1 atm). Rapid release of the sample pore pressure at isothermal conditions between 242 and 271 K preserves up to 93% of the hydrate for at least 24 h, reflecting the greatly suppressed rates of dissociation that characterize this regime. Subsequent warming through the H2O ice point then induces rapid and complete dissociation, allowing controlled recovery of the total expected gas yield. This behavior is in marked contrast to that exhibited by methane hydrate at both colder (193-240 K) and warmer (272-290 K) test conditions, where dissociation rates increase monotonically with increasing temperature. Anomalous preservation has potential application for successful retrieval of natural gas hydrate or hydrate-bearing sediments from remote settings, as well as for temporary low-pressure transport and storage of natural gas.

  4. Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair.

    PubMed

    Du, Fengxia; Zhang, Minjie; Li, Xiaohua; Yang, Caiyun; Meng, Hao; Wang, Dong; Chang, Shuang; Xu, Ye; Price, Brendan; Sun, Yingli

    2014-10-03

    The ATM protein kinase, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer and phosphorylates the opposite strand of the dimer in response to DNA damage. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. ATM cannot phosphorylate the substrates when it could not undergo dimer monomer transition. After DNA repair, the active monomer will undergo dephosphorylation to form dimer again and dephosphorylation is critical for dimer re-formation. Our work reveals novel function of ATM dimer monomer transition and explains why ATM dimer monomer transition plays such important role for ATM cellular activity during DNA repair.

  5. ATM QoS Experiments Using TCP Applications: Performance of TCP/IP Over ATM in a Variety of Errored Links

    NASA Technical Reports Server (NTRS)

    Frantz, Brian D.; Ivancic, William D.

    2001-01-01

    Asynchronous Transfer Mode (ATM) Quality of Service (QoS) experiments using the Transmission Control Protocol/Internet Protocol (TCP/IP) were performed for various link delays. The link delay was set to emulate a Wide Area Network (WAN) and a Satellite Link. The purpose of these experiments was to evaluate the ATM QoS requirements for applications that utilize advance TCP/IP protocols implemented with large windows and Selective ACKnowledgements (SACK). The effects of cell error, cell loss, and random bit errors on throughput were reported. The detailed test plan and test results are presented herein.

  6. Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies.

    PubMed

    Gaudio, Eugenio; Spizzo, Riccardo; Paduano, Francesco; Luo, Zhenghua; Efanov, Alexey; Palamarchuk, Alexey; Leber, Amanda S; Kaou, Mohamed; Zanesi, Nicola; Bottoni, Arianna; Costinean, Stefan; Rassenti, Laura Z; Nakamura, Tatsuya; Kipps, Thomas J; Aqeilan, Rami I; Pekarsky, Yuri; Trapasso, Francesco; Croce, Carlo M

    2012-01-05

    The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas.

  7. The ATM Kinase Induces MicroRNA Biogenesis in the DNA Damage Response

    PubMed Central

    Zhang, Xinna; Wan, Guohui; Berger, Franklin G.; He, Xiaoming; Lu, Xiongbin

    2011-01-01

    SUMMARY The DNA damage response involves a complex network of processes that detect and repair DNA damage. Here we show that miRNA biogenesis is globally induced upon DNA damage in an ATM-dependent manner. About one fourth of miRNAs are significantly up-regulated after DNA damage, while loss of ATM abolishes their induction. KSRP (KH-type splicing regulatory protein) is a key player that translates DNA damage signaling to miRNA biogenesis. The ATM kinase directly binds to and phosphorylates KSRP, leading to enhanced interaction between KSRP and pri-miRNAs and increased KSRP activity in miRNA processing. Mutations of the ATM phosphorylation sites of KSRP impaired its activity in regulating miRNAs. These findings reveal a mechanism by which DNA damage signaling is linked to miRNA biogenesis. PMID:21329876

  8. DNA double-strand breaks and ATM activation by transcription-blocking DNA lesions.

    PubMed

    Sordet, Olivier; Nakamura, Asako J; Redon, Christophe E; Pommier, Yves

    2010-01-15

    A taxia telangiectasia mutated (ATM), the deficiency of which causes a severe neurodegenerative disease, is a crucial mediator for the DNA double-strand break (DSB) response. We recently showed that transcription-blocking topoisomerase I cleavage complexes (TOP1cc) produce DSBs related to R-loop formation and activate ATM in post-mitotic neurons and lymphocytes. Here we discuss how TOP1cc can produce transcription arrest with R-loop formation and generate DSBs that activate ATM, as well as data suggesting that those transcription-dependent DSBs tend to form at the IgH locus and at specific genomic sites. We also address the potential roles of ATM in response to transcription-blocking TOP1cc.

  9. ATM specifically mediates repair of double-strand breaks with blocked DNA ends.

    PubMed

    Álvarez-Quilón, Alejandro; Serrano-Benítez, Almudena; Lieberman, Jenna Ariel; Quintero, Cristina; Sánchez-Gutiérrez, Daniel; Escudero, Luis M; Cortés-Ledesma, Felipe

    2014-02-27

    Ataxia telangiectasia is caused by mutations in ATM and represents a paradigm for cancer predisposition and neurodegenerative syndromes linked to deficiencies in the DNA-damage response. The role of ATM as a key regulator of signalling following DNA double-strand breaks (DSBs) has been dissected in extraordinary detail, but the impact of this process on DSB repair still remains controversial. Here we develop novel genetic and molecular tools to modify the structure of DSB ends and demonstrate that ATM is indeed required for efficient and accurate DSB repair, preventing cell death and genome instability, but exclusively when the ends are irreversibly blocked. We therefore identify the nature of ATM involvement in DSB repair, presenting blocked DNA ends as a possible pathogenic trigger of ataxia telangiectasia and related disorders.

  10. ATM specifically mediates repair of double-strand breaks with blocked DNA ends

    PubMed Central

    Álvarez-Quilón, Alejandro; Serrano-Benítez, Almudena; Ariel Lieberman, Jenna; Quintero, Cristina; Sánchez-Gutiérrez, Daniel; Escudero, Luis M.; Cortés-Ledesma, Felipe

    2014-01-01

    Ataxia telangiectasia is caused by mutations in ATM and represents a paradigm for cancer predisposition and neurodegenerative syndromes linked to deficiencies in the DNA-damage response. The role of ATM as a key regulator of signalling following DNA double-strand breaks (DSBs) has been dissected in extraordinary detail, but the impact of this process on DSB repair still remains controversial. Here we develop novel genetic and molecular tools to modify the structure of DSB ends and demonstrate that ATM is indeed required for efficient and accurate DSB repair, preventing cell death and genome instability, but exclusively when the ends are irreversibly blocked. We therefore identify the nature of ATM involvement in DSB repair, presenting blocked DNA ends as a possible pathogenic trigger of ataxia telangiectasia and related disorders. PMID:24572510

  11. The Advanced Technology Microwave Sounder (ATMS): A New Operational Sensor Series

    NASA Technical Reports Server (NTRS)

    Kim, Edward; Lyu, Cheng-H Joseph; Leslie, R. Vince; Baker, Neal; Mo, Tsan; Sun, Ninghai; Bi, Li; Anderson, Mike; Landrum, Mike; DeAmici, Giovanni; Gu, Degui; Foo, Alex; Ibrahim, Wael; Robinson, Kris; Chidester, Lynn; Shiue, James

    2012-01-01

    ATMS is a new satellite microwave sounding sensor designed to provide operational weather agencies with atmospheric temperature and moisture profile information for global weather forecasting and climate applications. ATMS will continue the microwave sounding capabilities first provided by its predecessors, the Microwave Sounding Unit (MSU) and Advanced Microwave Sounding Unit (AMSU). The first ATMS was launched October 28, 2011 on board the Suomi National Polar-orbiting Partnership (S-NPP) satellite. Microwave soundings by themselves are the highest-impact input data used by Numerical Weather Prediction (NWP) models; and ATMS, when combined with the Cross-track Infrared Sounder (CrIS), forms the Cross-track Infrared and Microwave Sounding Suite (CrIMSS). The microwave soundings help meet NWP sounding requirements under cloudy sky conditions and provide key profile information near the surface

  12. Fabrication and characterization of MCC (Materials Characterization Center) approved testing material: ATM-10 glass

    SciTech Connect

    Maupin, G.D.; Bowen, W.M.; Daniel, J.L.

    1988-04-01

    The Materials Characterization Center ATM-10 glass represents a reference commercial high-level waste form similar to that which will be produced by the West Valley Nuclear Service Co. Inc., West Valley, New York. The target composition and acceptable range of composition were defined by the sponsor, West Valley Nuclear Service. The ATM-10 glass was produced in accordance with the Pacific Northwest Laboratory QA Manual for License-Related Programs, MCC technical procedures, and MCC QA Plan that were in effect during the course of the work. The method and procedure to be used in the fabrication and characterization of the ATM-10 glass were specified in two run plans for glass preparation and a characterization plan. All of the ATM-10 glass was produced in the form of bars 1.9 /times/ 1.9 /times/ 10 cm nominal size, and 93 g nominal mass. A total of 15 bars of ATM-10 glass weighing 1394 g was produced. The production bars were characterized to determine the mean composition, oxidation state, and microstructure of the ATM-10 product. Table A summarizes the characterization results. The ATM-10 glass meets all specifications. The elemental composition and oxidation state of the glass are within the specifications of the client. Visually, the ATM-10 glass bars appear uniformly glassy and generally without exterior features. Microscopic examination revealed low (less than 2 wt %) concentractions of 3-..mu..m iron-chrome (suspected spinel) crystals and /approximately/0.5-..mu..m ruthenium inclusions scattered randomly throughout the glassy matrix. Closed porosity, with pores ranging in diameter from 5 to 250 ..mu..m, was observed in all samples. 4 refs., 10 figs., 21 tabs.

  13. Interactive multimedia service platform using the ATM transport engine for business and institutional communities

    NASA Astrophysics Data System (ADS)

    Roh, Jangrai; Kim, Jongwon; Hong, Han K.; Kook, Kyoungmook

    1996-01-01

    This paper describes the architecture of an interactive multimedia service platform in addition to implementation techniques based on the ATM transport engine under consideration. To support the interactive multimedia service, office environments need to integrate retrieval, on- demand, communicative, messaging and transactional capabilities into multi-homed hosts and heterogeneous infrastructures. Especially the various over ATM' and service provisioning mechanisms have to be considered in an evolutionary view of the platform.

  14. ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation

    PubMed Central

    Barlow, Carrolee; Ribaut-Barassin, Catherine; Zwingman, Theresa A.; Pope, Amber J.; Brown, Kevin D.; Owens, Jennie W.; Larson, Denise; Harrington, Elizabeth A.; Haeberle, Anne-Marie; Mariani, Jean; Eckhaus, Michael; Herrup, Karl; Bailly, Yannick; Wynshaw-Boris, Anthony

    2000-01-01

    We previously generated a mouse model with a mutation in the murine Atm gene that recapitulates many aspects of the childhood neurodegenerative disease ataxia-telangiectasia. Atm-deficient (Atm−/−) mice show neurological defects detected by motor function tests including the rota-rod, open-field tests and hind-paw footprint analysis. However, no gross histological abnormalities have been observed consistently in the cerebellum of any line of Atm−/− mice analyzed in most laboratories. Therefore, it may be that the neurologic dysfunction found in these animals is associated with predegenerative lesions. We performed a detailed analysis of the cerebellar morphology in two independently generated lines of Atm−/− mice to determine whether there was evidence of neuronal abnormality. We found a significant increase in the number of lysosomes in Atm−/− mice in the absence of any detectable signs of neuronal degeneration or other ultrastructural anomalies. In addition, we found that the ATM protein is predominantly cytoplasmic in Purkinje cells and other neurons, in contrast to the nuclear localization of ATM protein observed in cultured cells. The cytoplasmic localization of ATM in Purkinje cells is similar to that found in human cerebellum. These findings suggest that ATM may be important as a cytoplasmic protein in neurons and that its absence leads to abnormalities of cytoplasmic organelles reflected as an increase in lysosomal numbers. PMID:10639172

  15. ATM is the predominant kinase involved in the phosphorylation of histone H2AX after heating.

    PubMed

    Takahashi, Akihisa; Mori, Eiichiro; Su, Xiaoming; Nakagawa, Yosuke; Okamoto, Noritomo; Uemura, Hirokazu; Kondo, Natsuko; Noda, Taichi; Toki, Atsushi; Ejima, Yosuke; Chen, David J; Ohnishi, Ken; Ohnishi, Takeo

    2010-01-01

    Heating induces histone H2AX phosphorylation at serine 139 (gammaH2AX). Phosphorylated H2AX subsequently forms foci in numerous mammalian cell lines. The aim of this study was to clarify details in the mechanisms involved in the phosphorylation of H2AX after heating. The cell lines used were DNA-PKcs knockout cells, ATM knockout cells, and their parental cell lines. To elucidate mechanisms of induction of phosphorylation of H2AX after heating, ATM/ATR inhibitor (CGK733) and DNA-PK inhibitor (NU7026) were used. The intensity of gammaH2AX signals was assayed with flow cytometry. The thermal dose-response curve for the fluorescence intensity of gammaH2AX appearance in DNA-PKcs-/- cells during the heating period was similar to that observed in DNA-PKcs+/+ cells. On the other hand, the slope of thermal dose-response curve for them in ATM-/- cells was lower than that in ATM+/+ cells. Phosphorylation of H2AX after heating was suppressed by a combination of CGK733 and NU7026 in the culture medium in DNA-PKcs-/- cells, ATM-/- cells and in their parental cells. Although the phosphorylation of H2AX after heating was not suppressed by NU7026 in their parental cells, such phosphorylation was suppressed by CGK733 in their parental cells. These results indicate that ATM is the predominant protein which is active in the phosphorylation of histone H2AX after heating.

  16. ATM-Dependent Phosphorylation of All Three Members of the MRN Complex: From Sensor to Adaptor

    PubMed Central

    Lavin, Martin F.; Kozlov, Sergei; Gatei, Magtouf; Kijas, Amanda W.

    2015-01-01

    The recognition, signalling and repair of DNA double strand breaks (DSB) involves the participation of a multitude of proteins and post-translational events that ensure maintenance of genome integrity. Amongst the proteins involved are several which when mutated give rise to genetic disorders characterised by chromosomal abnormalities, cancer predisposition, neurodegeneration and other pathologies. ATM (mutated in ataxia-telangiectasia (A-T) and members of the Mre11/Rad50/Nbs1 (MRN complex) play key roles in this process. The MRN complex rapidly recognises and locates to DNA DSB where it acts to recruit and assist in ATM activation. ATM, in the company of several other DNA damage response proteins, in turn phosphorylates all three members of the MRN complex to initiate downstream signalling. While ATM has hundreds of substrates, members of the MRN complex play a pivotal role in mediating the downstream signalling events that give rise to cell cycle control, DNA repair and ultimately cell survival or apoptosis. Here we focus on the interplay between ATM and the MRN complex in initiating signaling of breaks and more specifically on the adaptor role of the MRN complex in mediating ATM signalling to downstream substrates to control different cellular processes. PMID:26512707

  17. Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice

    NASA Technical Reports Server (NTRS)

    Weil, M. M.; Kittrell, F. S.; Yu, Y.; McCarthy, M.; Zabriskie, R. C.; Ullrich, R. L.

    2001-01-01

    Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm(+/+) mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.

  18. ATM-Dependent Phosphorylation of All Three Members of the MRN Complex: From Sensor to Adaptor.

    PubMed

    Lavin, Martin F; Kozlov, Sergei; Gatei, Magtouf; Kijas, Amanda W

    2015-10-23

    The recognition, signalling and repair of DNA double strand breaks (DSB) involves the participation of a multitude of proteins and post-translational events that ensure maintenance of genome integrity. Amongst the proteins involved are several which when mutated give rise to genetic disorders characterised by chromosomal abnormalities, cancer predisposition, neurodegeneration and other pathologies. ATM (mutated in ataxia-telangiectasia (A-T) and members of the Mre11/Rad50/Nbs1 (MRN complex) play key roles in this process. The MRN complex rapidly recognises and locates to DNA DSB where it acts to recruit and assist in ATM activation. ATM, in the company of several other DNA damage response proteins, in turn phosphorylates all three members of the MRN complex to initiate downstream signalling. While ATM has hundreds of substrates, members of the MRN complex play a pivotal role in mediating the downstream signalling events that give rise to cell cycle control, DNA repair and ultimately cell survival or apoptosis. Here we focus on the interplay between ATM and the MRN complex in initiating signaling of breaks and more specifically on the adaptor role of the MRN complex in mediating ATM signalling to downstream substrates to control different cellular processes.

  19. Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency.

    PubMed

    Jiang, Dewei; Zhang, Ying; Hart, Ronald P; Chen, Jianmin; Herrup, Karl; Li, Jiali

    2015-12-01

    A long-standing mystery surrounding ataxia-telangiectasia is why it is mainly cerebellar neurons, Purkinje cells in particular, that appear vulnerable to ATM deficiency. Here we present data showing that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human ataxia-telangiectasia and Atm(-/-) mouse cerebellar Purkinje cells. We further show that TET1, an enzyme that converts 5-methylcytosine (5mC) to 5hmC, responds to DNA damage and manipulation of TET1 activity directly affects the DNA damage signalling and ATM-deficient neuronal cell cycle re-entry and death. Quantitative genome-wide analysis of 5hmC-containing sequences shows that in ATM deficiency there is a cerebellum- and Purkinje cell-specific shift in 5hmC enrichment in both regulatory elements and repeated sequences. Finally, we verify that TET1-mediated 5hmC production is linked to the degenerative process of Purkinje cells and behavioural deficits in Atm(-/-) mice. Taken together, the selective loss of 5hmC plays a critical role in driving Purkinje cell vulnerability in ATM deficiency.

  20. Cross talk between poly(ADP-ribose) polymerase 1 methylation and oxidative stress involved in the toxic effect of anatase titanium dioxide nanoparticles

    PubMed Central

    Bai, Wenlin; Chen, Yujiao; Gao, Ai

    2015-01-01

    Given the tremendous growth in the application of titanium dioxide nanoparticles (TNPs), concerns about the potential health hazards of TNPs to humans have been raised. Poly(ADP-ribose) polymerase 1 (PARP-1), a highly conserved DNA-binding protein, is involved in many molecular and cellular processes. Limited data demonstrated that certain nanomaterials induced the aberrant hypermethylation of PARP-1. However, the mechanism involved in TNP-induced PARP-1 abnormal methylation has not been studied. A549 cells were incubated with anatase TNPs (22.1 nm) for 24 hours pretreatment with or without methyltransferase inhibitor 5-aza-2′-deoxycytidine and the reactive oxygen species (ROS) scavenger α-lipoic acid to assess the possible role of methylation and ROS in the toxic effect of TNPs. After TNPs characterization, a battery of assays was performed to evaluate the toxic effect of TNPs, PARP-1 methylation status, and oxidative damage. Results showed that TNPs decreased the cell viability in a dose-dependent manner, in accordance with the increase of lactate dehydrogenase activity, which indicated membrane damage of cells. Similar to the high level of PARP-1 methylation, the generation of ROS was significantly increased after exposure to TNPs for 24 hours. Furthermore, α-lipoic acid decreased TNP-induced ROS generation and then attenuated TNP-triggered PARP-1 hypermethylation. Meanwhile, 5-aza-2′-deoxycytidine simultaneously decreased the ROS generation induced by TNPs, resulting in the decline of PARP-1 methylation. In summary, TNPs triggered the aberrant hypermethylation of the PARP-1 promoter and there was a cross talk between oxidative stress and PARP-1 methylation in the toxic effect of TNPs. PMID:26366077

  1. p63 involvement in poly(ADP-ribose) polymerase 1 signaling of topoisomerase I-dependent DNA damage in carcinoma cells.

    PubMed

    Montariello, Daniela; Troiano, Annaelena; Malanga, Maria; Calabrò, Viola; Quesada, Piera

    2013-04-01

    Poly(ADP-ribose)polymerase 1 (PARP-1) inhibitors are thought as breakthrough for cancer treatment in solid tumors such as breast cancer through their effects on PARP's enzymatic activity. Our previous findings showed that the hydrophilic PARP inhibitor PJ34 enhances the sensitivity of p53 proficient MCF7 breast carcinoma cells to topotecan, a DNA Topoisomerase I (TOP 1) inhibitor. In the present study, we combine the classical TOP 1 poison camptothecin or its water-soluble derivative topotecan with PJ34 to investigate the potentiation of chemotherapeutic efficiency in MCF7 (p53(WT)), MDA-MB231 (p53(mut)) breast carcinoma cells and SCC022 (p53(null)) squamous carcinoma cells. We show that, following TPT-PJ34 combined treatment, MCF7 cells exhibit apoptotic death while MDA-MB231 and SCC022 cells are more resistant to these agents. Specifically, in MCF7, (i) PJ34 in combination with TPT causes a G2/M cell cycle arrest followed by massive apoptosis; (ii) PJ34 addition reverts TPT-dependent PARP-1 automodification and triggers caspase-dependent PARP-1 proteolysis; (iii) TPT, used as a single agent, stimulates p53 expression while in combination with PJ34 increases p53, TAp63α and TAp63γ protein levels with a concomitant reduction of MDM2 protein. The identification of p63 proteins as new players involved in the cancer cell response to TPT-PJ34 is relevant for a better understanding of the PARP1-dependent signaling of DNA damage. Furthermore, our data indicate that, in response to TPT-PJ34 combined chemotherapy, a functional cooperation between p53 and TAp63 proteins may occur and be essential to trigger apoptotic cell death.

  2. Cross talk between poly(ADP-ribose) polymerase 1 methylation and oxidative stress involved in the toxic effect of anatase titanium dioxide nanoparticles.

    PubMed

    Bai, Wenlin; Chen, Yujiao; Gao, Ai

    2015-01-01

    Given the tremendous growth in the application of titanium dioxide nanoparticles (TNPs), concerns about the potential health hazards of TNPs to humans have been raised. Poly(ADP-ribose) polymerase 1 (PARP-1), a highly conserved DNA-binding protein, is involved in many molecular and cellular processes. Limited data demonstrated that certain nanomaterials induced the aberrant hypermethylation of PARP-1. However, the mechanism involved in TNP-induced PARP-1 abnormal methylation has not been studied. A549 cells were incubated with anatase TNPs (22.1 nm) for 24 hours pretreatment with or without methyltransferase inhibitor 5-aza-2'-deoxycytidine and the reactive oxygen species (ROS) scavenger α-lipoic acid to assess the possible role of methylation and ROS in the toxic effect of TNPs. After TNPs characterization, a battery of assays was performed to evaluate the toxic effect of TNPs, PARP-1 methylation status, and oxidative damage. Results showed that TNPs decreased the cell viability in a dose-dependent manner, in accordance with the increase of lactate dehydrogenase activity, which indicated membrane damage of cells. Similar to the high level of PARP-1 methylation, the generation of ROS was significantly increased after exposure to TNPs for 24 hours. Furthermore, α-lipoic acid decreased TNP-induced ROS generation and then attenuated TNP-triggered PARP-1 hypermethylation. Meanwhile, 5-aza-2'-deoxycytidine simultaneously decreased the ROS generation induced by TNPs, resulting in the decline of PARP-1 methylation. In summary, TNPs triggered the aberrant hypermethylation of the PARP-1 promoter and there was a cross talk between oxidative stress and PARP-1 methylation in the toxic effect of TNPs.

  3. Poly(ADP-Ribose) Polymerase-1 and DNA-Dependent Protein Kinase Have Equivalent Roles in Double Strand Break Repair Following Ionizing Radiation

    SciTech Connect

    Mitchell, Jody; Smith, Graeme; Curtin, Nicola J.

    2009-12-01

    Purpose: Radiation-induced DNA double strand breaks (DSBs) are predominantly repaired by nonhomologous end joining (NHEJ), involving DNA-dependent protein kinase (DNA-PK). Poly(ADP-ribose) polymerase-1 (PARP-1), well characterized for its role in single strand break repair, may also facilitate DSB repair. We investigated the activation of these enzymes by differing DNA ends and their interaction in the cellular response to ionizing radiation (IR). Methods and Materials: The effect of PARP and DNA-PK inhibitors (KU-0058684 and NU7441) on repair of IR-induced DSBs was investigated in DNA-PK and PARP-1 proficient and deficient cells by measuring gammaH2AX foci and neutral comets. Complementary in vitro enzyme kinetics assays demonstrated the affinities of DNA-PK and PARP-1 for DSBs with varying DNA termini. Results: DNA-PK and PARP-1 both promoted the fast phase of resolution of IR-induced DSBs in cells. Inactivation of both enzymes was not additive, suggesting that PARP-1 and DNA-PK cooperate within the same pathway to promote DSB repair. The affinities of the two enzymes for oligonucleotides with blunt, 3' GGG or 5' GGG overhanging termini were similar and overlapping (K{sub dapp} = 2.6-6.4nM for DNA-PK; 1.7-4.5nM for PARP-1). DNA-PK showed a slightly greater affinity for overhanging DNA and was significantly more efficient when activated by a 5' GGG overhang. PARP-1 had a preference for blunt-ended DNA and required a separate factor for efficient stimulation by a 5' GGG overhang. Conclusion: DNA-PK and PARP-1 are both required in a pathway facilitating the fast phase of DNA DSB repair.

  4. The relationship between the plant-encoded RNA-dependent RNA polymerase 1 and alternative oxidase in tomato basal defense against Tobacco mosaic virus.

    PubMed

    Liao, Yang-Wen-Ke; Liu, Ya-Ru; Liang, Jia-Yang; Wang, Wen-Ping; Zhou, Jie; Xia, Xiao-Jian; Zhou, Yan-Hong; Yu, Jing-Quan; Shi, Kai

    2015-03-01

    Salicylic acid (SA) plays a critical role in plant defense against pathogen attack. The SA-induced viral defense in plants is distinct from the pathways mediating bacterial and fungal defense, which is pathogenesis-related protein-independent but involves an RNA-dependent RNA polymerase 1 (RDR1)-mediated RNA silencing mechanism and/or an alternative oxidase (AOX)-associated defense pathway. However, the relationship between these two viral defense-related pathways remains unclear. In this study, Tobacco mosaic virus (TMV) inoculation onto Solanum lycopersicum (tomato) leaves induced a rapid induction of the SlAOX1a transcript level as well as the total and CN-resistant respiration at 0.5 dpi, followed by an increase in SlRDR1 gene expression at 1 dpi in the upper uninoculated leaves. Silencing SlRDR1 using virus-induced gene silencing system significantly reduced SlRDR1 expression and tomato defense against TMV but had no evident effect on SlAOX1a transcription. Conversely, silencing SlAOX1a not only effectively reduced the AOX1a transcript level, but also blocked the TMV-induced SlRDR1 expression and decreased the basal defense against TMV. Furthermore, the application of an exogenous AOX activator on empty vector-silenced control plants greatly induced the accumulation of SlRDR1 and SlAOX1a transcript and reduced TMV viral RNA accumulation, but failed to have such effects on SlRDR1-silenced plants. Moreover, RDR1-overexpressed transgenic Nicotiana benthamiana plants enhanced defense against TMV than the empty vector-transformed plants, but these effects were not affected by the exogenous AOX activator or inhibitor. These results indicate that RDR1 is involved in the AOX-mediated defense pathway against TMV infection and plays a crucial role in enhancing RNA silencing to limit virus systemic spread.

  5. Global analysis of transcriptional regulation by poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in MCF-7 human breast cancer cells.

    PubMed

    Frizzell, Kristine M; Gamble, Matthew J; Berrocal, Jhoanna G; Zhang, Tong; Krishnakumar, Raga; Cen, Yana; Sauve, Anthony A; Kraus, W Lee

    2009-12-04

    Poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG) are enzymes that modify target proteins by the addition and removal, respectively, of ADP-ribose polymers. Although a role for PARP-1 in gene regulation has been well established, the role of PARG is less clear. To investigate how PARP-1 and PARG coordinately regulate global patterns of gene expression, we used short hairpin RNAs to stably knock down PARP-1 or PARG in MCF-7 cells followed by expression microarray analyses. Correlation analyses showed that the majority of genes affected by the knockdown of one factor were similarly affected by the knockdown of the other factor. The most robustly regulated common genes were enriched for stress-response and metabolic functions. In chromatin immunoprecipitation assays, PARP-1 and PARG localized to the promoters of positively and negatively regulated target genes. The levels of chromatin-bound PARG at a given promoter generally correlated with the levels of PARP-1 across the subset of promoters tested. For about half of the genes tested, the binding of PARP-1 at the promoter was dependent on the binding of PARG. Experiments using stable re-expression of short hairpin RNA-resistant catalytic mutants showed that PARP-1 and PARG enzymatic activities are required for some, but not all, target genes. Collectively, our results indicate that PARP-1 and PARG, nuclear enzymes with opposing enzymatic activities, localize to target promoters and act in a similar, rather than antagonistic, manner to regulate gene expression.

  6. Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair

    SciTech Connect

    Du, Fengxia; Zhang, Minjie; Li, Xiaohua; Yang, Caiyun; Meng, Hao; Wang, Dong; Chang, Shuang; Xu, Ye; Price, Brendan; Sun, Yingli

    2014-10-03

    Highlights: • ATM phosphorylates the opposite strand of the dimer in response to DNA damage. • The PETPVFRLT box of ATM plays a key role in its dimer dissociation in DNA repair. • The dephosphorylation of ATM is critical for dimer re-formation after DNA repair. - Abstract: The ATM protein kinase, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer and phosphorylates the opposite strand of the dimer in response to DNA damage. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. ATM cannot phosphorylate the substrates when it could not undergo dimer monomer transition. After DNA repair, the active monomer will undergo dephosphorylation to form dimer again and dephosphorylation is critical for dimer re-formation. Our work reveals novel function of ATM dimer monomer transition and explains why ATM dimer monomer transition plays such important role for ATM cellular activity during DNA repair.

  7. ATM-Mediated Transcriptional and Developmental Responses to γ-rays in Arabidopsis

    PubMed Central

    Renou, Jean-Pierre; Pichon, Olivier; Fochesato, Sylvain; Ortet, Philippe; Montané, Marie-Hélène

    2007-01-01

    ATM (Ataxia Telangiectasia Mutated) is an essential checkpoint kinase that signals DNA double-strand breaks in eukaryotes. Its depletion causes meiotic and somatic defects in Arabidopsis and progressive motor impairment accompanied by several cell deficiencies in patients with ataxia telangiectasia (AT). To obtain a comprehensive view of the ATM pathway in plants, we performed a time-course analysis of seedling responses by combining confocal laser scanning microscopy studies of root development and genome-wide expression profiling of wild-type (WT) and homozygous ATM-deficient mutants challenged with a dose of γ-rays (IR) that is sublethal for WT plants. Early morphologic defects in meristematic stem cells indicated that AtATM, an Arabidopsis homolog of the human ATM gene, is essential for maintaining the quiescent center and controlling the differentiation of initial cells after exposure to IR. Results of several microarray experiments performed with whole seedlings and roots up to 5 h post-IR were compiled in a single table, which was used to import gene information and extract gene sets. Sequence and function homology searches; import of spatio-temporal, cell cycling, and mutant-constitutive expression characteristics; and a simplified functional classification system were used to identify novel genes in all functional classes. The hundreds of radiomodulated genes identified were not a random collection, but belonged to functional pathways such as those of the cell cycle; cell death and repair; DNA replication, repair, and recombination; and transcription; translation; and signaling, indicating the strong cell reprogramming and double-strand break abrogation functions of ATM checkpoints. Accordingly, genes in all functional classes were either down or up-regulated concomitantly with downregulation of chromatin deacetylases or upregulation of acetylases and methylases, respectively. Determining the early transcriptional indicators of prolonged S-G2 phases that

  8. Functional Variations in the ATM Gene and Susceptibility to Differentiated Thyroid Carcinoma

    PubMed Central

    Xu, Li; Morari, Elaine Cristina; Wei, Qingyi

    2012-01-01

    Context: ATM is critical in response to ionizing radiation-induced DNA damage. Objective: Variations in ATM are hypothesized to affect individual susceptibility to thyroid cancer. Our objective was to evaluate the association between ATM polymorphisms and thyroid cancer risk. Design, Participants, and Methods: Six ATM single nucleotide polymorphisms (SNP) were genotyped in two independent case-control series including 592 patients with differentiated thyroid carcinoma (DTC) and 885 healthy individuals. An unconditional logistic regression model was applied to calculate odds ratios (OR) and 95% confidence intervals (CI) for each SNP with respect to risk of DTC and the combination effect of SNP on cancer risk. Results: The risk-allele frequencies of all the SNP were similar in the two case-control populations. Under a dominant model of inheritance, the G allele of ATM rs189037 exhibited a protective effect against DTC (adjusted OR = 0.8; 95% CI, 0.6–1.0; P = 0.04), and the G allele of rs1800057 was associated with increased risk of DTC (adjusted OR = 1.9; 95% CI, 1.1–3.1; P = 0.02). A protective haplotype (A-G-C-T-C-A) was associated with decreased risk of DTC in non-Hispanic whites (adjusted OR = 0.2; 95% CI, 0.0–0.8; P = 0.03). A significant dose-response relationship was observed between the total number of risk alleles of ATM and DTC risk (P = 0.01). Carriers of a combination of six to seven and eight to 10 risk alleles were at 30% (adjusted OR = 1.3; 95% CI, 1.0–1.7) and 50% (adjusted OR = 1.5; 95% CI, 1.1–2.1) increased risk of DTC, respectively. Conclusion: Individual susceptibility to DTC may be attributable to polymorphisms of ATM, and the associations warrant confirmation in independent studies. PMID:22438227

  9. DNA-PKcs and ATM Co-Regulate DNA Double-Strand Break Repair

    PubMed Central

    Shrivastav, Meena; Miller, Cheryl A.; De Haro, Leyma P.; Durant, Stephen T.; Chen, Benjamin P.C.; Chen, David J.; Nickoloff, Jac A.

    2009-01-01

    DNA double-strand breaks (DSBs) are repaired by nonhomologous end-joining (NHEJ) and homologous recombination (HR). The NHEJ/HR decision is under complex regulation and involves DNA-dependent protein kinase (DNA-PKcs). HR is elevated in DNA-PKcs null cells, but suppressed by DNA-PKcs kinase inhibitors, suggesting that kinase-inactive DNA-PKcs (DNA-PKcs-KR) would suppress HR. Here we use a direct repeat assay to monitor HR repair of DSBs induced by I-SceI nuclease. Surprisingly, DSB-induced HR in DNA-PKcs-KR cells was 2- to 3-fold above the elevated HR level of DNA-PKcs null cells, and ∼4- to 7-fold above cells expressing wild-type DNA-PKcs. The hyperrecombination in DNA-PKcs-KR cells compared to DNA-PKcs null cells was also apparent as increased resistance to DNA crosslinks induced by mitomycin C. ATM phosphorylates many HR proteins, and ATM is expressed at a low level in cells lacking DNA-PKcs, but restored to wild-type level in cells expressing DNA-PKcs-KR. Several clusters of phosphorylation sites in DNA-PKcs, including the T2609 cluster, which is phosphorylated by DNA-PKcs and ATM, regulate access of repair factors to broken ends. Our results indicate that ATM-dependent phosphorylation of DNA-PKcs-KR contributes to the hyperrecombination phenotype. Interestingly, DNA-PKcs null cells showed more persistent ionizing radiation-induced RAD51 foci (but lower HR levels) compared to DNA-PKcs-KR cells, consistent with HR completion requiring RAD51 turnover. ATM may promote RAD51 turnover, suggesting a second (not mutually exclusive) mechanism by which restored ATM contributes to hyperrecombination in DNA-PKcs-KR cells. We propose a model in which DNA-PKcs and ATM coordinately regulate DSB repair by NHEJ and HR. PMID:19535303

  10. Immunoglobulin Class Switch Recombination Is Impaired in Atm-deficient Mice

    PubMed Central

    Lumsden, Joanne M.; McCarty, Thomas; Petiniot, Lisa K.; Shen, Rhuna; Barlow, Carrolee; Wynn, Thomas A.; Morse, Herbert C.; Gearhart, Patricia J.; Wynshaw-Boris, Anthony; Max, Edward E.; Hodes, Richard J.

    2004-01-01

    Immunoglobulin class switch recombination (Ig CSR) involves DNA double strand breaks (DSBs) at recombining switch regions and repair of these breaks by nonhomologous end-joining. Because the protein kinase ataxia telengiectasia (AT) mutated (ATM) plays a critical role in DSB repair and AT patients show abnormalities of Ig isotype expression, we assessed the role of ATM in CSR by examining ATM-deficient mice. In response to T cell–dependent antigen (Ag), Atm−/− mice secreted substantially less Ag-specific IgA, IgG1, IgG2b, and IgG3, and less total IgE than Atm+/+ controls. To determine whether Atm−/− B cells have an intrinsic defect in their ability to undergo CSR, we analyzed in vitro responses of purified B cells. Atm−/− cells secreted substantially less IgA, IgG1, IgG2a, IgG3, and IgE than wild-type (WT) controls in response to stimulation with lipopolysaccharide, CD40 ligand, or anti-IgD plus appropriate cytokines. Molecular analysis of in vitro responses indicated that WT and Atm−/− B cells produced equivalent amounts of germline IgG1 and IgE transcripts, whereas Atm−/− B cells produced markedly reduced productive IgG1 and IgE transcripts. The reduction in isotype switching by Atm−/− B cells occurs at the level of genomic DNA recombination as measured by digestion–circularization PCR. Analysis of sequences at CSR sites indicated that there is greater microhomology at the μ–γ1 switch junctions in ATM B cells than in wild-type B cells, suggesting that ATM function affects the need or preference for sequence homology in the CSR process. These findings suggest a role of ATM in DNA DSB recognition and/or repair during CSR. PMID:15504820

  11. Analysis of CrIS-ATMS Data Using an AIRS Science Team Version 6 - Like Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis C.

    2013-01-01

    CrIS/ATMS is flying on NPP and is scheduled to fly on JPSS-1. CrIS/ATMS has roughly equivalent capabilities to AIRS/AMSU. The AIRS Science Team Version 6 retrieval algorithm is currently producing very high quality level-3 Climate Data Records (CDR's) that will be critical for understanding climate processes AIRS CDRs should eventually cover the period September 2002 through at least 2020. CrIS/ATMS is the only scheduled follow on to AIRS AMSU. I have been asked by Ramesh Kakar if CrIS/ATMS can be counted on to adequately continue the AIRS/AMSU CDRs beyond 2020, or is something better needed? This research is being done to answer that question. A minimum requirement to obtain a yes answer is that CrIS/ATMS be analyzed using an AIRS Version 6 - like algorithm. NOAA is currently generating CrIS/ATMS products using 2 algorithms: IDPS and NUCAPS

  12. Existing and Required Modeling Capabilities for Evaluating ATM Systems and Concepts

    NASA Technical Reports Server (NTRS)

    Odoni, Amedeo R.; Bowman, Jeremy; Delahaye, Daniel; Deyst, John J.; Feron, Eric; Hansman, R. John; Khan, Kashif; Kuchar, James K.; Pujet, Nicolas; Simpson, Robert W.

    1997-01-01

    ATM systems throughout the world are entering a period of major transition and change. The combination of important technological developments and of the globalization of the air transportation industry has necessitated a reexamination of some of the fundamental premises of existing Air Traffic Management (ATM) concepts. New ATM concepts have to be examined, concepts that may place more emphasis on: strategic traffic management; planning and control; partial decentralization of decision-making; and added reliance on the aircraft to carry out strategic ATM plans, with ground controllers confined primarily to a monitoring and supervisory role. 'Free Flight' is a case in point. In order to study, evaluate and validate such new concepts, the ATM community will have to rely heavily on models and computer-based tools/utilities, covering a wide range of issues and metrics related to safety, capacity and efficiency. The state of the art in such modeling support is adequate in some respects, but clearly deficient in others. It is the objective of this study to assist in: (1) assessing the strengths and weaknesses of existing fast-time models and tools for the study of ATM systems and concepts and (2) identifying and prioritizing the requirements for the development of additional modeling capabilities in the near future. A three-stage process has been followed to this purpose: 1. Through the analysis of two case studies involving future ATM system scenarios, as well as through expert assessment, modeling capabilities and supporting tools needed for testing and validating future ATM systems and concepts were identified and described. 2. Existing fast-time ATM models and support tools were reviewed and assessed with regard to the degree to which they offer the capabilities identified under Step 1. 3 . The findings of 1 and 2 were combined to draw conclusions about (1) the best capabilities currently existing, (2) the types of concept testing and validation that can be carried

  13. BMI1 attenuates etoposide-induced G2/M checkpoints via reducing ATM activation.

    PubMed

    Wei, F; Ojo, D; Lin, X; Wong, N; He, L; Yan, J; Xu, S; Major, P; Tang, D

    2015-06-04

    The BMI1 protein contributes to stem cell pluripotency and oncogenesis via multiple functions, including its newly identified role in DNA damage response (DDR). Although evidence clearly demonstrates that BMI1 facilitates the repair of double-stranded breaks via homologous recombination (HR), it remains unclear how BMI1 regulates checkpoint activation during DDR. We report here that BMI1 has a role in G2/M checkpoint activation in response to etoposide (ETOP) treatment. Ectopic expression of BMI1 in MCF7 breast cancer and DU145 prostate cancer cells significantly reduced ETOP-induced G2/M arrest. Conversely, knockdown of BMI1 in both lines enhanced the arrest. Consistent with ETOP-induced activation of the G2/M checkpoints via the ATM pathway, overexpression and knockdown of BMI1, respectively, reduced and enhanced ETOP-induced phosphorylation of ATM at serine 1981 (ATM pS1981). Furthermore, the phosphorylation of ATM targets, including γH2AX, threonine 68 (T68) on CHK2 (CHK2 pT68) and serine 15 (S15) on p53 were decreased in overexpression and increased in knockdown BMI1 cells in response to ETOP. In line with the requirement of NBS1 in ATM activation, we were able to show that BMI1 associates with NBS1 and that this interaction altered the binding of NBS1 with ATM. BMI1 consists of a ring finger (RF), helix-turn-helix-turn-helix-turn (HT), proline/serine (PS) domain and two nuclear localization signals (NLS). Although deletion of either RF or HT did not affect the association of BMI1 with NBS1, the individual deletions of PS and one NLS (KRMK) robustly reduced the interaction. Stable expression of these BMI1 mutants decreased ETOP-induced ATM pS1981 and CHK2 pT68, but not ETOP-elicited γH2AX in MCF7 cells. Furthermore, ectopic expression of BMI1 in non-transformed breast epithelial MCF10A cells also compromised ETOP-initiated ATM pS1981 and γH2AX. Taken together, we provide compelling evidence that BMI1 decreases ETOP-induced G2/M checkpoint activation via

  14. The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain.

    PubMed

    Kanu, Nnennaya; Penicud, Kay; Hristova, Mariya; Wong, Barnaby; Irvine, Elaine; Plattner, Florian; Raivich, Gennadij; Behrens, Axel

    2010-12-03

    Progressive accumulation of DNA damage is causally involved in cellular senescence and organismal aging. The DNA damage kinase ATM plays a central role in maintaining genomic stability. ATM mutations cause the genetic disorder ataxia telangiectasia, which is primarily characterized by progressive neurodegeneration and cancer susceptibility. Although the importance of ATM function to protect against oxidative DNA damage and during aging is well described, the mechanism of ATM activation by these stimuli is not known. Here we identify ATM interactor (ATMIN) as an essential component of the ATM signaling pathway in response to oxidative stress and aging. Embryos lacking ATMIN (atmin(Δ/Δ)) died in utero and showed increased numbers of cells positive for phosphorylated histone H2aX, indicative of increased DNA damage. atmin(Δ/Δ) mouse embryonic fibroblasts accumulated DNA damage and prematurely entered senescence when cultured at atmospheric oxygen levels (20%), but this defect was rescued by addition of an antioxidant and also by culturing cells at physiological oxygen levels (3%). In response to acute oxidative stress, atmin(Δ/Δ) mouse embryonic fibroblasts showed slightly lower levels of ATM phosphorylation and reduced ATM substrate phosphorylation. Conditional deletion of ATMIN in the murine nervous system (atmin(ΔN)) resulted in reduced numbers of dopaminergic neurons, as does ATM deficiency. ATM activity was observed in old, but not in young, control mice, but aging-induced ATM signaling was impaired by ATMIN deficiency. Consequently, old atmin(ΔN) mice showed accumulation of DNA damage in the cortex accompanied by gliosis, resulting in increased mortality of aging mutant mice. These results suggest that ATMIN mediates ATM activation by oxidative stress, and thereby ATMIN protects the aging brain by preventing accumulation of DNA damage.

  15. ATM modulates the loading of recombination proteins onto a chromosomal translocation breakpoint hotspot.

    PubMed

    Sun, Jiying; Oma, Yukako; Harata, Masahiko; Kono, Kazuteru; Shima, Hiroki; Kinomura, Aiko; Ikura, Tsuyoshi; Suzuki, Hidekazu; Mizutani, Shuki; Kanaar, Roland; Tashiro, Satoshi

    2010-10-27

    Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the incidence of chromosome translocations. However, how ATM protects cells from chromosome translocations is still unclear. Chromosome translocations involving the MLL gene on 11q23 are the most frequent chromosome abnormalities in secondary leukemias associated with chemotherapy employing etoposide, a topoisomerase II poison. Here we show that ATM deficiency results in the excessive binding of the DNA recombination protein RAD51 at the translocation breakpoint hotspot of 11q23 chromosome translocation after etoposide exposure. Binding of Replication protein A (RPA) and the chromatin remodeler INO80, which facilitate RAD51 loading on damaged DNA, to the hotspot were also increased by ATM deficiency. Thus, in addition to activating DNA damage signaling, ATM may avert chromosome translocations by preventing excessive loading of recombinational repair proteins onto translocation breakpoint hotspots.

  16. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice

    PubMed Central

    Borghesani, Paul R.; Alt, Frederick W.; Bottaro, Andrea; Davidson, Laurie; Aksoy, Saime; Rathbun, Gary A.; Roberts, Thomas M.; Swat, Wojciech; Segal, Rosalind A.; Gu, Yansong

    2000-01-01

    Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia–telangiectasia (A-T), which is caused by mutations in the ATM gene. Through gene targeting, we have generated a line of Atm mutant mice, Atmy/y mice. In contrast to other Atm mutant mice, Atmy/y mice show a lower incidence of thymic lymphoma and survive beyond a few months of age. Atmy/y mice exhibit deficits in motor learning indicative of cerebellar dysfunction. Even though we found no gross cerebellar degeneration in older Atmy/y animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages. These findings establish that some neuropathological abnormalities seen in A-T patients also are present in Atm mutant mice. In addition, we report a previously unrecognized effect of Atm deficiency on development or maintenance of CD4+8+ thymocytes. We discuss these findings in the context of the hypothesis that abnormal development of Purkinje cells and lymphocytes contributes to the pathogenesis of A-T. PMID:10716718

  17. SNM1A Acts Downstream of ATM to Promote the G1 Cell Cycle Checkpoint

    PubMed Central

    Akhter, Shamima; Legerski, Randy J.

    2008-01-01

    We have shown previously that SNM1A co-localizes with 53BP1 at sites of double-strand breaks (DSBs) induced by IR, and that these proteins interact with or without DNA damage. However, the role of SNM1A in the DNA damage response has not been elucidated. Here, we show that SNM1A is required for an efficient G1 checkpoint arrest after IR exposure. Interestingly, the localization of SNM1A to sites of DSBs does not require either 53BP1 or H2AX, nor does the localization of 53BP1 require SNM1A. However, the localization of SNM1A does require ATM. Furthermore, SNM1A is shown to be a phosphorylation substrate of ATM in vitro, and to interact with ATM in vivo particularly after exposure of cells to IR. In addition, in the absence of SNM1A the activation of the downstream ATM target p53 is reduced. These findings suggest that SNM1A acts with ATM to promote the G1 cell cycle checkpoint. PMID:18848520

  18. Limited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor Suppression

    PubMed Central

    Martinez-Pastor, Barbara; Ortega-Molina, Ana; Soria, Rebeca; Collado, Manuel; Fernandez-Capetillo, Oscar; Serrano, Manuel

    2009-01-01

    Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability. PMID:19421407

  19. Authenticated tracking and monitoring system (ATMS) tracking shipments from an Australian uranium mine

    SciTech Connect

    Schoeneman, J.L.

    1998-08-01

    The Authenticated Tracking and Monitoring System (ATMS) answers the need for global monitoring of the status and location of sensitive items on a worldwide basis, 24 hours a day. ATMS uses wireless sensor packs to monitor the status of the items and environmental conditions. A receiver and processing unit collect a variety of sensor event data. The collected data are transmitted to the INMARSAT satellite communication system, which then sends the data to appropriate ground stations. Authentication and encryption algorithms secure the data during communication activities. A typical ATMS application would be to track and monitor the safety and security of a number of items in transit along a scheduled shipping route. The resulting tracking, timing, and status information could then be processed to ensure compliance with various agreements. Following discussions between the Australian Safeguards Office (ASO), the US Department of Energy (DOE), and Sandia National Laboratories (SNL) in early 1995, the parties mutually agreed to conduct and evaluate a field trial prototype ATMS to track and monitor shipments of uranium ore concentrate (UOC) from an operating uranium mine in Australia to a final destination in Rotterdam, the Netherlands, with numerous stops along the way. During the months of February and March 1998, the trial was conducted on a worldwide basis, with tracking and monitoring stations located at sites in both Australia and the US. This paper describes ATMS and the trial.

  20. The risk for developing cancer in Israeli ATM, BLM, and FANCC heterozygous mutation carriers.

    PubMed

    Laitman, Yael; Boker-Keinan, Lital; Berkenstadt, Michal; Liphsitz, Irena; Weissglas-Volkov, Daphna; Ries-Levavi, Liat; Sarouk, Ifat; Pras, Elon; Friedman, Eitan

    2016-03-01

    Cancer risks in heterozygous mutation carriers of the ATM, BLM, and FANCC genes are controversial. To shed light on this issue, cancer rates were evaluated by cross referencing asymptomatic Israeli heterozygous mutation carriers in the ATM, BLM, and FANCC genes with cancer diagnoses registered at the Israeli National Cancer Registry (INCR). Comparison of observed to expected Standardized Incidence Rates (SIR) was performed. Overall, 474 individuals participated in the study: 378 females; 25 Arab and 31 Jewish ATM carriers, 152 BLM carriers, and 170 FANCC carriers (all Ashkenazim). Age range at genotyping was 19-53 years (mean + SD 30.6 + 5 years). In addition, 96 males were included; 5, 34, and 57 ATM, BLM, and FANCC mutation carriers, respectively. Over 5-16 years from genotyping (4721 person/years), 15 new cancers were diagnosed in mutation carriers: 5 breast, 4 cervical, 3 melanomas, and one each bone sarcoma, pancreatic, and colorectal cancer. No single cancer diagnosis was more prevalent then expected in all groups combined or per gene analyzed. Specifically breast cancer SIR was 0.02-0.77. We conclude that Israeli ATM, BLM, and FANCC heterozygous mutation carriers are not at an increased risk for developing cancer.

  1. Inter-calibration and validation of observations from SAPHIR and ATMS instruments

    NASA Astrophysics Data System (ADS)

    Moradi, I.; Ferraro, R. R.

    2015-12-01

    We present the results of evaluating observations from microwave instruments aboard the Suomi National Polar-orbiting Partnership (NPP, ATMS instrument) and Megha-Tropiques (SAPHIR instrument) satellites. The study includes inter-comparison and inter-calibration of observations of similar channels from the two instruments, evaluation of the satellite data using high-quality radiosonde data from Atmospheric Radiation Measurement Program and GPS Radio Occultaion Observations from COSMIC mission, as well as geolocation error correction. The results of this study are valuable for generating climate data records from these instruments as well as for extending current climate data records from similar instruments such as AMSU-B and MHS to the ATMS and SAPHIR instruments. Reference: Moradi et al., Intercalibration and Validation of Observations From ATMS and SAPHIR Microwave Sounders. IEEE Transactions on Geoscience and Remote Sensing. 01/2015; DOI: 10.1109/TGRS.2015.2427165

  2. Performance analysis and comparison of PTOP and LANE for IP transmission over ATM networks

    NASA Astrophysics Data System (ADS)

    Zubairi, Junaid A.; Al-Irhayim, Sufyan; Al-Khateeb, Wajdi; Wajdi, Yahya

    1998-12-01

    Due to its traffic control and performance assurance characteristics, ATM is being employed as the core network in most campuses. However, bulk of the workstations remain on Ethernet, generating IP traffic that passes through ATM using special schemes such as PTOP or LANE. In such a network, the performance is affected due to the extra overheads in multiple conversions between cells and packets and managing virtual circuits. The aim of this paper is to compare the performance of PTOP and LANE in passing the IP traffic under various conditions. This study helps in understanding the various performance issues in these environments in order to define the end-to-end quality of service for Ethernet-ATM networks.

  3. ATM Dependent Silencing Links Nucleolar Chromatin Reorganization to DNA Damage Recognition.

    PubMed

    Harding, Shane M; Boiarsky, Jonathan A; Greenberg, Roger A

    2015-10-13

    Resolution of DNA double-strand breaks (DSBs) is essential for the suppression of genome instability. DSB repair in transcriptionally active genomic regions represents a unique challenge that is associated with ataxia telangiectasia mutated (ATM) kinase-mediated transcriptional silencing. Despite emerging insights into the underlying mechanisms, how DSB silencing connects to DNA repair remains undefined. We observe that silencing within the rDNA depends on persistent DSBs. Non-homologous end-joining was the predominant mode of DSB repair allowing transcription to resume. ATM-dependent rDNA silencing in the presence of persistent DSBs led to the large-scale reorganization of nucleolar architecture, with movement of damaged chromatin to nucleolar cap regions. These findings identify ATM-dependent temporal and spatial control of DNA repair and provide insights into how communication between DSB signaling and ongoing transcription promotes genome integrity.

  4. Transcriptional elongation factor ENL phosphorylated by ATM recruits polycomb and switches off transcription for DSB repair.

    PubMed

    Ui, Ayako; Nagaura, Yuko; Yasui, Akira

    2015-05-07

    Transcription is repressed if a DNA double-strand break (DSB) is introduced in close proximity to a transcriptional activation site at least in part by H2A-ubiquitination. While ATM signaling is involved, how it controls H2A-ubiquitination remains unclear. Here, we identify that, in response to DSBs, a transcriptional elongation factor, ENL (MLLT1), is phosphorylated by ATM at conserved SQ sites. This phosphorylation increases the interaction between ENL and the E3-ubiquitin-ligase complex of Polycomb Repressive Complex 1 (PRC1) via BMI1. This interaction promotes enrichment of PRC1 at transcription elongation sites near DSBs to ubiquitinate H2A leading to transcriptional repression. ENL SQ sites and BMI1 are necessary for KU70 accumulation at DSBs near active transcription sites and cellular resistance to DSBs. Our data suggest that ATM-dependent phosphorylation of ENL functions as switch from elongation to Polycomb-mediated repression to preserve genome integrity.

  5. An ATM-independent S-phase checkpoint response involves CHK1 pathway

    NASA Technical Reports Server (NTRS)

    Zhou, Xiang-Yang; Wang, Xiang; Hu, Baocheng; Guan, Jun; Iliakis, George; Wang, Ya

    2002-01-01

    After exposure to genotoxic stress, proliferating cells actively slow down the DNA replication through a S-phase checkpoint to provide time for repair. We report that in addition to the ataxia-telangiectasia mutated (ATM)-dependent pathway that controls the fast response, there is an ATM-independent pathway that controls the slow response to regulate the S-phase checkpoint after ionizing radiation in mammalian cells. The slow response of S-phase checkpoint, which is resistant to wortmannin, sensitive to caffeine and UCN-01, and related to cyclin-dependent kinase phosphorylation, is much stronger in CHK1 overexpressed cells, and it could be abolished by Chk1 antisense oligonucleotides. These results provide evidence that the ATM-independent slow response of S-phase checkpoint involves CHK1 pathway.

  6. Sandia`s network for supercomputing `95: Validating the progress of Asynchronous Transfer Mode (ATM) switching

    SciTech Connect

    Pratt, T.J.; Vahle, O.; Gossage, S.A.

    1996-04-01

    The Advanced Networking Integration Department at Sandia National Laboratories has used the annual Supercomputing conference sponsored by the IEEE and ACM for the past three years as a forum to demonstrate and focus communication and networking developments. For Supercomputing `95, Sandia elected: to demonstrate the functionality and capability of an AT&T Globeview 20Gbps Asynchronous Transfer Mode (ATM) switch, which represents the core of Sandia`s corporate network, to build and utilize a three node 622 megabit per second Paragon network, and to extend the DOD`s ACTS ATM Internet from Sandia, New Mexico to the conference`s show floor in San Diego, California, for video demonstrations. This paper documents those accomplishments, discusses the details of their implementation, and describes how these demonstrations supports Sandia`s overall strategies in ATM networking.

  7. Experiences in teleradiology using a combination of ATM and ISDN wide-area networks

    NASA Astrophysics Data System (ADS)

    Eichelberg, Marco; Cordonnier, Emmanuel; Piqueras, Joachim; Hewett, Andrew J.; Jensch, Peter F.

    1996-05-01

    The current developments in the health care sector facilitate the deployment of telemedical applications which promise to decrease costs and improve treatment quality. The regular use of telemedicine as a means of exchanging knowledge and patient information over long distance requires a natural integration of human communication with all available information sources like imaging modalities and patient data. ATM and ISDN are network technologies which allow the transmission of both digital data and real-time information like video and speech and therefore recommend themselves for telemedical applications. In the future a heterogeneous infrastructure with ATM, ISDN and other network technologies can be expected, increasing the importance of `connectivity' among the network services. This contribution describes an application scenario for teleradiology using a combination of ATM and ISDN wide area networks and experiences with the experimental use of such a system.

  8. An experimental study of VBR video over various ATM switch architectures

    SciTech Connect

    Tsang, R.P.; Hsieh, J.; Du, D.H.C.

    1997-12-31

    One of the most important components of an Asynchronous Transfer Mode (ATM) network is the switch. Switch design is not a part of the ATM standards so vendors use a wide variety of techniques to build their switches. In this paper, the authors present experimental results of switching and multiplexing real-time Variable Bit Rate (VBR) video traffic (JPEG, MPEG-1, and MPEG-2) through two different ATM switch architectures. Real-time VBR traffic, such as digital video, is particularly interesting due to its high demands in terms of bandwidth, real-time delivery and processing requirements. The experiments show that the fastest switches, i.e., lowest latencies, do not necessarily perform better when transmitting VBR video. The impact of the high speed network components; characteristics, such as switch fabric architecture, buffering strategies, and higher layer transport protocols (i.e., UDP, TCP/IP), are illustrated through the experimental results.

  9. Authenticated Tracking and Monitoring System (ATMS) tracking shipments from an Australian uranium mine

    SciTech Connect

    Schoeneman, J.L.; Sorokowski, D.

    1997-10-01

    The Authenticated Tracking and Monitoring System (ATMS) answers the need for global monitoring of the status and location of sensitive items on a worldwide basis, 24 hours a day. The ATMS concept uses wireless sensor packs to monitor the status of the items and environmental conditions, to collect a variety of sensor event data, and to transmit the data through the INMARSAT satellite communication system, which then sends that data to appropriate ground stations for tracking and monitoring. Authentication and encryption algorithms are used throughout the system to secure the data during communication activities. A typical ATMS application would be to track and monitor the safety and security of a number of items in transit along a scheduled shipping route. The resulting tracking, timing, and status information could then be processed to ensure compliance with various agreements.

  10. WIPP Transparency Project - container tracking and monitoring demonstration using the Authenticated Tracking and Monitoring System (ATMS)

    SciTech Connect

    SCHOENEMAN, J. LEE; SMARTT, HEIDI ANNE; HOFER, DENNIS

    2000-01-27

    The Authenticated Tracking and Monitoring System (ATMS) is designed to answer the need for global monitoring of the status and location of proliferation-sensitive items on a worldwide basis, 24 hours a day. ATMS uses wireless sensor packs to monitor the status of the items within the shipment and surrounding environmental conditions. Receiver and processing units collect a variety of sensor event data that is integrated with GPS tracking data. The collected data are transmitted to the International Maritime Satellite (INMARSAT) communication system, which then sends the data to mobile ground stations. Authentication and encryption algorithms secure the data during communication activities. A typical ATMS application would be to track and monitor the stiety and security of a number of items in transit along a scheduled shipping route. The resulting tracking, timing, and status information could then be processed to ensure compliance with various agreements.

  11. DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis.

    PubMed

    Enriquez-Rios, Vanessa; Dumitrache, Lavinia C; Downing, Susanna M; Li, Yang; Brown, Eric J; Russell, Helen R; McKinnon, Peter J

    2017-01-25

    The DNA damage response (DDR) orchestrates a network of cellular processes that integrates cell-cycle control and DNA repair or apoptosis, which serves to maintain genome stability. DNA-PKcs (the catalytic subunit of the DNA-dependent kinase, encoded by PRKDC), ATM (ataxia telangiectasia, mutated), and ATR (ATM and Rad3-related) are related PI3K-like protein kinases and central regulators of the DDR. Defects in these kinases have been linked to neurodegenerative or neurodevelopmental syndromes. In all cases, the key neuroprotective function of these kinases is uncertain. It also remains unclear how interactions between the three DNA damage-responsive kinases coordinate genome stability, particularly in a physiological context. Here, we used a genetic approach to identify the neural function of DNA-PKcs and the interplay between ATM and ATR during neurogenesis. We found that DNA-PKcs loss in the mouse sensitized neuronal progenitors to apoptosis after ionizing radiation because of excessive DNA damage. DNA-PKcs was also required to prevent endogenous DNA damage accumulation throughout the adult brain. In contrast, ATR coordinated the DDR during neurogenesis to direct apoptosis in cycling neural progenitors, whereas ATM regulated apoptosis in both proliferative and noncycling cells. We also found that ATR controls a DNA damage-induced G2/M checkpoint in cortical progenitors, independent of ATM and DNA-PKcs. These nonoverlapping roles were further confirmed via sustained murine embryonic or cortical development after all three kinases were simultaneously inactivated. Thus, our results illustrate how DNA-PKcs, ATM, and ATR have unique and essential roles during the DDR, collectively ensuring comprehensive genome maintenance in the nervous system.

  12. Fabrication and characterization of MCC approved testing material - ATM-12 glass

    SciTech Connect

    Wald, J.W.

    1985-10-01

    The Materials Characterization Center (MCC) Approved Testing Material ATM-12 is a borosilicate glass that incorporates elements typical of high-level waste (HLW) resulting from the reprocessing of commercial nuclear reactor fuels. The composition has been adjusted to match that predicted for HLW type 76-68 glass at an age of 300 y. Radioactive constituents contained in this glass include depleted uranium, {sup 99}Tc, {sup 237}Np, {sup 239}Pu, and {sup 241}Am. The glass was produced by the MCC at the Pacific Northwest Laboratory (PNL). ATM-12 glass ws produced from July to November of 1984 at the request of the Nevada Nuclear Waste Site Investigations (NNWSI) Program and is the third in a series of glasses produced for NNWSI. Most of the glass produced was in the form of cast bars; special castings and crushed material were also produced. Three kilograms of ATM-12 glass were produced from a feedstock melted in a nitrogen-atmosphere glove box at 1150{sup 0}C in a platinum crucible, and formed into stress-annealed rectangular bars and the special casting shapes requested by NNWSI. Bars of ATM-12 were nominally 1.9 x 1.9 x 10 cm, with an average mass of 111 g each. Nineteen bars and 37 special castings were made. ATM-12 glass has been provided to the NNWSI Program, in the form of bars, crushed powder and special castings. As of August 1985 approximately 590 g of ATM-12 is available for distribution. Requests for materials or services related to this glass should be directed to the Materials Characterization Center Program Office, PNL.

  13. The profiles of gamma-H2AX along with ATM/DNA-PKcs activation in the lymphocytes and granulocytes of rat and human blood exposed to gamma rays.

    PubMed

    Wang, Jing; Yin, Lina; Zhang, Junxiang; Zhang, Yaping; Zhang, Xuxia; Ding, Defang; Gao, Yun; Li, Qiang; Chen, Honghong

    2016-08-01

    Establishing a rat model suitable for γ-H2AX biodosimeter studies has important implications for dose assessment of internal radionuclide contamination in humans. In this study, γ-H2AX, p-ATM and p-DNA-PKcs foci were enumerated using immunocytofluorescence method, and their protein levels were measured by Western blot in rat blood lymphocytes and granulocytes exposed to γ-rays compared with human blood lymphocytes and granulocytes. It was found that DNA double-strand break repair kinetics and linear dose responses in rat lymphocytes were similar to those observed in the human counterparts. Moreover, radiation induced clear p-ATM and p-DNA-PKcs foci formation and an increase in ratio of co-localization of p-ATM or p-DNA-PKcs with γ-H2AX foci in rat lymphocytes similar to those of human lymphocytes. The level of γ-H2AX protein in irradiated rat and human lymphocytes was significantly reduced by inhibitors of ATM and DNA-PKcs. Surprisingly, unlike human granulocytes, rat granulocytes with DNA-PKcs deficiency displayed a rapid accumulation, but delayed disappearance of γ-H2AX foci with essentially no change from 10 h to 48 h post-irradiation. Furthermore, inhibition of ATM activity in rat granulocytes also decreased radiation-induced γ-H2AX foci formation. In comparison, human granulocytes showed no response to irradiation regarding γ-H2AX, p-ATM or p-DNA-PKcs foci. Importantly, incidence of γ-H2AX foci in lymphocytes after total-body radiation of rats was consistent with that of in vitro irradiation of rat lymphocytes. These findings show that rats are a useful in vivo model for validation of γ-H2AX biodosimetry for dose assessment in humans. ATM and DNA-PKcs participate together in DSB repair in rat lymphocytes similar to that of human lymphocytes. Further, rat granulocytes, which have the characteristic of delayed disappearance of γ-H2AX foci in response to radiation, may be a useful experimental system for biodosimetry studies.

  14. Leo Satellite Communication through a LEO Constellation using TCP/IP Over ATM

    NASA Technical Reports Server (NTRS)

    Foore, Lawrence R.; Konangi, Vijay K.; Wallett, Thomas M.

    1999-01-01

    The simulated performance characteristics for communication between a terrestrial client and a Low Earth Orbit (LEO) satellite server are presented. The client and server nodes consist of a Transmission Control Protocol /Internet Protocol (TCP/IP) over ATM configuration. The ATM cells from the client or the server are transmitted to a gateway, packaged with some header information and transferred to a commercial LEO satellite constellation. These cells are then routed through the constellation to a gateway on the globe that allows the client/server communication to take place. Unspecified Bit Rate (UBR) is specified as the quality of service (QoS). Various data rates are considered.

  15. Final Report for the Scaled Asynchronous Transfer Mode (ATM) Encryption Laboratory Directed Research and Development Project

    SciTech Connect

    Pierson, L.G.; Witzke, E.L.

    1999-01-01

    This effort studied the integration of innovative methods of key management crypto synchronization, and key agility while scaling encryption speed. Viability of these methods for encryption of ATM cell payloads at the SONET OC- 192 data rate (10 Gb/s), and for operation at OC-48 rates (2.5 Gb/s) was shown. An SNL-Developed pipelined DES design was adapted for the encryption of ATM cells. A proof-of-principle prototype circuit board containing 11 Electronically Programmable Logic Devices (each holding the equivalent of 100,000 gates) was designed, built, and used to prototype a high speed encryptor.

  16. Experiments at SRT Using the NOAA CrIS/ATMS Proxy Data Set

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena

    2011-01-01

    The objectives of the talk are: (1) Assess the performance of NGAS Version-1.5.03.00 CrIS/ATMS retrieval algorithm as delivered by LaRC, modified to include the MW and IR tuning coefficients and new CrIS noise model (a) Percent acceptance (b) RMS and mean differences of T(p) vs. ECMWF truth as a function of % yield (2) Compare performance of NGAS retrieval algorithm with an AIRS Science Team Version-6 like retrieval algorithm modified at Sounder Research Team (SRT) for CrIS/ATMS

  17. Thermal control evaluation of a Shuttle Orbiter solar observatory using Skylab ATM backup hardware

    NASA Technical Reports Server (NTRS)

    Class, C. R.; Presta, G.; Trucks, H.

    1975-01-01

    A study under the sponsorship of Marshall Space Flight Center (MSFC) established the feasibility to utilize the Skylab Apollo Telescope Mount (ATM) backup hardware for early low cost Shuttle Orbiter solar observation missions. A solar inertial attitude and a seven-day, full sun exposure were baselined. As a portion of the study, a series of thermal control evaluations were performed to resolve the problems caused by the relocation of the ATM to the Shuttle Orbiter bay and resulting configuration changes. Thermal control requirements, problems, the use of solar shields, Spacelab supplied fluid cooling and component placement are discussed.

  18. Shallot and licorice constituent isoliquiritigenin arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and initiation of the mitochondrial system in human cervical carcinoma HeLa cells.

    PubMed

    Hsu, Ya-Ling; Chia, Chun-Chieh; Chen, Ping-Jye; Huang, Su-Er; Huang, Soon-Cen; Kuo, Po-Lin

    2009-07-01

    This study is the first to investigate the anticancer effect of isoliquiritigenin (ISL) in human cervical carcinoma HeLa cells. The results reveal that ISL inhibits HeLa cells by blocking cell cycle progression in the G2/M phase and inducing apoptosis. Blockade of cell cycle is associated with increased activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by ISL phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, ISL-mediated G2/M phase arrest was also associated with decreases in the amounts of cyclin B, cyclin A, cdc2, and cdc25C, and increases in the phosphorylation of Chk2, cdc25C, and cdc2. The specific ATM inhibitor caffeine significantly decreased ISL-mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. ISL induced apoptotic cell death is associated with changes in the expression of Bax and Bak, decreasing levels of Bcl-2 and Bcl-X(L), and subsequently triggering mitochondrial apoptotic pathway. In addition, pretreatment of cells with caspase-9 inhibitor blocked ISL-induced apoptosis, indicating that caspase-9 activation is involved in ISL-mediated HeLa cell apoptosis. These findings suggest that ISL may be a promising chemopreventive agent against human uterine cervical cancer.

  19. ATM Heterozygosity and the Development of Radiation-Induced Erectile Dysfunction and Urinary Morbidity Following Radiotherapy for Prostate Cancer

    DTIC Science & Technology

    2007-02-01

    whether there is a correlation between the presence of a mutation, development of a radiation -induced complication , and impairment of ATM protein...associated with the development of radiation -induced proctitis following prostate cancer radiotherapy for patients who receive the full prescription...possession of genetic variants in the ATM gene is associated with the development of radiation -induced proctitis following prostate cancer

  20. An evaluation of the ATM man/machine interface. Phase 3: Analysis of SL-3 and SL-4 data

    NASA Technical Reports Server (NTRS)

    Bathurst, J. R., Jr.; Pain, R. F.; Ludewig, D. B.

    1974-01-01

    The functional adequacy of human factored crew operated systems under operational zero-gravity conditions is considered. Skylab ATM experiment operations generated sufficient telemetry and voice transcript data to support such an assessment effort. Discussions are presented pertaining to the methodology and procedures used to evaluate the hardware, training and directive aspects of Skylab 3 and Skylab 4 manned ATM experiment operations.

  1. Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies

    PubMed Central

    Gaudio, Eugenio; Spizzo, Riccardo; Paduano, Francesco; Luo, Zhenghua; Efanov, Alexey; Palamarchuk, Alexey; Leber, Amanda S.; Kaou, Mohamed; Zanesi, Nicola; Bottoni, Arianna; Costinean, Stefan; Rassenti, Laura Z.; Nakamura, Tatsuya; Kipps, Thomas J.; Aqeilan, Rami I.; Pekarsky, Yuri; Trapasso, Francesco

    2012-01-01

    The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas. PMID:22065599

  2. ATM prevents DSB formation by coordinating SSB repair and cell cycle progression.

    PubMed

    Khoronenkova, Svetlana V; Dianov, Grigory L

    2015-03-31

    DNA single-strand breaks (SSBs) arise as a consequence of spontaneous DNA instability and are also formed as DNA repair intermediates. Their repair is critical because they otherwise terminate gene transcription and generate toxic DNA double-strand breaks (DSBs) on replication. To prevent the formation of DSBs, SSB repair must be completed before DNA replication. To accomplish this, cells should be able to detect unrepaired SSBs, and then delay cell cycle progression to allow more time for repair; however, to date there is no evidence supporting the coordination of SSB repair and replication in human cells. Here we report that ataxia-telangiectasia mutated kinase (ATM) plays a major role in restricting the replication of SSB-containing DNA and thus prevents DSB formation. We show that ATM is activated by SSBs and coordinates their repair with DNA replication. SSB-mediated ATM activation is followed by a G1 cell cycle delay that allows more time for repair and thus prevents the replication of damaged DNA and DSB accrual. These findings establish an unanticipated role for ATM in the signaling of DNA SSBs and provide important insight into the molecular defects leading to genetic instability in patients with ataxia-telangiectasia.

  3. Characterization of LWR spent fuel MCC-approved testing material - ATM-101. Revision 1

    SciTech Connect

    Barner, J.O.

    1985-06-01

    The characterization data, obtained to date, for Materials Characterization Center (MCC) Approved Testing Material (ATM)-101, spent fuel from H.B. Robinson, Unit 2, Assembly B0-5, are described. ATM-101 consists of 27 equal-length segments from nine fuel rods. Characterizations provided for ATM-101 include: (1) reactor, assembly, and fuel rod descriptions; (2) Assembly BO-5 irradiation history; (3) a description of unusual incidents that occurred to the rods; (4) fission gas release measurements; (5) results of ceramography/metallography examinations; (6) fuel burnup measurement results and correlations; (7) results of gamma scanning; (8) calculated values of the radionuclide inventory; and (9) results of a radionuclide chemical overcheck. Calculations for and measurement of radial distributions of selected radionuclides are planned, but not scheduled. A description of pertinent results from other studies on sibling rods from Assembly B0-5 is also included. The distribution of ATM-101 to date is described along with characterization results on specially processed material. It is intended that this report be revised and updated as additional characterization data become available. 6 refs., 30 figs., 20 tabs.

  4. SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons

    PubMed Central

    Dobbin, Matthew M; Madabhushi, Ram; Pan, Ling; Chen, Yue; Kim, Dohoon; Gao, Jun; Ahononu, Biafra; Pao, Ping-Chieh; Qiu, Yi; Zhao, Yingming; Tsai, Li-Huei

    2016-01-01

    Summary Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease. Yet the mechanisms that protect neurons from genotoxic stress remain largely obscure. In this report, we characterize the roles of the NAD+-dependent deacetylase, SIRT1, in the neuronal response to DNA double-strand breaks (DSBs). We show that SIRT1 is rapidly recruited to DSBs in postmitotic neurons, where it exhibits a synergistic relationship with ATM. SIRT1 recruitment to breaks is ATM-dependent; however, SIRT1 also stimulates ATM auto-phosphorylation and activity and stabilizes ATM at DSB sites. Upon DSB induction, SIRT1 also binds the neuroprotective class I histone deacetylase, HDAC1. We show that SIRT1 deacetylates HDAC1 and stimulates its enzymatic activity, which is necessary for DSB repair through the nonhomologous end-joining (NHEJ) pathway. HDAC1 mutants that mimic a constitutively acetylated state render neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promote HDAC1 deacetylation also reduce DNA damage in two mouse models of neurodegeneration. We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration. PMID:23852118

  5. Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency

    PubMed Central

    Jiang, Dewei; Zhang, Ying; Hart, Ronald P.; Chen, Jianmin; Herrup, Karl

    2015-01-01

    A long-standing mystery surrounding ataxia-telangiectasia is why it is mainly cerebellar neurons, Purkinje cells in particular, that appear vulnerable to ATM deficiency. Here we present data showing that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human ataxia-telangiectasia and Atm−/− mouse cerebellar Purkinje cells. We further show that TET1, an enzyme that converts 5-methylcytosine (5mC) to 5hmC, responds to DNA damage and manipulation of TET1 activity directly affects the DNA damage signalling and ATM-deficient neuronal cell cycle re-entry and death. Quantitative genome-wide analysis of 5hmC-containing sequences shows that in ATM deficiency there is a cerebellum- and Purkinje cell-specific shift in 5hmC enrichment in both regulatory elements and repeated sequences. Finally, we verify that TET1-mediated 5hmC production is linked to the degenerative process of Purkinje cells and behavioural deficits in Atm−/− mice. Taken together, the selective loss of 5hmC plays a critical role in driving Purkinje cell vulnerability in ATM deficiency. PMID:26510954

  6. Fabrication and characterization of MCC approved testing material: ATM-WV/205 glass

    SciTech Connect

    Maupin, G.D.; Bowen, W.M.; Daniel, J.L.

    1988-08-01

    The ATM-WV/205 glass was produced in accordance with PNL's QA Manual for License-Related Programs, MCC technical procedures, and MCC QA Plan that were in effect during the course of this work. The method and procedure to be used in the fabrication and characterization of the ATM-WV/205 glass were specified in two run plans for glass preparation and a characterization plan. The ATM-WV/205 glass meets all specifications. The elemental composition and oxidation state of the glass are within the sponsor's specifications. Visually, the ATM-WV/205 glass bars appear uniformly glassy and generally without exterior features. Microscopic examination and x-ray diffraction revealed low (about 0.5 wt %) concentrations of 3-..mu..m iron chrome spinel crystals and 1-..mu..m ruthenium inclusions scattered randomly throughout the glassy matrix. Closed porosity, with pores ranging in diameter from 20 to 135 ..mu..m, was observed in all samples. 3 refs., 10 figs., 21 tabs.

  7. Designing a Strategic Plan through an Emerging Knowledge Generation Process: The ATM Experience

    ERIC Educational Resources Information Center

    Zanotti, Francesco

    2012-01-01

    Purpose: The aim of this contribution is to describe a new methodology for designing strategic plans and how it was implemented by ATM, a public transportation agency based in Milan, Italy. Design/methodology/approach: This methodology is founded on a new system theory, called "quantum systemics". It is based on models and metaphors both…

  8. The Advanced Technology Microwave Sounder (ATMS): The First 10 Months On-Orbit

    NASA Technical Reports Server (NTRS)

    Kim, Edward; Lyu, C-H Joseph; Blackwell, Willaim; Leslie, R. Vince; Baker, Neal; Mo, Tsan; Sun, Ninghai; Bi, Li; Anderson, Kent; Landrum, Mike; DeAmici, Giovanni; Gu, Degui; Foo, Alex; Ibrahim, Wael; Robinson, Kris; Chidester, Lynn; Shiue, James

    2012-01-01

    The Advanced Technology Microwave Sounder (ATMS) is a new satellite microwave sounding sensor designed to provide operational weather agencies with atmospheric temperature and moisture profile information for global weather forecasting and climate applications. A TMS will continue the microwave sounding capabilities first provided by its predecessors, the Microwave Sounding Unit (MSU) and Advanced Microwave Sounding Unit (AMSU). The first ATMS was launched October 28, 2011 on board the NPOESS Preparatory Project (NPP) satellite. Microwave soundings by themselves are the highest-impact input data used by Numerical Weather Prediction (NWP) models, especially under cloudy sky conditions. ATMS has 22 channels spanning 23-183 GHz, closely following the channel set of the MSU, AMSU-A1/2, AMSU-B, Microwave Humidity Sounder (MHS), and Humidity Sounder for Brazil (HSB). All this is accomplished with approximately 1/4 the volume, 1/2 the mass, and 1/2 the power of the three AMSUs. A description of ATMS cal/val activities will be presented followed by examples of its performance after its first 10 months on orbit.

  9. Characterization of LWR spent fuel MCC-approved testing material-ATM-101

    SciTech Connect

    Barner, J.O.

    1984-06-01

    The characterization data, obtained to date, for Materials Characterization Center (MCC) Approved Testing Materials (ATM)-101, spent fuel from H.B. Robinson, Unit 2, Assembly BO-5, are described. ATM-101 consists of 27 equal-length segments from nine fuel rods. Characterizations provided for ATM-101 include, (1) reactor, assembly, and fuel rod descriptions, (2) Assembly BO-5 irradiation history, (3) a description of unusual incidents that occurred to the rods, (4) fission gas release measurements, (5) results of ceramography/metallography examinations, (6) fuel burnup measurement results and correlations, (7) results of gamma scanning, (8) calculated values of the radionuclide inventory, and (9) results of a radionuclide chemical overcheck. Calculations for and measurement of radial distributions of selected radionuclides are planned. A description of pertinent results from other studies on sibling rods from Assembly BO-5 is also included. The distribution of ATM-101 to date is described along with characterization results on specially processed material. It is intended that this report be revised and updated as additional characterization data become available. 6 references, 23 figures, 19 tables.

  10. Evaluating ATM Technology for Distance Education in Library and Information Science.

    ERIC Educational Resources Information Center

    Stanford, Serena W.

    1997-01-01

    Investigates the impact of asynchronous transfer mode (ATM) technology in an interactive environment providing distance education in library and information science at two San Jose State University (California) sites. The main purpose of the study was to develop a reliable and valid evaluation instrument. Contains 6 tables. (Author/AEF)

  11. S-NPP ATMS Instrument Prelaunch and On-Orbit Performance Evaluation

    NASA Technical Reports Server (NTRS)

    Kim, Edward; Lyu, Cheng-Hsuan; Anderson, Kent; Leslie, Vincent R.; Blackwell, William J.

    2014-01-01

    The first of a new generation of microwave sounders was launched aboard the Suomi-National Polar-Orbiting Partnership satellite in October 2011. The Advanced Technology Microwave Sounder (ATMS) combines the capabilities and channel sets of three predecessor sounders into a single package to provide information on the atmospheric vertical temperature and moisture profiles that are the most critical observations needed for numerical weather forecast models. Enhancements include size/mass/power approximately one third of the previous total, three new sounding channels, the first space-based, Nyquist-sampled cross-track microwave temperature soundings for improved fusion with infrared soundings, plus improved temperature control and reliability. This paper describes the ATMS characteristics versus its predecessor, the advanced microwave sounding unit (AMSU), and presents the first comprehensive evaluation of key prelaunch and on-orbit performance parameters. Two-year on-orbit performance shows that the ATMS has maintained very stable radiometric sensitivity, in agreement with prelaunch data, meeting requirements for all channels (with margins of 40% for channels 1-15), and improvements over AMSU-A when processed for equivalent spatial resolution. The radiometric accuracy, determined by analysis from ground test measurements, and using on-orbit instrument temperatures, also shows large margins relative to requirements (specified as <1.0K for channels 1, 2, and 16-22 and <0.75 K for channels 3-15). A thorough evaluation of the performance of ATMS is especially important for this first proto-flight model unit of what will eventually be a series of ATMS sensors providing operational sounding capability for the U.S. and its international partners well into the next decade.

  12. Variants in the ATM gene associated with a reduced risk of contralateral breast cancer.

    PubMed

    Concannon, Patrick; Haile, Robert W; Børresen-Dale, Anne-Lise; Rosenstein, Barry S; Gatti, Richard A; Teraoka, Sharon N; Diep, T Anh; Jansen, Laila; Atencio, David P; Langholz, Bryan; Capanu, Marinela; Liang, Xiaolin; Begg, Colin B; Thomas, Duncan C; Bernstein, Leslie; Olsen, Jørgen H; Malone, Kathleen E; Lynch, Charles F; Anton-Culver, Hoda; Bernstein, Jonine L

    2008-08-15

    Between 5% and 10% of women who survive a first primary breast cancer will subsequently develop a second primary cancer in the contralateral breast. The Women's Environment, Cancer, and Radiation Epidemiology Study was designed to identify genetic and environmental determinants of contralateral breast cancer (CBC). In this study, 708 women with asynchronous CBC served as cases and 1,397 women with unilateral breast cancer served as controls. ATM, a serine-threonine kinase, controls the cellular response to DNA double-strand breaks, and has been implicated in breast cancer risk. Complete mutation screening of the ATM gene in all 2,105 study participants identified 240 distinct sequence variants; only 15 were observed in >1% of subjects. Among the rare variants, deleterious alleles resulting in loss of ATM function were associated with a nonsignificant increase in risk of CBC. In contrast, carriers of common variants had a statistically significant reduction in risk of CBC. Four of these 15 variants were individually associated with a significantly decreased risk of second primary breast cancer [c.1899-55T>G, rate ratio (RR), 0.5; 95% confidence interval (CI), 0.3-0.8; c.3161C>G, RR, 0.5; 95% CI, 0.3-0.9; c.5558A>T, RR, 0.2; 95% CI, 0.1-0.6; c.6348-54T>C RR, 0.2; 95% CI, 0.1-0.8]. These data suggest that some alleles of ATM may exert an antineoplastic effect, perhaps by altering the activity of ATM as an initiator of DNA damage responses or a regulator of p53.

  13. 7-Ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells

    PubMed Central

    Chang, Mei-Chi; Chen, Yi-Jane; Liou, Eric Jein-Wein; Tseng, Wan-Yu; Chan, Chiu-Po; Lin, Hseuh-Jen; Liao, Wan-Chuen; Chang, Ya-Ching; Jeng, Po-Yuan; Jeng, Jiiang-Huei

    2016-01-01

    Cardiovascular diseases (atherosclerosis, stroke, myocardiac infarction etc.) are the major systemic diseases of elder peoples in the world. This is possibly due to increased levels of oxidized low-density lipoproteins (oxLDLs) such as 7-ketocholesterol (7-KC) and lysophosphatidylcholine (LPC) that damage vascular endothelial cells, induce inflammatory responses, to elevate the risk of cardiovascular diseases, Alzheimer's disease, and age-related macular degeneration. However the toxic effects of 7-KC on endothelial cells are not known. In this study, 7-KC showed cytotoxicity to endothelial cells at concentrations higher than 10 μg/ml. 7-KC stimulated ATM/Chk2, ATR-Chk1 and p53 signaling pathways in endothelial cells. 7-KC also induced G0/G1 cell cycle arrest and apoptosis with an inhibition of Cyclin dependent kinase 1 (Cdk1) and cyclin B1 expression. Secretion and expression of IL-8 in endothelial cells were stimulated by 7-KC. 7-KC further induced intracellular ROS production as shown by increase in DCF fluorescence and Akt phosphorylation. LY294002 attenuated the 7-KC-induced apoptosis and IL-8 mRNA expression of endothelial cells. These results indicate that oxLDLs such as 7-KC may contribute to the pathogenesis of atherosclerosis, thrombosis and cardiovascular diseases by induction of endothelial damage, apoptosis and inflammatory responses. These events are associated with ROS production, activation of ATM/Chk2, ATR/Chk1, p53 and PI3K/Akt signaling pathways. PMID:27740938

  14. 7-Ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells.

    PubMed

    Chang, Mei-Chi; Chen, Yi-Jane; Liou, Eric Jein-Wein; Tseng, Wan-Yu; Chan, Chiu-Po; Lin, Hseuh-Jen; Liao, Wan-Chuen; Chang, Ya-Ching; Jeng, Po-Yuan; Jeng, Jiiang-Huei

    2016-11-15

    Cardiovascular diseases (atherosclerosis, stroke, myocardiac infarction etc.) are the major systemic diseases of elder peoples in the world. This is possibly due to increased levels of oxidized low-density lipoproteins (oxLDLs) such as 7-ketocholesterol (7-KC) and lysophosphatidylcholine (LPC) that damage vascular endothelial cells, induce inflammatory responses, to elevate the risk of cardiovascular diseases, Alzheimer's disease, and age-related macular degeneration. However the toxic effects of 7-KC on endothelial cells are not known. In this study, 7-KC showed cytotoxicity to endothelial cells at concentrations higher than 10 µg/ml. 7-KC stimulated ATM/Chk2, ATR-Chk1 and p53 signaling pathways in endothelial cells. 7-KC also induced G0/G1 cell cycle arrest and apoptosis with an inhibition of Cyclin dependent kinase 1 (Cdk1) and cyclin B1 expression. Secretion and expression of IL-8 in endothelial cells were stimulated by 7-KC. 7-KC further induced intracellular ROS production as shown by increase in DCF fluorescence and Akt phosphorylation. LY294002 attenuated the 7-KC-induced apoptosis and IL-8 mRNA expression of endothelial cells. These results indicate that oxLDLs such as 7-KC may contribute to the pathogenesis of atherosclerosis, thrombosis and cardiovascular diseases by induction of endothelial damage, apoptosis and inflammatory responses. These events are associated with ROS production, activation of ATM/Chk2, ATR/Chk1, p53 and PI3K/Akt signaling pathways.

  15. p27Kip1 Is Required to Mediate a G1 Cell Cycle Arrest Downstream of ATM following Genotoxic Stress

    PubMed Central

    Cassimere, Erica K.; Mauvais, Claire; Denicourt, Catherine

    2016-01-01

    The DNA damage response (DDR) is a coordinated signaling network that ensures the maintenance of genome stability under DNA damaging stress. In response to DNA lesions, activation of the DDR leads to the establishment of cell cycle checkpoints that delay cell-cycle progression and allow repair of the defects. The tumor suppressor p27Kip1 is a cyclin-CDK inhibitor that plays an important role in regulating quiescence in a variety of tissues. Several studies have suggested that p27Kip1 also plays a role in the maintenance of genomic integrity. Here we demonstrate that p27Kip1 is essential for the establishment of a G1 checkpoint arrest after DNA damage. We also uncovered that ATM phosphorylates p27Kip1 on a previously uncharacterized residue (Ser-140), which leads to its stabilization after induction of DNA double-strand breaks. Inhibition of this stabilization by replacing endogenous p27Kip1 with a Ser-140 phospho-mutant (S140A) significantly sensitized cells to IR treatments. Our findings reveal a novel role for p27Kip1 in the DNA damage response pathway and suggest that part of its tumor suppressing functions relies in its ability to mediate a G1 arrest after the induction of DNA double strand breaks. PMID:27611996

  16. MPEG-2 Over Asynchronous Transfer Mode (ATM) Over Satellite Quality of Service (QoS) Experiments: Laboratory Tests

    NASA Technical Reports Server (NTRS)

    Ivancic, William D.; Frantz, Brian D.; Spells, Marcus J.

    1998-01-01

    Asynchronous transfer mode (ATM) quality of service (QoS) experiments were performed using MPEG-2 (ATM application layer 5, AAL5) over ATM over an emulated satellite link. The purpose of these experiments was to determine the free-space link quality necessary to transmit high-quality multimedia information by using the ATM protocol. The detailed test plan and test configuration are described herein as are the test results. MPEG-2 transport streams were baselined in an errored environment, followed by a series of tests using, MPEG-2 over ATM. Errors were created both digitally as well as in an IF link by using a satellite modem and commercial gaussian noise test set for two different MPEG-2 decoder implementations. The results show that ITU-T Recommendation 1.356 Class 1, stringent ATM applications will require better link quality than currently specified; in particular, cell loss ratios of better than 1.0 x 10(exp -8) and cell error ratios of better than 1.0 x 10(exp -7) are needed. These tests were conducted at the NASA Lewis Research Center in support of satellite-ATM interoperability research.

  17. The ATM- and ATR-related SCD domain is over-represented in proteins involved in nervous system development.

    PubMed

    Cara, Lukas; Baitemirova, Medina; Follis, Jack; Larios-Sanz, Maia; Ribes-Zamora, Albert

    2016-01-08

    ATM and ATR are cellular kinases with a well-characterized role in the DNA-damage response. Although the complete set of ATM/ATR targets is unknown, they often contain clusters of S/TQ motifs that constitute an SCD domain. In this study, we identified putative ATM/ATR targets that have a conserved SCD domain across vertebrates. Using this approach, we have identified novel putative ATM/ATR targets in pathways known to be under direct control of these kinases. Our analysis has also unveiled significant enrichment of SCD-containing proteins in cellular pathways, such as vesicle trafficking and actin cytoskeleton, where a regulating role for ATM/ATR is either unknown or poorly understood, hinting at a much broader and overarching role for these kinases in the cell. Of particular note is the overrepresentation of conserved SCD-containing proteins involved in pathways related to neural development. This finding suggests that ATM/ATR could be directly involved in controlling this process, which may be linked to the adverse neurological effects observed in patients with mutations in ATM.

  18. A novel ATM-dependent checkpoint defect distinct from loss of function mutation promotes genomic instability in melanoma.

    PubMed

    Spoerri, Loredana; Brooks, Kelly; Chia, KeeMing; Grossman, Gavriel; Ellis, Jonathan J; Dahmer-Heath, Mareike; Škalamera, Dubravka; Pavey, Sandra; Burmeister, Bryan; Gabrielli, Brian

    2016-05-01

    Melanomas have high levels of genomic instability that can contribute to poor disease prognosis. Here, we report a novel defect of the ATM-dependent cell cycle checkpoint in melanoma cell lines that promotes genomic instability. In defective cells, ATM signalling to CHK2 is intact, but the cells are unable to maintain the cell cycle arrest due to elevated PLK1 driving recovery from the arrest. Reducing PLK1 activity recovered the ATM-dependent checkpoint arrest, and over-expressing PLK1 was sufficient to overcome the checkpoint arrest and increase genomic instability. Loss of the ATM-dependent checkpoint did not affect sensitivity to ionizing radiation demonstrating that this defect is distinct from ATM loss of function mutations. The checkpoint defective melanoma cell lines over-express PLK1, and a significant proportion of melanomas have high levels of PLK1 over-expression suggesting this defect is a common feature of melanomas. The inability of ATM to impose a cell cycle arrest in response to DNA damage increases genomic instability. This work also suggests that the ATM-dependent checkpoint arrest is likely to be defective in a higher proportion of cancers than previously expected.

  19. Poly(ADP) ribose polymerase-1 ablation alters eicosanoid and docosanoid signaling and metabolism in a murine model of contact hypersensitivity.

    PubMed

    Kiss, Borbála; Szántó, Magdolna; Szklenár, Mónika; Brunyánszki, Attila; Marosvölgyi, Tamás; Sárosi, Eszter; Remenyik, Éva; Gergely, Pál; Virág, László; Decsi, Tamás; Rühl, Ralph; Bai, Peter

    2015-04-01

    Poly(ADP‑ribose) polymerase (PARP)‑1 is a pro‑inflammatory protein. The inhibition of PARP‑1 reduces the activity of numerous pro‑inflammatory transcription factors, which results in the reduced production of pro‑inflammatory cytokines, chemokines, matrix metalloproteinases and inducible nitric oxide synthase, culminating in reduced inflammation of the skin and other organs. The aim of the present study was to investigate the effects of the deletion of PARP‑1 expression on polyunsaturated fatty acids (PUFA), and PUFA metabolite composition, in mice under control conditions or undergoing an oxazolone (OXA)‑induced contact hypersensitivity reaction (CHS). CHS was elicited using OXA in both the PARP‑1+/+ and PARP‑1/ mice, and the concentration of PUFAs and PUFA metabolites in the diseased skin were assessed using lipidomics experiments. The levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were shown to be increased in the PARP‑1/ mice, as compared with the control, unsensitized PARP‑1+/+ mice. In addition, higher expression levels of fatty acid binding protein 7 (FABP7) were detected in the PARP‑1/ mice. FABP7 is considered to be a specific carrier of DHA and EPA. Furthermore, the levels of the metabolites of DHA and EPA (considered mainly as anti‑inflammatory or pro‑resolving factors) were higher, as compared with the metabolites of arachidonic acid (considered mainly pro‑inflammatory), both in the unsensitized control and OXA‑sensitized PARP‑1/ mice. The results of the present study suggest that the genetic deletion of PARP‑1 may affect the PUFA‑homeostasis of the skin, resulting in an anti‑inflammatory milieu, including increased DHA and EPA levels, and DHA and EPA metabolite levels. This may be an important component of the anti‑inflammatory action of PARP‑1 inhibition.

  20. Defective ATM-Kap-1-mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model.

    PubMed

    Liu, Baohua; Wang, Zimei; Ghosh, Shrestha; Zhou, Zhongjun

    2013-04-01

    ATM-mediated phosphorylation of KAP-1 triggers chromatin remodeling and facilitates the loading and retention of repair proteins at DNA lesions. Mouse embryonic fibroblasts (MEFs) derived from Zmpste24(-/-) mice undergo early senescence, attributable to delayed recruitment of DNA repair proteins. Here, we show that ATM-Kap-1 signaling is compromised in Zmpste24(-/-) MEFs, leading to defective DNA damage-induced chromatin remodeling. Knocking down Kap-1 rescues impaired chromatin remodeling, defective DNA repair and early senescence in Zmpste24(-/-) MEFs. Thus, ATM-Kap-1-mediated chromatin remodeling plays a critical role in premature aging, carrying significant implications for progeria therapy.

  1. Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen.

    PubMed

    Kozlov, Sergei V; Waardenberg, Ashley J; Engholm-Keller, Kasper; Arthur, Jonathan W; Graham, Mark E; Lavin, Martin

    2016-03-01

    Ataxia-telangiectasia, mutated (ATM) protein plays a central role in phosphorylating a network of proteins in response to DNA damage. These proteins function in signaling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoints, initiating DNA repair, and regulating gene expression. ATM kinase can be activated by a variety of stimuli, including oxidative stress. Here, we confirmed activation of cytoplasmic ATM by autophosphorylation at multiple sites. Then we employed a global quantitative phosphoproteomics approach to identify cytoplasmic proteins altered in their phosphorylation state in control and ataxia-telangiectasia (A-T) cells in response to oxidative damage. We demonstrated that ATM was activated by oxidative damage in the cytoplasm as well as in the nucleus and identified a total of 9,833 phosphorylation sites, including 6,686 high-confidence sites mapping to 2,536 unique proteins. A total of 62 differentially phosphorylated peptides were identified; of these, 43 were phosphorylated in control but not in A-T cells, and 19 varied in their level of phosphorylation. Motif enrichment analysis of phosphopeptides revealed that consensus ATM serine glutamine sites were overrepresented. When considering phosphorylation events, only observed in control cells (not observed in A-T cells), with predicted ATM sites phosphoSerine/phosphoThreonine glutamine, we narrowed this list to 11 candidate ATM-dependent cytoplasmic proteins. Two of these 11 were previously described as ATM substrates (HMGA1 and UIMCI/RAP80), another five were identified in a whole cell extract phosphoproteomic screens, and the remaining four proteins had not been identified previously in DNA damage response screens. We validated the phosphorylation of three of these proteins (oxidative stress responsive 1 (OSR1), HDGF, and ccdc82) as ATM dependent after H2O2 exposure, and another protein (S100A11) demonstrated ATM

  2. Skylab ATM/S-056 X-ray event analyzer: Instrument description, parameter determination, and analysis example (15 June 1973 1B/M3 flare)

    NASA Technical Reports Server (NTRS)

    Wilson, R. M.

    1976-01-01

    The Skylab ATM/S-056 X-Ray Event Analyzer, part of an X-ray telescope experiment, is described. The techniques employed in the analysis of its data to determine electron temperatures and emission measures are reviewed. The analysis of a sample event - the 15 June 1973 1B/M3 flare - is performed. Comparison of the X-Ray Event Analyzer data with that of the SolRad 9 observations indicates that the X-Ray Event Analyzer accurately monitored the sun's 2.5 to 7.25 A X-ray emission and to a lesser extent the 6.1 to 20 A emission. A mean average peak temperature of 15 million K at 1,412 UT and a mean average peak electron density (assuming a flare volume of 10 to the 13 power cu km) of 27 million/cu mm at 1,416 to 1,417 UT are deduced for the event. The X-Ray Event Analyzer data, having a 2.5 s time resolution, should be invaluable in comparisons with other high-time resolution data (e.g., radio bursts).

  3. Issues in ATM Support of High-Performance, Geographically Distributed Computing

    NASA Technical Reports Server (NTRS)

    Claus, Russell W.; Dowd, Patrick W.; Srinidhi, Saragur M.; Blade, Eric D.G

    1995-01-01

    This report experimentally assesses the effect of the underlying network in a cluster-based computing environment. The assessment is quantified by application-level benchmarking, process-level communication, and network file input/output. Two testbeds were considered, one small cluster of Sun workstations and another large cluster composed of 32 high-end IBM RS/6000 platforms. The clusters had Ethernet, fiber distributed data interface (FDDI), Fibre Channel, and asynchronous transfer mode (ATM) network interface cards installed, providing the same processors and operating system for the entire suite of experiments. The primary goal of this report is to assess the suitability of an ATM-based, local-area network to support interprocess communication and remote file input/output systems for distributed computing.

  4. Experimental investigation and model development of the Skylab ATM secondary nickel-cadmium batteries

    NASA Technical Reports Server (NTRS)

    Kirsch, W. W.

    1974-01-01

    The performance of a Ni-Cd battery was evaluated and the cyclic battery controls to be used on the ATM batteries were determined. Cell and battery performance models were developed which to predict the performance of the secondary Ni-Cd batteries on the ATM. Capacity degradation and charge acceptance characteristics were considered. Mathematical models for each of these operating areas were developed based on data from two separate test programs. The capacity degradation model describes the expected usable battery capacity as a function of time, temperature, and depth-of-discharge. The charge acceptance model describes the cell charge acceptance as a function of charge rate, temperature, and state of charge. The models were designed for computer use and to facilitate possible battery modification. They can be used to predict expected performance or to compare real time performance during flight.

  5. Results from CrIS-ATMS Obtained Using the AIRS Science Team Retrieval Methodology

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis C.; Iredell, Lena

    2013-01-01

    AIRS was launched on EOS Aqua in May 2002, together with AMSU-A and HSB (which subsequently failed early in the mission), to form a next generation polar orbiting infrared and microwave atmospheric sounding system. AIRS/AMSU had two primary objectives. The first objective was to provide real-time data products available for use by the operational Numerical Weather Prediction Centers in a data assimilation mode to improve the skill of their subsequent forecasts. The second objective was to provide accurate unbiased sounding products with good spatial coverage that are used to generate stable multi-year climate data sets to study the earth's interannual variability, climate processes, and possibly long-term trends. AIRS/AMSU data for all time periods are now being processed using the state of the art AIRS Science Team Version-6 retrieval methodology. The Suomi-NPP mission was launched in October 2011 as part of a sequence of Low Earth Orbiting satellite missions under the "Joint Polar Satellite System" (JPSS). NPP carries CrIS and ATMS, which are advanced infra-red and microwave atmospheric sounders that were designed as follow-ons to the AIRS and AMSU instruments. The main objective of this work is to assess whether CrIS/ATMS will be an adequate replacement for AIRS/AMSU from the perspective of the generation of accurate and consistent long term climate data records, or if improved instruments should be developed for future flight. It is critical for CrIS/ATMS to be processed using an algorithm similar to, or at least comparable to, AIRS Version-6 before such an assessment can be made. We have been conducting research to optimize products derived from CrIS/ATMS observations using a scientific approach analogous to the AIRS Version-6 retrieval algorithm. Our latest research uses Version-5.70 of the CrIS/ATMS retrieval algorithm, which is otherwise analogous to AIRS Version-6, but does not yet contain the benefit of use of a Neural-Net first guess start-up system

  6. Analysis of CrIS ATMS and AIRS AMSU Data Using Scientifically Equivalent Retrieval Algorithms

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena; Blaisdell, John

    2016-01-01

    Monthly mean August 2014 Version-6.28 AIRS and CrIS products agree well with OMPS and CERES, and reasonably well with each other. Version-6.28 CrIS total precipitable water is biased dry compared to AIRS. AIRS and CrIS Version-6.36 water vapor products are both improved compared to Version-6.28. Version-6.36 AIRS and CrIS total precipitable water also shows improved agreement with each other. AIRS Version-6.36 total ozone agrees even better with OMPS than does AIRS Version-6.28, and gives reasonable results during polar winter where OMPS does not generate products. CrIS and ATMS are high spectral resolution IR and Microwave atmospheric sounders currently flying on the SNPP satellite, and are also scheduled for flight on future NPOESS satellites. CrIS/ATMS have similar sounding capabilities to those of the AIRS/AMSU sounder suite flying on EOS Aqua. The objective of this research is to develop and implement scientifically equivalent AIRS/AMSU and CrIS/ATMS retrieval algorithms with the goal of generating a continuous data record of AIRS/AMSU and CrIS/ATMS level-3 data products with a seamless transition between them in time. To achieve this, monthly mean AIRS/AMSU and CrIS/ATMS retrieved products, and more importantly their interannual differences, should show excellent agreement with each other. The currently operational AIRS Science Team Version-6 retrieval algorithm has generated 14 years of level-3 data products. A scientifically improved AIRS Version-7 retrieval algorithm is expected to become operational in 2017. We see significant improvements in water vapor and ozone in Version-7 retrieval methodology compared to Version-6.We are working toward finalization and implementation of scientifically equivalent AIRS/AMSU and CrIS/ATMS Version-7 retrieval algorithms to be used for the eventual processing of all AIRS/AMSU and CrIS/ATMS data. The latest version of our retrieval algorithm is Verison-6.36, which includes almost all the improvements we want in Version-7

  7. Results from CrIS/ATMS Obtained Using an "AIRS Version-6 Like" Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena; Blaisdell, John

    2015-01-01

    AIRS and CrIS Version-6.22 O3(p) and q(p) products are both superior to those of AIRS Version-6.Monthly mean August 2014 Version-6.22 AIRS and CrIS products agree reasonably well with OMPS, CERES, and witheach other. JPL plans to process AIRS and CrIS for many months and compare interannual differences. Updates to thecalibration of both CrIS and ATMS are still being finalized. We are also working with JPL to develop a joint AIRS/CrISlevel-1 to level-3 processing system using a still to be finalized Version-7 retrieval algorithm. The NASA Goddard DISCwill eventually use this system to reprocess all AIRS and recalibrated CrIS/ATMS. .

  8. CIPP: a versatile analytical model for VBR traffic in ATM networks

    NASA Astrophysics Data System (ADS)

    Manivasakan, R.; Desai, U. B.; Karandikar, Abhay

    1999-08-01

    Correlated Interarrival time Process (CIPP) has been proposed, for modeling both the composite arrival process of packets in broadband networks and the individual source modeling. The CIPP--a generalization of the Poisson process- - is a stationary counting process and is parameterized by a correlation parameter `p' which represents the degree of correlation in adjacent interarrivals in addition to `(lambda) ' the intensity of the process. In this paper, we present the performance modeling of VBR video traffic in ATM networks, using CIPP/M/1 queue. We first give the expressions for stationary distributions for CIPP/M/1 queue. The, we derive the queuing measures of interest. We simulate a queue with smoothed VBR video trace data as input (with exponential services) to compare with the theoretical measures derived above. Experimental results show that the CIPP/M/1 queue, models well with ATM multiplexer performance with the real world VBR video traffic input.

  9. D-ATM, a working example of health care interoperability: From dirt path to gravel road.

    PubMed

    DeClaris, John-William

    2009-01-01

    For many years, there have been calls for interoperability within health care systems. The technology currently exists and is being used in business areas like banking and commerce, to name a few. Yet the question remains, why has interoperability not been achieved in health care? This paper examines issues encountered and success achieved with interoperability during the development of the Digital Access To Medication (D-ATM) project, sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA). D-ATM is the first government funded interoperable patient management system. The goal of this paper is to provide lessons learned and propose one possible road map for health care interoperability within private industry and how government can help.

  10. Virtual queueing techniques for UBR+ service in ATM with fair access and minimum bandwidth guarantee

    SciTech Connect

    Siu, K.Y.; Wu, Y.; Ren, W.

    1998-11-01

    The ATM Forum is currently discussing the need for a new best-effort service called UBR+, which is an enhancement to the existing UBR service, to support data traffic. The objective of the UBR+ service is to provide each user with a minimum service rate guarantee and a fair access to any excess available bandwidth. In this paper, the authors present a new efficient scheme for supporting this service. The key advantage of the scheme is that it employs only FIFO queueing (instead of per-VC queueing) and admits simple implementation in ATM switches. The ideas involve a simple scheduling mechanism that is based on per-VC queueing and incorporate the virtual queueing technique that can efficiently emulate per-VC queueing on a shared FIFO queue. Simulation results are presented to show that the schemes can deliver almost ideal performance for supporting the new service requirements of UBR+.

  11. Fielded ATM network for the Air National Guard Global Yankee Fort Drum exercise

    NASA Astrophysics Data System (ADS)

    Kaminski, Robert L.; Hague, Daniel; Maciag, Chester

    1996-06-01

    This paper will review the deployment, demonstration, and test of an Asynchronous Transfer Mode (ATM) network to support the Air National Guard `Global Yankee' field exercise held at Fort Drum, New York. The network provided forty five (45) megabit per second (mbps) ATM connections between the Air Operations Center (AOC) and Forward Operating Location (FOL) located at Fort Drum, the State University of New York (SUNY) Health Science Center located in Syracuse, New York and Rome Laboratory located in Rome, New York. Connections were made with both fiber and free space equipment. The fiber connections used were part of the existing ATM New York Network (NYNet) between Rome Lab, SUNY Health Science Center and NYNEX Corporation. This network was extended to Watertown, New York by NYNEX to provide connectivity to Fort Drum. The free space links were provided by commercial DS-3 (45 mbps) radios, and 2 to 6 mbps Troposcatter Satellite Support Radios (TSSRs). This paper will also discuss significant digital Command, Control, Communications and Intelligence enhancements to the battlefield provided by the deployed ATM network. For example, videoconferencing and shared workspace capability was demonstrated over the AOC-to-FOL TSSR link, enabling remote intelligence briefings, pilot Battle Damage Assessment, and Search and Rescue coordination. Remote Medical Diagnostics videoconferencing with MRI high resolution digital imagery was demonstrated between the FOL, AOC, and SUNY Health Science Center. Finally, the network provided connectivity between the AOC and the Joint Surveillance System (JSS) radar's located at Griffiss Air Force BAse. The JSS data combined with the Rome Lab developed Radar Analysis Program provided AOC personnel with air picture areas of interest.

  12. ATM Coastal Topography - Louisiana, 2001: UTM Zone 16 (Part 2 of 2)

    USGS Publications Warehouse

    Yates, Xan; Nayegandhi, Amar; Brock, John C.; Sallenger, Asbury H.; Klipp, Emily S.; Wright, C. Wayne

    2009-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of a portion of the Louisiana coastline beach face within UTM Zone 16, from Grand Isle to the Chandeleur Islands, acquired September 7 and 9, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and

  13. Repeated Six-Hour Dives 1.35 ATM Oxygen Partial Pressure

    DTIC Science & Technology

    2005-10-01

    hemoglobin and carboxyhemoglobin , visual refraction was tested, and pulmonary function was measured . Additionally, the divers completed the postdive...and single six-hour dives in water or in the dry chamber where divers breathed oxygen at a partial pressure of 1.6 atm.4 In all studies we measured ...bands for each variable, as the lower limits of normal. We did not measure visual refraction daily during the pairs of daily dives or five daily dives

  14. ATM Coastal Topography-Louisiana, 2001: UTM Zone 15 (Part 1 of 2)

    USGS Publications Warehouse

    Yates, Xan; Nayegandhi, Amar; Brock, John C.; Sallenger, A.H.; Klipp, Emily S.; Wright, C. Wayne

    2010-01-01

    These remotely sensed, geographically referenced elevation measurements of lidar-derived first-surface (FS) topography were produced collaboratively by the U.S. Geological Survey (USGS), Florida Integrated Science Center (FISC), St. Petersburg, FL, and the National Aeronautics and Space Administration (NASA), Wallops Flight Facility, VA. This project provides highly detailed and accurate datasets of a portion of the Louisiana coastline beach face within UTM Zone 15, from Isles Dernieres to Grand Isle, acquired September 7 and 10, 2001. The datasets are made available for use as a management tool to research scientists and natural-resource managers. An innovative scanning lidar instrument originally developed by NASA, and known as the Airborne Topographic Mapper (ATM), was used during data acquisition. The ATM system is a scanning lidar system that measures high-resolution topography of the land surface and incorporates a green-wavelength laser operating at pulse rates of 2 to 10 kilohertz. Measurements from the laser-ranging device are coupled with data acquired from inertial navigation system (INS) attitude sensors and differentially corrected global positioning system (GPS) receivers to measure topography of the surface at accuracies of +/-15 centimeters. The nominal ATM platform is a Twin Otter or P-3 Orion aircraft, but the instrument may be deployed on a range of light aircraft. Elevation measurements were collected over the survey area using the ATM system, and the resulting data were then processed using the Airborne Lidar Processing System (ALPS), a custom-built processing system developed in a NASA-USGS collaboration. ALPS supports the exploration and processing of lidar data in an interactive or batch mode. Modules for presurvey flight-line definition, flight-path plotting, lidar raster and waveform investigation, and digital camera image playback have been developed. Processing algorithms have been developed to extract the range to the first and last

  15. MRE11 and ATM Expression Levels Predict Rectal Cancer Survival and Their Association with Radiotherapy Response

    PubMed Central

    Revoltar, Maxine; Lim, Stephanie H.; Tut, Thein-Ga; Abubakar, Askar; Henderson, Chris J.; Chua, Wei; Ng, Weng; Lee, Mark; De Souza, Paul; Morgan, Matthew; Lee, C. Soon; Shin, Joo-Shik

    2016-01-01

    Background Aberrant expression of DNA repair proteins is associated with poor survival in cancer patients. We investigated the combined expression of MRE11 and ATM as a predictive marker of response to radiotherapy in rectal cancer. Methods MRE11 and ATM expression were examined in tumor samples from 262 rectal cancer patients who underwent surgery for rectal cancer, including a sub-cohort of 54 patients who were treated with neoadjuvant radiotherapy. The relationship between expression of the two-protein panel and tumor regression grade (TRG) was assessed by Mann–Whitney U test and receiver operating characteristics area under curve (ROC-AUC) analysis. The association between expression of the two-protein panel and clinicopathologic variables and survival was examined by Kaplan-Meier methods and Cox regression analysis. Results A high score for two-protein combined expression in the tumor center (TC) was significantly associated with worse disease-free survival (DFS) (P = 0.035) and overall survival (OS) (P = 0.003) in the whole cohort, and with DFS (P = 0.028) and OS (P = 0.024) in the neoadjuvant subgroup (n = 54). In multivariate analysis, the two-protein combination panel (HR = 2.178, 95% CI 1.115–4.256, P = 0.023) and perineural invasion (HR = 2.183, 95% CI 1.222–3.899, P = 0.008) were significantly associated with DFS. Using ROC-AUC analysis of good versus poor histological tumor response among patients treated preoperatively with radiotherapy, the average ROC-AUC was 0.745 for the combined panel, 0.618 for ATM alone, and 0.711 for MRE11 alone. Conclusions The MRE11/ATM two-protein panel developed in this study may have clinical value as a predictive marker of tumor response to neoadjuvant radiotherapy, and a prognostic marker for disease-free and overall survival. PMID:27930716

  16. ATM Mutations and the Development of Severe Radiation-Induced Morbidity Following Radiotherapy for Breast Cancer

    DTIC Science & Technology

    2006-07-01

    micronucleus test as an alternative to the in vitro chromosomal aberration assay: position of the GUM Working Group on the in vitro micronucleus test ...13. SUPPLEMENTARY NOTES 14. ABSTRACT The hypothesis being tested in this project is that a greater proportion of patients who develop...breast conservation management should be tested for ATM heterozygosity using the relatively rapid and efficient mutation screening approach outlined in

  17. Rare, Evolutionarily Unlikely Missense Substitutions in ATM Confer Increased Risk of Breast Cancer

    PubMed Central

    Tavtigian, Sean V.; Oefner, Peter J.; Babikyan, Davit; Hartmann, Anne; Healey, Sue; Le Calvez-Kelm, Florence; Lesueur, Fabienne; Byrnes, Graham B.; Chuang, Shu-Chun; Forey, Nathalie; Feuchtinger, Corinna; Gioia, Lydie; Hall, Janet; Hashibe, Mia; Herte, Barbara; McKay-Chopin, Sandrine; Thomas, Alun; Vallée, Maxime P.; Voegele, Catherine; Webb, Penelope M.; Whiteman, David C.; Sangrajrang, Suleeporn; Hopper, John L.; Southey, Melissa C.; Andrulis, Irene L.; John, Esther M.; Chenevix-Trench, Georgia

    2009-01-01

    The susceptibility gene for ataxia telangiectasia, ATM, is also an intermediate-risk breast-cancer-susceptibility gene. However, the spectrum and frequency distribution of ATM mutations that confer increased risk of breast cancer have been controversial. To assess the contribution of rare variants in this gene to risk of breast cancer, we pooled data from seven published ATM case-control mutation-screening studies, including a total of 1544 breast cancer cases and 1224 controls, with data from our own mutation screening of an additional 987 breast cancer cases and 1021 controls. Using an in silico missense-substitution analysis that provides a ranking of missense substitutions from evolutionarily most likely to least likely, we carried out analyses of protein-truncating variants, splice-junction variants, and rare missense variants. We found marginal evidence that the combination of ATM protein-truncating and splice-junction variants contribute to breast cancer risk. There was stronger evidence that a subset of rare, evolutionarily unlikely missense substitutions confer increased risk. On the basis of subset analyses, we hypothesize that rare missense substitutions falling in and around the FAT, kinase, and FATC domains of the protein may be disproportionately responsible for that risk and that a subset of these may confer higher risk than do protein-truncating variants. We conclude that a comparison between the graded distributions of missense substitutions in cases versus controls can complement analyses of truncating variants and help identify susceptibility genes and that this approach will aid interpretation of the data emerging from new sequencing technologies. PMID:19781682

  18. Studies of the expression of human poly(ADP-ribose) polymerase-1 in Saccharomyces cerevisiae and identification of PARP-1 substrates by yeast proteome microarray screening.

    PubMed

    Tao, Zhihua; Gao, Peng; Liu, Hung-Wen

    2009-12-15

    Poly(ADP-ribosyl)ation of various nuclear proteins catalyzed by a family of NAD(+)-dependent enzymes, poly(ADP-ribose) polymerases (PARPs), is an important posttranslational modification reaction. PARP activity has been demonstrated in all types of eukaryotic cells with the exception of yeast, in which the expression of human PARP-1 was shown to lead to retarded cell growth. We investigated the yeast growth inhibition caused by human PARP-1 expression in Saccharomyces cerevisiae. Flow cytometry analysis reveals that PARP-1-expressing yeast cells accumulate in the G(2)/M stage of the cell cycle. Confocal microscopy analysis shows that human PARP-1 is distributed throughout the nucleus of yeast cells but is enriched in the nucleolus. Utilizing yeast proteome microarray screening, we identified 33 putative PARP-1 substrates, six of which are known to be involved in ribosome biogenesis. The poly(ADP-ribosyl)ation of three of these yeast proteins, together with two human homologues, was confirmed by an in vitro PARP-1 assay. Finally, a polysome profile analysis using sucrose gradient ultracentrifugation demonstrated that the ribosome levels in yeast cells expressing PARP-1 are lower than those in control yeast cells. Overall, our data suggest that human PARP-1 may affect ribosome biogenesis by modifying certain nucleolar proteins in yeast. The artificial PARP-1 pathway in yeast may be used as a simple platform to identify substrates and verify function of this important enzyme.

  19. Initiation of the ATM-Chk2 DNA damage response through the base excision repair pathway.

    PubMed

    Chou, Wen-Cheng; Hu, Ling-Yueh; Hsiung, Chia-Ni; Shen, Chen-Yang

    2015-08-01

    The DNA damage response (DDR) is activated by various genotoxic stresses. Base lesions, which are structurally simple and predominantly fixed by base excision repair (BER), can trigger the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) pathway, a DDR component. How these lesions trigger DDR remains unclear. Here we show that, for alkylation damage, methylpurine-DNA glycosylase (MPG) and apurinic/apyrimidinic endonuclease 1, both of which function early in BER, are required for ATM-Chk2-dependent DDR. In addition, other DNA glycosylases, including uracil-DNA glycosylase and 8-oxoguanine glycosylase, which are involved in repairing deaminated bases and oxidative damage, also induced DDR. The early steps of BER therefore play a vital role in modulating the ATM-Chk2 DDR in response to base lesions, facilitating downstream BER processing for repair, in which the formation of a single-strand break was shown to play a critical role. Moreover, MPG knockdown rescued cell lethality, its overexpression led to cell death triggered by DNA damage and, more interestingly, higher MPG expression in breast and ovarian cancers corresponded with a greater probability of relapse-free survival after chemotherapy, underscoring the importance of glycosylase-dependent DDR. This study highlights the crosstalk between BER and DDR that contributes to maintaining genomic integrity and may have clinical applications in cancer therapy.

  20. Experiences with TCP/IP over an ATM OC12 WAN

    SciTech Connect

    Nitzan, Rebecca L.; Tierney, Brian L.

    1999-12-23

    This paper discusses the performance testing experiences of a 622.08 Mbps OC12 link. The link will be used for large bulk data transfer, and as such, of interest are both the ATM level throughput rates and end-to-end TCP/IP throughput rates. Tests were done to evaluate the ATM switches, the IP routers, the end hosts, as well as the underlying ATM service provided by the carrier. A low level of cell loss, (resulting in <.01 % packet loss), decreased the TCP throughput rate considerably when one TCP flow was trying to use the entire OC12 bandwidth. Identifying and correcting cell loss in the network proved to be extremely difficult. TCP Selective Acknowledgement (SACK) improved performance dramatically, and the maximum throughput rate increased from 300 Mbps to 400 Mbps. The effects of TCP slow start on performance at OC12 rates are also examined, and found to be insignificant for very large file transfers (e.g., for a 10 GB file). Finally, a history of TCP performance over high-speed networks is presented.

  1. Recent Greenland Thinning from Operation IceBridge ATM and LVIS Data

    NASA Astrophysics Data System (ADS)

    Sutterley, T. C.; Velicogna, I.

    2015-12-01

    We investigate regional thinning rates in Greenland using two Operation IceBridge lidar instruments, the Airborne Topographic Mapper (ATM) and the Land, Vegetation and Ice Sensor (LVIS). IceBridge and Pre-IceBridge ATM data are available from 1993 to present and IceBridge and Pre-Icebridge LVIS data are available from 2007 to present. We compare different techniques for combining the two datasets: overlapping footprints, triangulated irregular network meshing and radial basis functions. We validate the combination for periods with near term overlap of the two instruments. By combining the two lidar datasets, we are able to investigate intra-annual, annual, interannual surface elevation change. We investigate both the high melt season of 2012 and the low melt season of 2013. In addition, the major 2015 IceBridge Arctic campaign provides new crucial data for determining seasonal ice sheet thinning rates. We compare our LVIS/ATM results with surface mass balance outputs from two regional climate models: the Regional Atmospheric Climate Model (RACMO) and the Modèle Atmosphérique Régional (MAR). We also investigate the thinning rates of major outlet glaciers.

  2. MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice.

    PubMed

    Gupta, Arun; Hunt, Clayton R; Hegde, Muralidhar L; Chakraborty, Sharmistha; Chakraborty, Sharmistha; Udayakumar, Durga; Horikoshi, Nobuo; Singh, Mayank; Ramnarain, Deepti B; Hittelman, Walter N; Namjoshi, Sarita; Asaithamby, Aroumougame; Hazra, Tapas K; Ludwig, Thomas; Pandita, Raj K; Tyler, Jessica K; Pandita, Tej K

    2014-07-10

    Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and that phosphorylated MOF colocalizes with γ-H2AX, ATM, and 53BP1 foci. Mutation of the phosphorylation site (MOF-T392A) impedes DNA repair in S and G2 phase but not G1 phase cells. Expression of MOF-T392A also blocks the reduction in DSB-associated 53BP1 seen in wild-type S/G2 phase cells, resulting in enhanced 53BP1 and reduced BRCA1 association. Decreased BRCA1 levels at DSB sites correlates with defective repairosome formation, reduced HR repair, and decreased cell survival following irradiation. These data support a model whereby ATM-mediated MOF-T392 phosphorylation modulates 53BP1 function to facilitate the subsequent recruitment of HR repair proteins, uncovering a regulatory role for MOF in DSB repair pathway choice during S/G2 phase.

  3. ATMS- and AMSU-A-derived hurricane warm core structures using a modified retrieval algorithm

    NASA Astrophysics Data System (ADS)

    Tian, Xiaoxu; Zou, Xiaolei

    2016-11-01

    The Advanced Technology Microwave Sounder (ATMS) is a cross-track microwave radiometer. Its temperature sounding channels 5-15 can provide measurements of thermal radiation emitted from different layers of the atmosphere. In this study, a traditional Advanced Microwave Sounding Unit-A (AMSU-A) temperature retrieval algorithm is modified to remove the scan biases in the temperature retrieval and to include only those ATMS sounding channels that are correlated with the atmospheric temperatures on the pressure level of the retrieval. The warm core structures derived for Hurricane Sandy when it moved from tropics to middle latitudes are examined. It is shown that scan biases that are present in the traditional retrieval are adequately removed using the modified algorithm. In addition, temperature retrievals in the upper troposphere ( 250 hPa) obtained by using the modified algorithm have more homogeneous warm core structures and those from the traditional retrieval are affected by small-scale features from the low troposphere such as precipitation. Based on ATMS observations, Hurricane Sandy's warm core was confined to the upper troposphere during its intensifying stage and when it was located in the tropics but extended to the entire troposphere when it moved into subtropics and middle latitudes and stopped its further intensification. The modified algorithm was also applied to AMSU-A observation data to retrieve the warm core structures of Hurricane Michael. The retrieved warm core features are more realistic when compared with those from the operational Microwave Integrated Retrieval System (MIRS).

  4. ATM induces MacroD2 nuclear export upon DNA damage

    PubMed Central

    Golia, Barbara; Moeller, Giuliana Katharina; Jankevicius, Gytis; Schmidt, Andreas; Hegele, Anna; Preißer, Julia; Tran, Mai Ly; Imhof, Axel; Timinszky, Gyula

    2017-01-01

    ADP-ribosylation is a dynamic post-translation modification that regulates the early phase of various DNA repair pathways by recruiting repair factors to chromatin. ADP-ribosylation levels are defined by the activities of specific transferases and hydrolases. However, except for the transferase PARP1/ARDT1 little is known about regulation of these enzymes. We found that MacroD2, a mono-ADP-ribosylhydrolase, is exported from the nucleus upon DNA damage, and that this nuclear export is induced by ATM activity. We show that the export is dependent on the phosphorylation of two SQ/TQ motifs, suggesting a novel direct interaction between ATM and ADP-ribosylation. Lastly, we show that MacroD2 nuclear export temporally restricts its recruitment to DNA lesions, which may decrease the net ADP-ribosylhydrolase activity at the site of DNA damage. Together, our results identify a novel feedback regulation between two crucial DNA damage-induced signaling pathways: ADP-ribosylation and ATM activation. PMID:28069995

  5. ATM Heterozygosity and the Development of Radiation-Induced Erectile Dysfunction and Urinary Morbidity Following Radiotherapy for Prostate Cancer

    DTIC Science & Technology

    2009-02-01

    these results. Each irradiation was performed a total of three times. The mean values (with standard deviations) for wild type cells incubated either...ATM 5 protein levels were measured in each cell line in three separate experiments and divided by the average value obtained for the five wild type...compared with wild type cells. In addition, the levels of p53 phosphorylation are consistently lower than those detected in wild type cells. The ATM

  6. ATM Heterozygosity and the Development of Radiation-Induced Erectile Dysfunction and Urinary Morbidity Following Radiotherapy for Prostate Cancer

    DTIC Science & Technology

    2006-02-01

    mutation are more likely to develop radiation -induced complications . The principal goal of this project is to determine whether men who inherit a...W81XWH-04-1-0172 TITLE: ATM Heterozygosity and the Development of Radiation -Induced Erectile Dysfunction and Urinary Morbidity Following...SUBTITLE 5a. CONTRACT NUMBER ATM Heterozygosity and the Development of Radiation -Induced Erectile Dysfunction and Urinary Morbidity Following

  7. Induction of ATM/ATR pathway combined with Vγ2Vδ2 T cells enhances cytotoxicity of ovarian cancer cells.

    PubMed

    Lu, Jingwei; Das, Manjusri; Kanji, Suman; Aggarwal, Reeva; Joseph, Matthew; Ray, Alo; Shapiro, Charles L; Pompili, Vincent J; Das, Hiranmoy

    2014-07-01

    Many ovarian cancer cells express stress-related molecule MICA/B on their surface that is recognized by Vγ2Vδ2 T cells through their NKG2D receptor, which is transmitted to downstream stress-signaling pathway. However, it is yet to be established how Vγ2Vδ2 T cell-mediated recognition of MICA/B signal is transmitted to downstream stress-related molecules. Identifying targeted molecules would be critical to develop a better therapy for ovarian cancer cells. It is well established that ATM/ATR signal transduction pathways, which is modulated by DNA damage, replication stress, and oxidative stress play central role in stress signaling pathway regulating cell cycle checkpoint and apoptosis. We investigated whether ATM/ATR and its down stream molecules affect Vγ2Vδ2 T cell-mediated cytotoxicity. Herein, we show that ATM/ATR pathway is modulated in ovarian cancer cells in the presence of Vγ2Vδ2 T cells. Furthermore, downregulation of ATM pathway resulted downregulation of MICA, and reduced Vγ2Vδ2 T cell-mediated cytotoxicity. Alternately, stimulating ATM pathway enhanced expression of MICA, and sensitized ovarian cancer cells for cytotoxic lysis by Vγ2Vδ2 T cells. We further show that combining currently approved chemotherapeutic drugs, which induced ATM signal transduction, along with Vγ2Vδ2 T cells enhanced cytotoxicity of resistant ovarian cancer cells. These findings indicate that ATM/ATR pathway plays an important role in tumor recognition, and drugs promoting ATM signaling pathway might be considered as a combination therapy together with Vγ2Vδ2 T cells for effectively treating resistant ovarian cancer cells.

  8. Formación del contínuo de Lyman en atmósferas de estrellas B

    NASA Astrophysics Data System (ADS)

    Rohrmann, R. D.

    Se presentan resultados de modelos de atmósferas para estrellas tempranas que poseen una estructura cromosférica y una atmósfera extendida en expansión. Se analiza con rigurosidad el acople del campo de radiación en el continuo de Lyman y su relación con las poblaciones en equilibrio estadístico del H y He.

  9. Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts

    NASA Technical Reports Server (NTRS)

    Worgul, Basil V.; Smilenov, Lubomir; Brenner, David J.; Junk, Anna; Zhou, Wei; Hall, Eric J.

    2002-01-01

    It is important to know whether the human population includes genetically predisposed radiosensitive subsets. In vitro studies have shown that cells from individuals homozygous for ataxia telangiectasia (A-T) are much more radiosensitive than cells from unaffected individuals. Although cells heterozygous for the ATM gene (ATM(+/-)) may be slightly more radiosensitive in vitro, it remained to be determined whether the greater susceptibility of ATM(+/-) cells translates into an increased sensitivity for late effects in vivo, though there is a suggestion that radiotherapy patients that are heterozygous for the ATM gene may be more at risk of developing late normal tissue damage. We chose cataractogenesis in the lens as a means to assay for the effects of ATM deficiency in a late-responding tissue. One eye of wild-type, Atm heterozygous and homozygous knockout mice was exposed to 0.5-, 1.0-, 2.0-, or 4.0-Gy x rays. The animals were followed weekly for cataract development by conventional slit-lamp biomicroscopy. Cataract development in the animals of all three groups was strongly dependent on dose. The lenses of homozygous mice were the first to opacify at any given dose. Most important in the present context is that cataracts appeared earlier in the heterozygous versus wild-type animals. The data suggest that ATM heterozygotes in the human population may also be radiosensitive. This may influence the choice of individuals destined to be exposed to higher than normal doses of radiation, such as astronauts, and may also suggest that radiotherapy patients who are ATM heterozygotes could be predisposed to increased late normal tissue damage.

  10. Results from CrIS/ATMS Obtained Using an "AIRS Version-6 Like Retrieval Algorithm

    NASA Astrophysics Data System (ADS)

    Susskind, J.

    2015-12-01

    A main objective of AIRS/AMSU on EOS is to provide accurate sounding products that are used to generate climate data sets. Suomi NPP carries CrIS/ATMS that were designed as follow-ons to AIRS/AMSU. Our objective is to generate a long term climate data set of products derived from CrIS/ATMS to serve as a continuation of the AIRS/AMSU products. The Goddard DISC has generated AIRS/AMSU retrieval products, extending from September 2002 through real time, using the AIRS Science Team Version-6 retrieval algorithm. Level-3 gridded monthly mean values of these products, generated using AIRS Version-6, form a state of the art multi-year set of Climate Data Records (CDRs), which is expected to continue through 2022 and possibly beyond, as the AIRS instrument is extremely stable. The goal of this research is to develop and implement a CrIS/ATMS retrieval system to generate CDRs that are compatible with, and are of comparable quality to, those generated operationally using AIRS/AMSU data. The AIRS Science Team has made considerable improvements in AIRS Science Team retrieval methodology and is working on the development of an improved AIRS Science Team Version-7 retrieval methodology to be used to reprocess all AIRS data in the relatively near future. Research is underway by Dr. Susskind and co-workers at the NASA GSFC Sounder Research Team (SRT) towards the finalization of the AIRS Version-7 retrieval algorithm, the current version of which is called SRT AIRS Version-6.22. Dr. Susskind and co-workers have developed analogous retrieval methodology for analysis of CrIS/ATMS data, called SRT CrIS Version-6.22. Results will be presented that show that AIRS and CrIS products derived using a common further improved retrieval algorithm agree closely with each other and are both superior to AIRS Version 6. The goal of the AIRS Science Team is to continue to improve both AIRS and CrIS retrieval products and then use the improved retrieval methodology for the processing of past and

  11. Mice heterozygous for the ATM gene are more sensitive to heavy ions exposure than are wildtypes

    NASA Astrophysics Data System (ADS)

    Worgul, B.; Smilenov, L.; Brenner, D.; Vazquez, M.; Hall, E.

    Previous studies have shown that the eyes of atm heterozygous mice exposed to Low LET radiation (X-rays) are more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to High LET radiation damage. Again the lens and, its primary radiopathy, cataract, were used to assay for the effects of ATM deficiency in a late-responding tissue. Together with those of wildtypes, the eyes of AT heterozygous knockout mice were exposed to 325 mGy of 1 GEV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per nuclear area. As was the case in the earlier X-ray studies all irradiations were done on the 28th day after birth. Controls consisted of wildtype irradiated as well as unirradiated wildtype and heterozygotes. Ten mice from each group were examined weekly by conventional slitlamp biomicroscopy for a total of 35 weeks. The time required for prevalence to reach 50% (T50) as an endpoint for each stage indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the atm gene. For example the T50 for definitive cataract onset (stage 1) in the atm heterozygotes was 10 weeks whereas 17 weeks were required for the wildtypes. Similarly at the conclusion of the experiment (35 weeks), 40% of the lenses of allele-deficient mice had progressed to stage 3 (near fully opaque and obviously visually debilitating), while only one lens (5%) from the wildtype irradiated eyes achieved that stage. The data show that heterozygosity for the atm gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that AT heterozygotes in the

  12. Possession of ATM Sequence Variants as Predictor for Late Normal Tissue Responses in Breast Cancer Patients Treated With Radiotherapy

    SciTech Connect

    Ho, Alice Y.; Fan, Grace; Atencio, David P.; Green, Sheryl; Formenti, Silvia C.; Haffty, Bruce G.; Iyengar, Preetha B.A.; Bernstein, Jonine L.; Stock, Richard G.; Cesaretti, Jamie A.; Rosenstein, Barry S.

    2007-11-01

    Purpose: The ATM gene product is a central component of cell cycle regulation and genomic surveillance. We hypothesized that DNA sequence alterations in ATM predict for adverse effects after external beam radiotherapy for early breast cancer. Methods and Materials: A total of 131 patients with a minimum of 2 years follow-up who had undergone breast-conserving surgery and adjuvant radiotherapy were screened for sequence alterations in ATM using DNA from blood lymphocytes. Genetic variants were identified using denaturing high performance liquid chromatography. The Radiation Therapy Oncology Group late morbidity scoring schemes for skin and subcutaneous tissues were applied to quantify the radiation-induced effects. Results: Of the 131 patients, 51 possessed ATM sequence alterations located within exons or in short intron regions flanking each exon that encompass putative splice site regions. Of these 51 patients, 21 (41%) exhibited a minimum of a Grade 2 late radiation response. In contrast, of the 80 patients without an ATM sequence variation, only 18 (23%) had radiation-induced adverse responses, for an odds ratio of 2.4 (95% confidence interval, 1.1-5.2). Fifteen patients were heterozygous for the G{yields}A polymorphism at nucleotide 5557, which causes substitution of asparagine for aspartic acid at position 1853 of the ATM protein. Of these 15 patients, 8 (53%) exhibited a Grade 2-4 late response compared with 31 (27%) of the 116 patients without this alteration, for an odds ratio of 3.1 (95% confidence interval, 1.1-9.4). Conclusion: Sequence variants located in the ATM gene, in particular the 5557 G{yields}A polymorphism, may predict for late adverse radiation responses in breast cancer patients.

  13. Loss of p21 increases sensitivity to ionizing radiation and delays the onset of lymphoma in atm-deficient mice

    PubMed Central

    Wang, Y. Alan; Elson, Ari; Leder, Philip

    1997-01-01

    Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by growth retardation, cerebellar ataxia, oculocutaneous telangiectasias, and a high incidence of lymphomas and leukemias. In addition, AT patients are sensitive to ionizing radiation. Atm-deficient mice recapitulate most of the AT phenotype. p21cip1/waf1 (p21 hereafter), an inhibitor of cyclin-dependent kinases, has been implicated in cellular senescence and response to γ-radiation-induced DNA damage. To study the role of p21 in ATM-mediated signal transduction pathways, we examined the combined effect of the genetic loss of atm and p21 on growth control, radiation sensitivity, and tumorigenesis. As might have been expected, our data provide evidence that p21 modifies the in vitro senescent response seen in AT fibroblasts. Further, it is a downstream effector of ATM-mediated growth control. In addition, however, we find that loss of p21 in the context of an atm-deficient mouse leads to a delay in thymic lymphomagenesis and an increase in acute radiation sensitivity in vivo (the latter principally because of effects on the gut epithelium). Modification of these two crucial aspects of the ATM phenotype can be related to an apparent increase in spontaneous apoptosis seen in tumor cells and in the irradiated intestinal epithelium of mice doubly null for atm and p21. Thus, loss of p21 seems to contribute to tumor suppression by a mechanism that operates via a sensitized apoptotic response. These results have implications for cancer therapy in general and AT patients in particular. PMID:9405657

  14. Identification of landslides in clay terrains using Airborne Thematic Mapper (ATM) multispectral imagery

    NASA Astrophysics Data System (ADS)

    Whitworth, Malcolm; Giles, David; Murphy, William

    2002-01-01

    The slopes of the Cotswolds Escarpment in the United Kingdom are mantled by extensive landslide deposits, including both relict and active features. These landslides pose a significant threat to engineering projects and have been the focus of research into the use of airborne remote sensing data sets for landslide mapping. Due to the availability of extensive ground investigation data, a test site was chosen on the slopes of the Cotswolds Escarpment above the village of Broadway, Worcestershire, United Kingdom. Daedalus Airborne Thematic Mapper (ATM) imagery was subsequently acquired by the UK Natural Environment Research Council (NERC) to provide high-resolution multispectral imagery of the Broadway site. This paper assesses the textural enhancement of ATM imagery as an image processing technique for landslide mapping at the Broadway site. Results of three kernel based textural measures, variance, mean euclidean distance (MEUC) and grey level co-occurrence matrix (GLCM) entropy are presented. Problems encountered during textural analysis, associated with the presence of dense woodland within the project area, are discussed and a solution using Principal Component Analysis (PCA) is described. Landslide features in clay dominated terrains can be identified through textural enhancement of airborne multispectral imagery. The kernel based textural measures tested in the current study were all able to enhance areas of slope instability within ATM imagery. Additionally, results from supervised classification of the combined texture-principal component dataset show that texture based image classification can accurately classify landslide regions and that by including a Principal Component image, woodland and landslide classes can be differentiated successfully during the classification process.

  15. Fabrication and characterization of MCC approved testing material: ATM-9 glass

    SciTech Connect

    Wald, J.W.

    1986-06-01

    The Materials Characterization Center ATM-9 glass is designed to be representative of glass to be produced by the Defense Waste Processing Facility at the Savannah River Plant, Aiken, South Carolina. ATM-9 glass contains all of the major components of the DWPF glass and corresponds to a waste loading of 29 wt %. The feedstock material for this glass was supplied by Savannah River Laboratory, Aiken, SC, as SRL-165 Black Frit to which was added Ba, Cs, Md, Nd, Zr, as well as /sup 99/Tc, depleted U, /sup 237/Np, /sup 239 +240/Pu, and /sup 243/Am. The glass was produced under reducing conditions by the addition of 0.7 wt % graphite during the final melting process. Three kilograms of the glass were produced from April to May of 1984. On final melting, the glass was formed into stress-annealed rectangular bars of two sizes: 1.9 x 1.9 x 10 cm and 1.3 x 1.3 x 10 cm. Seventeen bars of each size were made. The analyzed composition of ATM-9 glass is listed. Examination by optical microscopy of a single transverse section from one bar showed random porosity estimated at 0.36 vol % with nominal pore diameters ranging from approx. 5 ..mu..m to 200 ..mu..m. Only one distinct second phase was observed and it was at a low concentraction level in the glass matrix. The phase appeared as spherical metallic particles. X-ray diffraction analysis of this same sample did not show any diffraction peaks from crystalline components, indicating that the glass contained less than 5 wt % of crystalline devitrification products. The even shading on the radiograph exposure indicated a generally uniform distribution of radioactivity throughout the glass matrix, with no distinct high-concentration regions.

  16. Motion picture experts group (MPEG) over ATM issues: a scenario overview

    NASA Astrophysics Data System (ADS)

    Bernabei, F.; Moscatelli, M.; Russo, Giuseppe; Talone, Paolo

    1995-02-01

    Specific mechanisms are required to carry MPEG coded information over an ATM network. After a brief description of the MPEG-2 video coding algorithm, this paper discusses the `isochronism' related requirements for the transmission of the coded data and the problems associated with the use of an anisochronous transmission mechanism. The main problems, concerning the choice of the ATM adaptation layer (AAL) for each level of interaction, are discussed. Even if the MPEG stream is inherently bursty, the technical literature considers both the constant bit rate (CBR) and variable bit rate (VBR) solutions. The paper reports on a study concerning the AAL choice, in relation with the degree of interactivity required by the application and with the delay constraints. A further issue is an overview of different scenarios for the provision of video services, by `MPEG or ATM.' Different possible network and service architectures are analyzed, and various solutions for storing video information are proposed. Three different service architectures are discussed: the fully centralized, the quasi- centralized, and the fully distributed. The last issue dealt with in the paper concerns a very attractive class of interactive video services, video-on-demand (VoD). In particular, the impact of the digital storage media-control command (DSM-CC) in the provision of a particular VoD service, the `video rental' service, is described. The network requirements to support DSM- CC commands allowing the user to perform the typical video cassette recorder (VCR) functions (freeze frame, fast forward, fast reverse) are stressed. Alternative approaches for the implementation of each command are discussed together with their impact on the traffic network.

  17. Retrieving Atmospheric Temperature and Moisture Profiles from NPP CRIS/ATMS Sensors Using Crimss EDR Algorithm

    NASA Technical Reports Server (NTRS)

    Liu, X.; Kizer, S.; Barnet, C.; Dvakarla, M.; Zhou, D. K.; Larar, A. M.

    2012-01-01

    The Joint Polar Satellite System (JPSS) is a U.S. National Oceanic and Atmospheric Administration (NOAA) mission in collaboration with the U.S. National Aeronautical Space Administration (NASA) and international partners. The NPP Cross-track Infrared Microwave Sounding Suite (CrIMSS) consists of the infrared (IR) Crosstrack Infrared Sounder (CrIS) and the microwave (MW) Advanced Technology Microwave Sounder (ATMS). The CrIS instrument is hyperspectral interferometer, which measures high spectral and spatial resolution upwelling infrared radiances. The ATMS is a 22-channel radiometer similar to Advanced Microwave Sounding Units (AMSU) A and B. It measures top of atmosphere MW upwelling radiation and provides capability of sounding below clouds. The CrIMSS Environmental Data Record (EDR) algorithm provides three EDRs, namely the atmospheric vertical temperature, moisture and pressure profiles (AVTP, AVMP and AVPP, respectively), with the lower tropospheric AVTP and the AVMP being JPSS Key Performance Parameters (KPPs). The operational CrIMSS EDR an algorithm was originally designed to run on large IBM computers with dedicated data management subsystem (DMS). We have ported the operational code to simple Linux systems by replacing DMS with appropriate interfaces. We also changed the interface of the operational code so that we can read data from both the CrIMSS science code and the operational code and be able to compare lookup tables, parameter files, and output results. The detail of the CrIMSS EDR algorithm is described in reference [1]. We will present results of testing the CrIMSS EDR operational algorithm using proxy data generated from the Infrared Atmospheric Sounding Interferometer (IASI) satellite data and from the NPP CrIS/ATMS data.

  18. ATM Suppresses SATB1-Induced Malignant Progression in Breast Epithelial Cells

    PubMed Central

    Furuta, Saori; Heiser, Laura M.; Jakkula, Lakshmi R.; Rodier, Francis; Spellman, Paul T.; Campisi, Judith; Gray, Joe W.; Bissell, Mina J.; Kohwi, Yoshinori; Kohwi-Shigematsu, Terumi

    2012-01-01

    SATB1 drives metastasis when expressed in breast tumor cells by radically reprogramming gene expression. Here, we show that SATB1 also has an oncogenic activity to transform certain non-malignant breast epithelial cell lines. We studied the non-malignant MCF10A cell line, which is used widely in the literature. We obtained aliquots from two different sources (here we refer to them as MCF10A-1 and MCF10A-2), but found them to be surprisingly dissimilar in their responses to oncogenic activity of SATB1. Ectopic expression of SATB1 in MCF10A-1 induced tumor-like morphology in three-dimensional cultures, led to tumor formation in immunocompromised mice, and when injected into tail veins, led to lung metastasis. The number of metastases correlated positively with the level of SATB1 expression. In contrast, SATB1 expression in MCF10A-2 did not lead to any of these outcomes. Yet DNA copy-number analysis revealed that MCF10A-1 is indistinguishable genetically from MCF10A-2. However, gene expression profiling analysis revealed that these cell lines have significantly divergent signatures for the expression of genes involved in oncogenesis, including cell cycle regulation and signal transduction. Above all, the early DNA damage-response kinase, ATM, was greatly reduced in MCF10A-1 cells compared to MCF10A-2 cells. We found the reason for reduction to be phenotypic drift due to long-term cultivation of MCF10A. ATM knockdown in MCF10A-2 and two other non-malignant breast epithelial cell lines, 184A1 and 184B4, enabled SATB1 to induce malignant phenotypes similar to that observed for MCF10A-1. These data indicate a novel role for ATM as a suppressor of SATB1-induced malignancy in breast epithelial cells, but also raise a cautionary note that phenotypic drift could lead to dramatically different functional outcomes. PMID:23251624

  19. Associations of ATM Polymorphisms With Survival in Advanced Esophageal Squamous Cell Carcinoma Patients Receiving Radiation Therapy

    SciTech Connect

    Du, Zhongli; Zhang, Wencheng; Zhou, Yuling; Yu, Dianke; Chen, Xiabin; Chang, Jiang; Qiao, Yan; Zhang, Meng; Huang, Ying; Wu, Chen; Xiao, Zefen; Tan, Wen; and others

    2015-09-01

    Purpose: To investigate whether single nucleotide polymorphisms (SNPs) in the ataxia telangiectasia mutated (ATM) gene are associated with survival in patients with esophageal squamous cell carcinoma (ESCC) receiving radiation therapy or chemoradiation therapy or surgery only. Methods and Materials: Four tagSNPs of ATM were genotyped in 412 individuals with clinical stage III or IV ESCC receiving radiation therapy or chemoradiation therapy, and in 388 individuals with stage I, II, or III ESCC treated with surgery only. Overall survival time of ESCC among different genotypes was estimated by Kaplan-Meier plot, and the significance was examined by log-rank test. The hazard ratios (HRs) and 95% confidence intervals (CIs) for death from ESCC among different genotypes were computed by a Cox proportional regression model. Results: We found 2 SNPs, rs664143 and rs664677, associated with survival time of ESCC patients receiving radiation therapy. Individuals with the rs664143A allele had poorer median survival time compared with the rs664143G allele (14.0 vs 20.0 months), with the HR for death being 1.45 (95% CI 1.12-1.89). Individuals with the rs664677C allele also had worse median survival time than those with the rs664677T allele (14.0 vs 23.5 months), with the HR of 1.57 (95% CI 1.18-2.08). Stratified analysis showed that these associations were present in both stage III and IV cancer and different radiation therapy techniques. Significant associations were also found between the SNPs and locosregional progression or progression-free survival. No association between these SNPs and survival time was detected in ESCC patients treated with surgery only. Conclusion: These results suggest that the ATM polymorphisms might serve as independent biomarkers for predicting prognosis in ESCC patients receiving radiation therapy.

  20. ATM is the primary kinase responsible for phosphorylation of Hsp90α after ionizing radiation

    PubMed Central

    Elaimy, Ameer L.; Ahsan, Aarif; Marsh, Katherine; Pratt, William B.; Ray, Dipankar; Lawrence, Theodore S.; Nyati, Mukesh K.

    2016-01-01

    Heat shock protein 90 is a chaperone that plays an essential role in the stabilization of a large number of signal transduction molecules, many of which are associated with oncogenesis. An Hsp90 isoform (Hsp90α) has been shown to be selectively phosphorylated on two N-terminal threonine residues (threonine 5 and 7) and is involved in the DNA damage response and apoptosis. However, the kinase that phosphorylates Hsp90α after ionizing radiation (IR) and its role in post-radiation DNA repair remains unclear. Inasmuch as several proteins of the DNA damage response machinery are Hsp90 clients, the functional consequences of Hsp90α phosphorylation following IR have implications for the design of novel radiosensitizing agents that specifically target the Hsp90α isoform. Here we show that ATM phosphorylates Hsp90α at the T5/7 residues immediately after IR. The kinetics of Hsp90α T5/7 phosphorylation correlate with the kinetics of H2AX S139 phosphorylation (γH2AX). Although Hsp90α is located in both the cytoplasm and nucleus, only nuclear Hsp90α is phosphorylated by ATM after IR. The siRNA mediated knockdown of Hsp90α sensitizes head and neck squamous cell carcinoma cells, lung cancer cells and lung fibroblasts to IR. Furthermore, MEF cells that are Hsp90α null have reduced levels of γH2AX indicating that Hsp90α is important for the formation of γH2AX. Thus, this study provides evidence that Hsp90α is a component of the signal transduction events mediated by ATM following IR, and that Hsp90α loss decreases γH2AX levels. This work supports additional investigation into Hsp90α T5/7 phosphorylation with the goal of developing targeted radiosensitizing therapies. PMID:27738310

  1. Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells.

    PubMed

    Zhang, Zhiyu; Wang, Chong-Zhi; Du, Guang-Jian; Qi, Lian-Wen; Calway, Tyler; He, Tong-Chuan; Du, Wei; Yuan, Chun-Su

    2013-07-01

    Soybean isoflavones have been used as a potential preventive agent in anticancer research for many years. Genistein is one of the most active flavonoids in soybeans. Accumulating evidence suggests that genistein alters a variety of biological processes in estrogen-related malignancies, such as breast and prostate cancers. However, the molecular mechanism of genistein in the prevention of human colon cancer remains unclear. Here we attempted to elucidate the anticarcinogenic mechanism of genistein in human colon cancer cells. First we evaluated the growth inhibitory effect of genistein and two other isoflavones, daidzein and biochanin A, on HCT-116 and SW-480 human colon cancer cells. In addition, flow cyto-metry was performed to observe the morphological changes in HCT-116/SW-480 cells undergoing apoptosis or cell cycle arrest, which had been visualized using Annexin V-FITC and/or propidium iodide staining. Real-time PCR and western blot analyses were also employed to study the changes in expression of several important genes associated with cell cycle regulation. Our data showed that genistein, daidzein and biochanin A exhibited growth inhibitory effects on HCT-116/SW-480 colon cancer cells and promoted apoptosis. Genistein showed a significantly greater effect than the other two compounds, in a time- and dose-dependent manner. In addition, genistein caused cell cycle arrest in the G2/M phase, which was accompanied by activation of ATM/p53, p21waf1/cip1 and GADD45α as well as downregulation of cdc2 and cdc25A demonstrated by q-PCR and immunoblotting assay. Interestingly, genistein induced G2/M cell cycle arrest in a p53-dependent manner. These findings exemplify that isoflavones, especially genistein, could promote colon cancer cell growth inhibition and facilitate apoptosis and cell cycle arrest in the G2/M phase. The ATM/p53-p21 cross-regulatory network may play a crucial role in mediating the anticarcinogenic activities of genistein in colon cancer.

  2. Loss of H3K9me3 Correlates with ATM Activation and Histone H2AX Phosphorylation Deficiencies in Hutchinson-Gilford Progeria Syndrome

    PubMed Central

    Zhang, Haoyue; Sun, Linlin; Wang, Kun; Wu, Di; Trappio, Mason; Witting, Celeste; Cao, Kan

    2016-01-01

    Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour. We find that the intensities of gammaH2AX foci appear significantly weaker in the G0/G1 phase HGPS cells compared to control cells. This reduction is associated with a delay in the recruitment of essential DDR factors. We further demonstrate that ataxia-telangiectasia mutated (ATM) is responsible for the amplification of gammaH2AX signals at DSBs during G0/G1 phase, and its activation is inhibited in the HGPS cells that display significant loss of H3K9me3. Moreover, methylene (MB) blue treatment, which is known to save heterochromatin loss in HGPS, restores H3K9me3, stimulates ATM activity, increases gammaH2AX signals and rescues deficient DDR. In summary, this study demonstrates an early DDR defect of attenuated gammaH2AX signals in G0/G1 phase HGPS cells and provides a plausible connection between H3K9me3 loss and DDR deficiency. PMID:27907109

  3. Loss of H3K9me3 Correlates with ATM Activation and Histone H2AX Phosphorylation Deficiencies in Hutchinson-Gilford Progeria Syndrome.

    PubMed

    Zhang, Haoyue; Sun, Linlin; Wang, Kun; Wu, Di; Trappio, Mason; Witting, Celeste; Cao, Kan

    2016-01-01

    Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour. We find that the intensities of gammaH2AX foci appear significantly weaker in the G0/G1 phase HGPS cells compared to control cells. This reduction is associated with a delay in the recruitment of essential DDR factors. We further demonstrate that ataxia-telangiectasia mutated (ATM) is responsible for the amplification of gammaH2AX signals at DSBs during G0/G1 phase, and its activation is inhibited in the HGPS cells that display significant loss of H3K9me3. Moreover, methylene (MB) blue treatment, which is known to save heterochromatin loss in HGPS, restores H3K9me3, stimulates ATM activity, increases gammaH2AX signals and rescues deficient DDR. In summary, this study demonstrates an early DDR defect of attenuated gammaH2AX signals in G0/G1 phase HGPS cells and provides a plausible connection between H3K9me3 loss and DDR deficiency.

  4. ATM C and D panel/EREP cooling system contamination problem. [on Skylab

    NASA Technical Reports Server (NTRS)

    Williamson, J. G.

    1973-01-01

    This report presents the history of a preflight contamination problem that occurred in the ATM C and D panel/EREP cooling system on the Skylab, the studies that were made to determine the cause of the problem, and corrective actions that were made prior to lift-off. The results of all the observations, analyses and laboratory testing indicated that the contamination came from one or more of the EREP tape recorder coldplates and was caused by some abnormal electrolytic action, either during bench testing or in the spacecraft. Studies indicate that no such electrolytic action is likely to occur under normal operating conditions.

  5. 2-Hydroxyethyl methacrylate-induced apoptosis through the ATM- and p53-dependent intrinsic mitochondrial pathway.

    PubMed

    Schweikl, Helmut; Petzel, Christine; Bolay, Carola; Hiller, Karl-Anton; Buchalla, Wolfgang; Krifka, Stephanie

    2014-03-01

    Resin monomers of dental composites like 2-hydroxyethyl methacrylate (HEMA) disturb cell functions including responses of the innate immune system, mineralization and differentiation of dental pulp-derived cells, or induce cell death via apoptosis. The induction of apoptosis is related to the availability of the antioxidant glutathione, although a detailed understanding of the signaling pathways is still unknown. The present study provides insight into the causal relationship between oxidative stress, oxidative DNA damage, and the specific signaling pathway leading to HEMA-induced apoptosis in RAW264.7 mouse macrophages. The differential expression of the antioxidative enzymes superoxide dismutase, glutathione peroxidase, and catalase in HEMA-exposed cells indicated oxidative stress, which was associated with the cleavage of pro-caspase 3 as a critical apoptosis executioner. A 2-fold increase in the amount of mitochondrial superoxide anions after a 24 h exposure to HEMA (6-8 mM) was paralleled by a considerable decrease in the mitochondrial membrane potential (MMP). Additionally, expression of proteins critical for the signaling of apoptosis through the intrinsic mitochondrial pathway was detected. Transcription-dependent and transcription-independent mechanisms of p53-regulated apoptosis were activated, and p53 was translocated from the cytosol to mitochondria. HEMA-induced transcriptional activity of p53 was indicated by increased levels of PUMA localized to mitochondria as a potent inducer of apoptosis. The expression of Bcl-xL and Bax suggested that cells responded to stress caused by HEMA via the activation of a complicated and antagonistic machinery of pro- and anti-apoptotic Bcl-2 family members. A HEMA-induced and oxidative stress-sensitive delay of the cell cycle, indicating a DNA damage response, occurred independent of the influence of KU55399, a potent inhibitor of ATM (ataxia-telangiectasia mutated) activity. However, ATM, a protein kinase which

  6. Analysis of Chromosomal Aberrations after Low and High Dose Rate Gamma Irradiation in ATM or NBS Suppressed Human Fibroblast Cells

    NASA Technical Reports Server (NTRS)

    Hada, M.; Huff, J. L.; Patel, Z.; Pluth, J. M.; George, K. A.; Cucinotta, F. A.

    2009-01-01

    A detailed understanding of the biological effects of heavy nuclei is needed for space radiation protection and for cancer therapy. High-LET radiation produces more complex DNA lesions that may be non-repairable or that may require additional processing steps compared to endogenous DSBs, increasing the possibility of misrepair. Interplay between radiation sensitivity, dose, and radiation quality has not been studied extensively. Previously we studied chromosome aberrations induced by low- and high- LET radiation in several cell lines deficient in ATM (ataxia telangactasia mutated; product of the gene that is mutated in ataxia telangiectasia patients) or NBS (nibrin; product of the gene mutated in the Nijmegen breakage syndrome), and gliomablastoma cells that are proficient or lacking in DNA-dependent protein kinase (DNA-PK) activity. We found that the yields of both simple and complex chromosomal aberrations were significantly increased in the DSB repair defective cells compared to normal cells. The increased aberrations observed for the ATM and NBS defective lines was due to a significantly larger quadratic dose-response term compared to normal fibroblasts for both simple and complex aberrations, while the linear dose-response term was significantly higher in NBS cells only for simple exchanges. These results point to the importance of the functions of ATM and NBS in chromatin modifications that function to facilitate correct DSB repair and minimize aberration formation. To further understand the sensitivity differences that were observed in ATM and NBS deficient cells, in this study, chromosomal aberration analysis was performed in normal lung fibroblast cells treated with KU-55933, a specific ATM kinase inhibitor, or Mirin, an MRN complex inhibitor involved in activation of ATM. We are also testing siRNA knockdown of these proteins. Normal and ATM or NBS suppressed cells were irradiated with gamma-rays and chromosomes were collected with a premature chromosome

  7. ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle.

    PubMed

    Ray, Alo; Blevins, Chessica; Wani, Gulzar; Wani, Altaf A

    2016-01-01

    Cell cycle checkpoint is mediated by ATR and ATM kinases, as a prompt early response to a variety of DNA insults, and culminates in a highly orchestrated signal transduction cascade. Previously, we defined the regulatory role of nucleotide excision repair (NER) factors, DDB2 and XPC, in checkpoint and ATR/ATM-dependent repair pathway via ATR and ATM phosphorylation and recruitment to ultraviolet radiation (UVR)-induced damage sites. Here, we have dissected the molecular mechanisms of DDB2- and XPC- mediated regulation of ATR and ATM recruitment and activation upon UVR exposures. We show that the ATR and ATM activation and accumulation to UVR-induced damage not only depends on DDB2 and XPC, but also on the NER protein XPA, suggesting that the assembly of an active NER complex is essential for ATR and ATM recruitment. ATR and ATM localization and H2AX phosphorylation at the lesion sites occur as early as ten minutes in asynchronous as well as G1 arrested cells, showing that repair and checkpoint-mediated by ATR and ATM starts early upon UV irradiation. Moreover, our results demonstrated that ATR and ATM recruitment and H2AX phosphorylation are dependent on NER proteins in G1 phase, but not in S phase. We reasoned that in G1 the UVR-induced ssDNA gaps or processed ssDNA, and the bound NER complex promote ATR and ATM recruitment. In S phase, when the UV lesions result in stalled replication forks with long single-stranded DNA, ATR and ATM recruitment to these sites is regulated by different sets of proteins. Taken together, these results provide evidence that UVR-induced ATR and ATM recruitment and activation differ in G1 and S phases due to the existence of distinct types of DNA lesions, which promote assembly of different proteins involved in the process of DNA repair and checkpoint activation.

  8. Concurrent V(D)J recombination and DNA end instability increase interchromosomal trans-rearrangements in ATM-deficient thymocytes.

    PubMed

    Bowen, Steven; Wangsa, Darawalee; Ried, Thomas; Livak, Ferenc; Hodes, Richard J

    2013-04-01

    During the CD4(-)CD8(-) (DN) stage of T-cell development, RAG-dependent DNA breaks and V(D)J recombination occur at three T-cell receptor (TCR) loci: TCRβ, TCRγ and TCRδ. During this stage, abnormal trans-rearrangements also take place between TCR loci, occurring at increased frequency in absence of the DNA damage response mediator ataxia telangiectasia mutated (ATM). Here, we use this model of physiologic trans-rearrangement to study factors that predispose to rearrangement and the role of ATM in preventing chromosomal translocations. The frequency of DN thymocytes with DNA damage foci at multiple TCR loci simultaneously is increased 2- to 3-fold in the absence of ATM. However, trans-rearrangement is increased 10 000- to 100 000-fold, indicating that ATM function extends beyond timely resolution of DNA breaks. RAG-mediated synaptic complex formation occurs between recombination signal sequences with unequal 12 and 23 base spacer sequences (12/23 rule). TCR trans-rearrangements violate this rule, as we observed similar frequencies of 12/23 and aberrant 12/12 or 23/23 recombination products. This suggests that trans-rearrangements are not the result of trans-synaptic complex formation, but they are instead because of unstable cis synaptic complexes that form simultaneously at distinct TCR loci. Thus, ATM suppresses trans-rearrangement primarily through stabilization of DNA breaks at TCR loci.

  9. Regulation of human polλ by ATM-mediated phosphorylation during non-homologous end joining.

    PubMed

    Sastre-Moreno, Guillermo; Pryor, John M; Moreno-Oñate, Marta; Herrero-Ruiz, Andrés M; Cortés-Ledesma, Felipe; Blanco, Luis; Ramsden, Dale A; Ruiz, Jose F

    2017-03-01

    DNA double strand breaks (DSBs) trigger a variety of cellular signaling processes, collectively termed the DNA-damage response (DDR), that are primarily regulated by protein kinase ataxia-telangiectasia mutated (ATM). Among DDR activated processes, the repair of DSBs by non-homologous end joining (NHEJ) is essential. The proper coordination of NHEJ factors is mainly achieved through phosphorylation by an ATM-related kinase, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the molecular basis for this regulation has yet to be fully elucidated. In this study we identify the major NHEJ DNA polymerase, DNA polymerase lambda (Polλ), as a target for both ATM and DNA-PKcs in human cells. We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ. Molecular evidence suggests that Polλ phosphorylation might favor Polλ interaction with the DNA-PK complex at DSBs. Altogether, our work provides the first demonstration of how Polλ is regulated by phosphorylation to connect with the NHEJ core machinery during DSB repair in human cells.

  10. Evidence toward an expanded international civil aviation organization (ICAO) concept of a single unified global communication navigation surveillance air traffic management (CNS/ATM) system: A quantitative analysis of ADS-B technology within a CNS/ATM system

    NASA Astrophysics Data System (ADS)

    Gardner, Gregory S.

    This research dissertation summarizes research done on the topic of global air traffic control, to include technology, controlling world organizations and economic considerations. The International Civil Aviation Organization (ICAO) proposed communication, navigation, surveillance, air traffic management system (CNS/ATM) plan is the basis for the development of a single global CNS/ATM system concept as it is discussed within this study. Research will be evaluated on the efficacy of a single technology, Automatic Dependent Surveillance-Broadcast (ADS-B) within the scope of a single global CNS/ATM system concept. ADS-B has been used within the Federal Aviation Administration's (FAA) Capstone program for evaluation since the year 2000. The efficacy of ADS-B was measured solely by using National Transportation Safety Board (NTSB) data relating to accident and incident rates within the Alaskan airspace (AK) and that of the national airspace system (NAS).

  11. DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression.

    PubMed

    Carlessi, L; De Filippis, L; Lecis, D; Vescovi, A; Delia, D

    2009-06-01

    Ataxia-telangiectasia (A-T) is a neurodegenerative disorder caused by defects in the ATM kinase, a component of the DNA-damage response (DDR). Here, we employed an immortalized human neural stem-cell line (ihNSC) capable of differentiating in vitro into neurons, oligodendrocytes and astrocytes to assess the ATM-dependent response and outcome of ATM ablation. The time-dependent differentiation of ihNSC was accompanied by an upregulation of ATM and DNA-PK, sharp downregulation of ATR and Chk1, transient induction of p53 and by the onset of apoptosis in a fraction of cells. The response to ionizing radiation (IR)-induced DNA lesions was normal, as attested by the phosphorylation of ATM and some of its substrates (e.g., Nbs1, Smc1, Chk2 and p53), and by the kinetics of gamma-H2AX nuclear foci formation. Depletion in these cells of ATM by shRNA interference (shATM) attenuated the differentiation-associated apoptosis and response to IR, but left unaffected the growth, self-renewal and genomic stability. shATM cells generated a normal number of MAP2/beta-tubulin III+ neurons, but a reduced number of GalC+ oligodendrocytes, which were nevertheless more susceptible to oxidative stress. Altogether, these findings highlight the potential of ihNSCs as an in vitro model system to thoroughly assess, besides ATM, the role of DDR genes in neurogenesis and/or neurodegeneration.

  12. An Operational Tool for Global Monitoring of Inundation Using NPP ATMS Data

    NASA Astrophysics Data System (ADS)

    Tesfagiorgis, K. B.

    2015-12-01

    The goal of this study is to introduce an operational microwave-based tool for the detection and monitoring of inundation across the globe using passive microwave observations from the Advanced Technology Microwave Sounder (ATMS) sensor onboard SUOMI NPP. ATMS surface sensitive channels, namely, the 23 GHz and the 89 GHz are used in this study. The inundation detection approach is based on the analysis of the standardized anomalies of a soil wetness index that is determined from the gradient between 89 and 23 GHz brightness temperatures. The dimensionless index is sensitive to extreme wetness conditions. Appropriate threshold-based techniques were implemented in the developed tool to detect and eliminate rainy pixels as well as snow and ice covered pixels. An automated tool was developed to process, analyze the data, develop the inundation product, and disseminate the detected inundated area through a web-based interface. The outputs of the developed algorithm were verified against records from the Darthmouth Flood Observatory data archive. The agreement was acceptable with POD reaching 80 % globally for flood with durations longer than 5 days. The analysis of the flood records showed that the most frequent flood events have a duration of 3 days. The flood detection and mapping system was able to reports more short duration events that lasted 1 day or less than what is in the flood observatory records. The inundation global mapping tool was deployed operationally using real time readouts from NOAA-CREST satellite receiving station in New York, USA.

  13. A New Player in the Development of TRAIL Based Therapies for Hepatocarcinoma Treatment: ATM Kinase

    PubMed Central

    Stagni, Venturina; Santini, Simonetta; Barilà, Daniela

    2012-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCCs are genetically and phenotypically heterogeneous tumors characterized by very poor prognosis, mainly due to the lack, at present, of effective therapeutic options, as these tumors are rarely suitable for radiotherapy and often resistant to chemotherapy protocols. In the last years, agonists targeting the Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) death receptor, has been investigated as a valuable promise for cancer therapy, based on their selectivity for malignant cells and low toxicity for healthy cells. However, many cancer models display resistance to death receptor induced apoptosis, pointing to the requirement for the development of combined therapeutic approaches aimed to selectively sensitize cancer cells to TRAIL. Recently, we identified ATM kinase as a novel modulator of the ability of chemotherapeutic agents to enhance TRAIL sensitivity. Here, we review the biological determinants of HCC responsiveness to TRAIL and provide an exhaustive and updated analysis of the molecular mechanisms exploited for combined therapy in this context. The role of ATM kinase as potential novel predictive biomarker for combined therapeutic approaches based on TRAIL and chemotherapeutic drugs will be closely discussed. PMID:24213315

  14. Demonstration of medical communications based on an ATM broadband network technology

    NASA Astrophysics Data System (ADS)

    Cox, Jerome R., Jr.; Blaine, G. James; Dubetz, Martin W.; Krieger, Kenneth; Jost, R. Gilbert; Moore, Stephen M.; Richard, William D.; Turner, Jonathan S.; Winterbauer, Albert

    1992-07-01

    The research and development efforts of several university and industry groups have brought digital imaging technologies into the practice of medicine. Radiographic images based on a digital data set can now be acquired, stored, communicated and presented for both primary interpretation and access by the referring physician. Moreover, conferences between a specialist and a primary care physician can be supported with audio and video links. A demonstration project at Washington University in collaboration with Southwestern Bell and NEC-America provides a testbed for deployment of ATM (Asynchronous Transfer Mode) broadband network technology supporting both LAN and WAN experiments in multimedia medical communications. A network based on four geographically dispersed ATM switches supports rapid display of high-resolution medical images, patient information, digital video and digitized real-time physiological signals at channel rates of 100 Mb/s. A prototype configuration of an Inquiry station is based on the NeXT computer with auxiliary displays for the medical images. Observations and preliminary performance results will be presented.

  15. High-speed IP packet forwarding over Internet using ATM technology

    NASA Astrophysics Data System (ADS)

    Esaki, Hiroshi

    1995-10-01

    Framework of IP packet delivery with high throughput and small latency using ATM technology in large scaled internets is proposed, while keeping the current subnet model. Router has the mapping functionality between flow-identifier (e.g. in IPv6 header) and VPI/VCI value to forward IP packets cell-by-cell, rather than the conventional packet-by- packet forwarding. By using this cut-thru IP packet forwarding, both resource reservation oriented IP packet flows (i.e. IP packet flow provided by RSVP) and nonresource reservation oriented IP packet flows (i.e. best effort service) experience less packet delivery latency and obtain higher throughput, compared to the conventional hop-by-hop packet forwarding does. In order to perform the cut-thru IP packet forwarding using cell relaying capability in the router, routers exchange the information how the IP packet flows are aggregated into ATM- VCC. This information exchanging is hop-by-hop base, and the cut-thru decision is a matter of every router's local decision. With the hop-by-hop cut-thru IP packet forwarding, soft-state oriented and scalable QoS-ed high speed communication platform can be provided.

  16. Transcriptional and post-transcriptional regulation of the ionizing radiation response by ATM and p53

    PubMed Central

    Venkata Narayanan, Ishwarya; Paulsen, Michelle T.; Bedi, Karan; Berg, Nathan; Ljungman, Emily A.; Francia, Sofia; Veloso, Artur; Magnuson, Brian; di Fagagna, Fabrizio d’Adda; Wilson, Thomas E.; Ljungman, Mats

    2017-01-01

    In response to ionizing radiation (IR), cells activate a DNA damage response (DDR) pathway to re-program gene expression. Previous studies using total cellular RNA analyses have shown that the stress kinase ATM and the transcription factor p53 are integral components required for induction of IR-induced gene expression. These studies did not distinguish between changes in RNA synthesis and RNA turnover and did not address the role of enhancer elements in DDR-mediated transcriptional regulation. To determine the contribution of synthesis and degradation of RNA and monitor the activity of enhancer elements following exposure to IR, we used the recently developed Bru-seq, BruChase-seq and BruUV-seq techniques. Our results show that ATM and p53 regulate both RNA synthesis and stability as well as enhancer element activity following exposure to IR. Importantly, many genes in the p53-signaling pathway were coordinately up-regulated by both increased synthesis and RNA stability while down-regulated genes were suppressed either by reduced synthesis or stability. Our study is the first of its kind that independently assessed the effects of ionizing radiation on transcription and post-transcriptional regulation in normal human cells. PMID:28256581

  17. Fast packet switching algorithms for dynamic resource control over ATM networks

    SciTech Connect

    Tsang, R.P.; Keattihananant, P.; Chang, T.; Heieh, J.; Du, D.

    1996-12-01

    Real-time continuous media traffic, such as digital video and audio, is expected to comprise a large percentage of the network load on future high speed packet switch networks such as ATM. A major feature which distinguishes high speed networks from traditional slower speed networks is the large amount of data the network must process very quickly. For efficient network usage, traffic control mechanisms are essential. Currently, most mechanisms for traffic control (such as flow control) have centered on the support of Available Bit Rate (ABR), i.e., non real-time, traffic. With regard to ATM, for ABR traffic, two major types of schemes which have been proposed are rate- control and credit-control schemes. Neither of these schemes are directly applicable to Real-time Variable Bit Rate (VBR) traffic such as continuous media traffic. Traffic control for continuous media traffic is an inherently difficult problem due to the time- sensitive nature of the traffic and its unpredictable burstiness. In this study, we present a scheme which controls traffic by dynamically allocating/de- allocating resources among competing VCs based upon their real-time requirements. This scheme incorporates a form of rate- control, real-time burst-level scheduling and link-link flow control. We show analytically potential performance improvements of our rate- control scheme and present a scheme for buffer dimensioning. We also present simulation results of our schemes and discuss the tradeoffs inherent in maintaining high network utilization and statistically guaranteeing many users` Quality of Service.

  18. AES Cardless Automatic Teller Machine (ATM) Biometric Security System Design Using FPGA Implementation

    NASA Astrophysics Data System (ADS)

    Ahmad, Nabihah; Rifen, A. Aminurdin M.; Helmy Abd Wahab, Mohd

    2016-11-01

    Automated Teller Machine (ATM) is an electronic banking outlet that allows bank customers to complete a banking transactions without the aid of any bank official or teller. Several problems are associated with the use of ATM card such card cloning, card damaging, card expiring, cast skimming, cost of issuance and maintenance and accessing customer account by third parties. The aim of this project is to give a freedom to the user by changing the card to biometric security system to access the bank account using Advanced Encryption Standard (AES) algorithm. The project is implemented using Field Programmable Gate Array (FPGA) DE2-115 board with Cyclone IV device, fingerprint scanner, and Multi-Touch Liquid Crystal Display (LCD) Second Edition (MTL2) using Very High Speed Integrated Circuit Hardware (VHSIC) Description Language (VHDL). This project used 128-bits AES for recommend the device with the throughput around 19.016Gbps and utilized around 520 slices. This design offers a secure banking transaction with a low rea and high performance and very suited for restricted space environments for small amounts of RAM or ROM where either encryption or decryption is performed.

  19. PTEN enhances G2/M arrest in etoposide-treated MCF‑7 cells through activation of the ATM pathway.

    PubMed

    Zhang, Ruopeng; Zhu, Li; Zhang, Lirong; Xu, Anli; Li, Zhengwei; Xu, Yijuan; He, Pei; Wu, Maoqing; Wei, Fengxiang; Wang, Chenhong

    2016-05-01

    As an effective tumor suppressor, phosphatase and tensin homolog (PTEN) has attracted the increased attention of scientists. Recent studies have shown that PTEN plays unique roles in the DNA damage response (DDR) and can interact with the Chk1 pathway. However, little is known about how PTEN contributes to DDR through the ATM-Chk2 pathway. It is well-known that etoposide induces G2/M arrest in a variety of cell lines, including MCF-7 cells. The DNA damage-induced G2/M arrest results from the activation of protein kinase ataxia telangiectasia mutated (ATM), followed by the activation of Chk2 that subsequently inactivates CDC25C, resulting in G2/M arrest. In the present study, we assessed the contribution of PTEN to the etoposide-induced G2/M cell cycle arrest. PTEN was knocked down in MCF-7 cells by specific shRNA, and the effects of PTEN on the ATM-Chk2 pathway were investigated through various approaches. The results showed that knockdown of PTEN strongly antagonized ATM activation in response to etoposide treatment, and thereby reduced the phosphorylation level of ATM substrates, including H2AX, P53 and Chk2. Furthermore, depletion of PTEN reduced the etoposide-induced phosphorylation of CDC25C and strikingly compromised etoposide-induced G2/M arrest in the MCF-7 cells. Altogether, we demonstrated that PTEN plays a unique role in etoposide-induced G2/M arrest by facilitating the activation of the ATM pathway, and PTEN was required for the proper activation of checkpoints in response to DNA damage in MCF-7 cells.

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

    PubMed

    Bellani, Marina A; Romanienko, Peter J; Cairatti, Damian A; Camerini-Otero, R Daniel

    2005-08-01

    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.

  1. Comparative Results of AIRS/AMSU and CrIS/ATMS Retrievals Using a Scientifically Equivalent Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena

    2016-01-01

    The AIRS Science Team Version-6 retrieval algorithm is currently producing high quality level-3 Climate Data Records (CDRs) from AIRS/AMSU which are critical for understanding climate processes. The AIRS Science Team is finalizing an improved Version-7 retrieval algorithm to reprocess all old and future AIRS data. AIRS CDRs should eventually cover the period September 2002 through at least 2020. CrIS/ATMS is the only scheduled follow on to AIRS/AMSU. The objective of this research is to prepare for generation of long term CrIS/ATMS CDRs using a retrieval algorithm that is scientifically equivalent to AIRS/AMSU Version-7.

  2. Research and implement on the high speed network system with CIINS based on ATM for aero manufacturing enterprise

    NASA Astrophysics Data System (ADS)

    Jiang, Zhi-qiang; Feng, Xi-lan; Zong, Xue-wen; Ding, Yu-cheng

    2005-12-01

    In this paper, the design and implementation on the high-speed network system of the Computer Integrated and Information Network System (CIINS) for aeronautical manufacturing enterprise based on ATM is explained. And designing the high-speed network, choosing the devices, network administration, and developing the network application are discussed. And also, the key technology of the network design is analyzed. The system safety is ensured, when the ATM with QoS in the main backbone network and the work team with network layer in intelligent Ethernet equipment are adapted, and a kind of firewall based on Hard-wall technology is implemented.

  3. Fabrication and characterization of MCC approved testing material: ATM-11 glass

    SciTech Connect

    Wald, J.W.; Daniel, J.L.

    1986-08-01

    ATM-11 glass is designed to be representative of defense high-level waste glasses that will be produced by the Defense Waste Processing Facility at the Savannah River Plant in Aiken, South Carolina. It is representative of a 300-year-old nuclear waste glass and was intended as a conservative compromise between 10-year-old waste and 1000-year-old waste. The feedstock material for this glass was supplied by Savannah River Laboratory, Aiken, SC, as SRL-165 black frit to which was added Ba, Cs, Mo, Nd, Ni, Pd, Rb, Ru, Sr, Te, Y, and Zr, as well as /sup 241/Am, /sup 237/Np, /sup 239+240/Pu, /sup 151/Sm, /sup 99/Tc, and depleted U. The glass was melted under the reducing conditions that resulted from the addition of 0.7 wt% graphite during the final melting process. Nearly 3 kg of ATM-11 glass were produced from a feedstock melted in a nitrogen-atmosphere glove box at 1250/sup 0/C in Denver Fire Clay crucibles. After final melting, the glass was formed into stress-annealed rectangular bars 1.9 x 1.9 x 10 cm nominal size. Twenty-six bars were cast with a nominal weight of about 100 g each. The analyzed composition of ATM-11 glass is tabulated. Examination of a single transverse section from one bar by reflected light microscopy showed random porosity estimated at 0.4 vol% with nominal pore diameters ranging from approx.5 ..mu..m to 175 ..mu..m. A distinct randomly distributed second phase was observed at a very low concentration in the glass matrix as agglomerated, metallic-like clusters. One form of the aggregates contained mainly a high concentration of iron, while a second form had regions of high nickel concentration, and of high palladium concentration. All aggregates also contained a low concentration of technetium and/or ruthenium. An autoradiograph of the sample provided an indication of the total radionuclide ditribution. X-ray diffraction analysis of this same sample indicates that the glass probably contained 5 wt% crystalline material.

  4. The Advanced Technology Microwave Sounder (ATMS): First Year On-Orbit

    NASA Technical Reports Server (NTRS)

    Kim, Edward J.

    2012-01-01

    The Advanced Technology Microwave Sounder (ATMS) is a new satellite microwave sounding sensor designed to provide operational weather agencies with atmospheric temperature and moisture profile information for global weather forecasting and climate applications. A TMS will continue the microwave sounding capabilities first provided by its predecessors, the Microwave Sounding Unit (MSU) and Advanced Microwave Sounding Unit (AMSU). The first flight unit was launched a year ago in October, 2011 aboard the Suomi-National Polar-Orbiting Partnership (S-NPP) satellite, part of the new Joint Polar-Orbiting Satellite System (JPSS). Microwave soundings by themselves are the highest-impact input data used by Numerical Weather Prediction models; and A TMS, when combined with the Cross-track Infrared Sounder (CrIS), forms the Cross-track Infrared and Microwave Sounding Suite (CrIMSS). The microwave soundings help meet sounding requirements under cloudy sky conditions and provide key profile information near the surface. ATMS was designed & built by Aerojet Corporation in Azusa, California, (now Northrop Grumman Electronic Systems). It has 22 channels spanning 23-183 GHz, closely following the channel set of the MSU, AMSU-AI/2, AMSU-B, Microwave Humidity Sounder (MHS), and Humidity Sounder for Brazil (HSB). It continues their cross-track scanning geometry, but for the first time, provides Nyquist sample spacing. All this is accomplished with approximately V. the volume, Y, the mass, and Y, the power of the three AMSUs. A description will be given of its performance from its first year of operation as determined by post-launch calibration activities. These activities include radiometric calibration using the on-board warm targets and cold space views, and geolocation determination. Example imagery and zooms of specific weather events will be shown. The second ATMS flight model is currently under construction and planned for launch on the "Jl" satellite of the JPSS program in

  5. Regulator of G Protein Signaling 6 (RGS6) Mediates Doxorubicin-induced ATM and p53 Activation by a Reactive Oxygen Species (ROS)-dependent Mechanism

    PubMed Central

    Huang, Jie; Yang, Jianqi; Maity, Biswanath; Mayuzumi, Daisuke; Fisher, Rory A.

    2011-01-01

    Doxorubicin (DXR), among the most widely used cancer chemotherapy agents, promotes cancer cell death via activation of ATM and the resultant up-regulation of tumor suppressor p53. The exact mechanism by which DXR activates ATM is not fully understood. Here we discovered a novel role for Regulator of G protein Signaling 6 (RGS6) in mediating activation of ATM and p53 by DXR. RGS6 was robustly induced by DXR, and genetic loss of RGS6 dramatically impaired DXR-induced activation of ATM and p53, as well as its in vivo apoptotic actions in heart. The ability of RGS6 to promote p53 activation in response to DXR was independent of RGS6 interaction with G proteins but required ATM. RGS6 mediated activation of ATM and p53 by DXR via a ROS-dependent and DNA damage-independent mechanism. This mechanism represents the primary means by which DXR promotes activation of the ATM-p53-apoptosis pathway that underlies its cytotoxic activity. Our findings contradict the canonical theories that DXR activates ATM primarily by promoting DNA damage either directly or indirectly (via ROS) and that RGS6 function is mediated by its interactions with G proteins. These findings reveal a new mechanism for the chemotherapeutic actions of DXR and identify RGS6 as a novel target for cancer chemotherapy. PMID:21859827

  6. Early B-cell-specific inactivation of ATM synergizes with ectopic CyclinD1 expression to promote pre-germinal center B-cell lymphomas in mice.

    PubMed

    Yamamoto, K; Lee, B J; Li, C; Dubois, R L; Hobeika, E; Bhagat, G; Zha, S

    2015-06-01

    Ataxia telangiectasia-mutated (ATM) kinase is a master regulator of the DNA damage response. ATM is frequently inactivated in human B-cell non-Hodgkin lymphomas, including ~50% of mantle cell lymphomas (MCLs) characterized by ectopic expression of CyclinD1. Here we report that early and robust deletion of ATM in precursor/progenitor B cells causes cell autonomous, clonal mature B-cell lymphomas of both pre- and post-germinal center (GC) origins. Unexpectedly, naive B-cell-specific deletion of ATM is not sufficient to induce lymphomas in mice, highlighting the important tumor suppressor function of ATM in immature B cells. Although EμCyclinD1 is not sufficient to induce lymphomas, EμCyclinD1 accelerates the kinetics and increases the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas toward pre-GC-derived small lymphocytic neoplasms, sharing morphological features of human MCL. This is in part due to CyclinD1-driven expansion of ATM-deficient naive B cells with genomic instability, which promotes the deletions of additional tumor suppressor genes (i.e. Trp53, Mll2, Rb1 and Cdkn2a). Together these findings define a synergistic function of ATM and CyclinD1 in pre-GC B-cell proliferation and lymphomagenesis and provide a prototypic animal model to study the pathogenesis of human MCL.

  7. Walking ATMs and the immigration spillover effect: The link between Latino immigration and robbery victimization.

    PubMed

    Barranco, Raymond E; Shihadeh, Edward S

    2015-07-01

    Media reports and prior research suggest that undocumented Latino migrants are disproportionately robbed because they rely on a cash-only economy and they are reluctant to report crimes to law-enforcement (the Walking ATM phenomenon). From this we generate two specific research questions. First, we probe for an immigration spillover effect - defined as increased native and documented Latino robbery victimization due to offenders' inability to distinguish between the statuses of potential victims. Second, we examine the oft-repeated claim that Blacks robbers disproportionately target Latino victims. Using National Incident-Based Reporting System (NIBRS) data from 282 counties, results show (1) support for an immigration spillover effect but, (2) no support for the claim that Latinos are disproportionately singled out by Black robbers. We discuss the implications of our findings.

  8. Antennas Designed for Advanced Communications for Air Traffic Management (AC/ATM) Project

    NASA Technical Reports Server (NTRS)

    Zakrajsek, Robert J.

    2000-01-01

    The goal of the Advanced Communications for Air Traffic Management (AC/ATM) Project at the NASA Glenn Research Center at Lewis Field is to enable a communications infrastructure that provides the capacity, efficiency, and flexibility necessary to realize a mature free-flight environment. The technical thrust of the AC/ATM Project is targeted at the design, development, integration, test, and demonstration of enabling technologies for global broadband aeronautical communications. Since Ku-band facilities and equipment are readily available, one of the near-term demonstrations involves a link through a Kuband communications satellite. Two conformally mounted antennas will support the initial AC/ATM communications links. Both of these are steered electronically through monolithic microwave integrated circuit (MMIC) amplifiers and phase shifters. This link will be asymmetrical with the downlink to the aircraft (mobile vehicle) at a throughput rate of greater than 1.5 megabits per second (Mbps), whereas the throughput rate of the uplink from the aircraft will be greater than 100 kilobits per second (kbps). The data on the downlink can be narrow-band, wide-band, or a combination of both, depending on the requirements of the experiment. The AC/ATM project is purchasing a phased-array Ku-band transmitting antenna for the uplink from the test vehicle. Many Ku-band receiving antennas have been built, and one will be borrowed for a short time to perform the initial experiments at the NASA Glenn Research Center at Lewis Field. The Ku-band transmitting antenna is a 254-element MMIC phased-array antenna being built by Boeing Phantom Works. Each element can radiate 100 mW. The antenna is approximately 43-cm high by 24-cm wide by 3.3-cm thick. It can be steered beyond 60 from broadside. The beamwidth varies from 6 at broadside to 12 degrees at 60 degrees, which is typical of phased-array antennas. When the antenna is steered to 60 degrees, the beamwidth will illuminate

  9. Modular and Stochastic Approaches to Molecular Pathway Models of ATM, TGF beta, and WNT Signaling

    NASA Technical Reports Server (NTRS)

    Cucinotta, Francis A.; O'Neill, Peter; Ponomarev, Artem; Carra, Claudio; Whalen, Mary; Pluth, Janice M.

    2009-01-01

    Deterministic pathway models that describe the biochemical interactions of a group of related proteins, their complexes, activation through kinase, etc. are often the basis for many systems biology models. Low dose radiation effects present a unique set of challenges to these models including the importance of stochastic effects due to the nature of radiation tracks and small number of molecules activated, and the search for infrequent events that contribute to cancer risks. We have been studying models of the ATM, TGF -Smad and WNT signaling pathways with the goal of applying pathway models to the investigation of low dose radiation cancer risks. Modeling challenges include introduction of stochastic models of radiation tracks, their relationships to more than one substrate species that perturb pathways, and the identification of a representative set of enzymes that act on the dominant substrates. Because several pathways are activated concurrently by radiation the development of modular pathway approach is of interest.

  10. Cris-atms Retrievals Using an AIRS Science Team Version 6-like Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis C.; Iredell, Lena

    2014-01-01

    CrIS is the infrared high spectral resolution atmospheric sounder launched on Suomi-NPP in 2011. CrISATMS comprise the IRMW Sounding Suite on Suomi-NPP. CrIS is functionally equivalent to AIRS, the high spectral resolution IR sounder launched on EOS Aqua in 2002 and ATMS is functionally equivalent to AMSU on EOS Aqua. CrIS is an interferometer and AIRS is a grating spectrometer. Spectral coverage, spectral resolution, and channel noise of CrIS is similar to AIRS. CrIS spectral sampling is roughly twice as coarse as AIRSAIRS has 2378 channels between 650 cm-1 and 2665 cm-1. CrIS has 1305 channels between 650 cm-1 and 2550 cm-1. Spatial resolution of CrIS is comparable to AIRS.

  11. The study of an ATM switch system used for on-board processing

    NASA Astrophysics Data System (ADS)

    Li, Yong; Xiong, Huibo

    2007-11-01

    On-board processing (OBP) is one of significant satellite communication technologies, and the Asynchronous Transfer Mode (ATM) is widely used in the OBP which can guarantee the QoS. This article presents the CAC (Call Admission Control) algorithm and Congestion Control algorithm. We combine with B-CAC algorithm, Bahadur-Rao's theory, Weiss theory, to improve the old method, and the simulation results show that when the PDR/LR is small the burst is high, the chain utilization and statistic multiplexing gain get a big advantage. Besides, concerning TCP congestion control, the article compared five strategies: Tahoe, Reno, Newreno, Sack and Vegas. The simulation results show that the Vegas can be used to predict congestion conditions correctly; its congestion window (cwnd) control is smoother and is superior to other algorithms in average RTT.

  12. Modest increased sensitivity to radiation oncogenesis in ATM heterozygous versus wild-type mammalian cells

    NASA Technical Reports Server (NTRS)

    Smilenov, L. B.; Brenner, D. J.; Hall, E. J.

    2001-01-01

    Subpopulations that are genetically predisposed to radiation-induced cancer could have significant public health consequences. Individuals homozygous for null mutations at the ataxia telangiectasia gene are indeed highly radiosensitive, but their numbers are very small. Ataxia Telangiectasia heterozygotes (1-2% of the population) have been associated with somewhat increased radiosensitivity for some end points, but none directly related to carcinogenesis. Here, intralitter comparisons between wild-type mouse embryo fibroblasts and mouse embryo fibroblasts carrying ataxia telangiectasia mutated (ATM) null mutation indicate that the heterozygous cells are more sensitive to radiation oncogenesis than their normal, litter-matched, counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally-significant radiosensitive human subpopulation.

  13. Fenómenos solares que afectan la atmósfera terrestre

    NASA Astrophysics Data System (ADS)

    Rovira, M.

    Se describen los principales fenómenos solares como fulguraciones, prominencias eruptivas, viento solar y eyecciones de masa coronal (CME) que tienen consecuencias en la atmósfera terrestre. En algunos casos el material es eyectado a velocidades superiores a los 900 km/seg y tarda menos de 48 horas en llegar a la Tierra. En general, estos CME no son peligrosos ya que el campo magnético terrestre actúa como protector siendo un aislante efectivo. Si el viento solar es muy intenso puede comprimir la magnetósfera y producir una tormenta geomagnética. En casos extremos, puede interferir la transmisión de potencia eléctrica, perturbar los satélites y producir auroras polares.

  14. End-to-End QoS for Differentiated Services and ATM Internetworking

    NASA Technical Reports Server (NTRS)

    Su, Hongjun; Atiquzzaman, Mohammed

    2001-01-01

    The Internet was initially design for non real-time data communications and hence does not provide any Quality of Service (QoS). The next generation Internet will be characterized by high speed and QoS guarantee. The aim of this paper is to develop a prioritized early packet discard (PEPD) scheme for ATM switches to provide service differentiation and QoS guarantee to end applications running over next generation Internet. The proposed PEPD scheme differs from previous schemes by taking into account the priority of packets generated from different application. We develop a Markov chain model for the proposed scheme and verify the model with simulation. Numerical results show that the results from the model and computer simulation are in close agreement. Our PEPD scheme provides service differentiation to the end-to-end applications.

  15. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

    PubMed Central

    Southey, Melissa C; Goldgar, David E; Winqvist, Robert; Pylkäs, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D; Dennis, Joe; Michailidou, Kyriaki; van Rensburg, Elizabeth J; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John L; Dörk, Thilo; Claes, Kathleen BM; Reis-Filho, Jorge; Teo, Zhi Ling; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice A; Dowty, James G; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; Verhoef, Senno; Carpenter, Jane; Clarke, Christine; Scott, Rodney J; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Bolla, Manjeet K; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Yang, Rongxi; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan; Ziogas, Argyrios; Clarke, Christina A; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V; Antonenkova, Natalia N; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Spurdle, Amanda B; Investigators, kConFab; Wauters, Els; Smeets, Dominiek; Beuselinck, Benoit; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Olson, Janet E; Vachon, Celine; Pankratz, Vernon S; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Kristensen, Vessela; Alnæs, Grethe Grenaker; Zheng, Wei; Hunter, David J; Lindstrom, Sara; Hankinson, Susan E; Kraft, Peter; Andrulis, Irene; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Jukkola-Vuorinen, Arja; Grip, Mervi; Kauppila, Saila; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Hollestelle, Antoinette; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Eccles, Diana M; Rafiq, Sajjad; Tapper, William J; Gerty, Sue M; Hooning, Maartje J; Martens, John W M; Collée, J Margriet; Tilanus-Linthorst, Madeleine; Hall, Per; Li, Jingmei; Brand, Judith S; Humphreys, Keith; Cox, Angela; Reed, Malcolm W R; Luccarini, Craig; Baynes, Caroline; Dunning, Alison M; Hamann, Ute; Torres, Diana; Ulmer, Hans Ulrich; Rüdiger, Thomas; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Simard, Jacques; Dumont, Martine; Soucy, Penny; Eeles, Rosalind; Muir, Kenneth; Wiklund, Fredrik; Gronberg, Henrik; Schleutker, Johanna; Nordestgaard, Børge G; Weischer, Maren; Travis, Ruth C; Neal, David; Donovan, Jenny L; Hamdy, Freddie C; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen; Schaid, Daniel J; Kelley, Joseph L; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Butterbach, Katja; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Benlloch, Sara; Renner, Stefan P; Hartmann, Arndt; Hein, Alexander; Ruebner, Matthias; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambretchs, Sandrina; Doherty, Jennifer A; Rossing, Mary Anne; Nickels, Stefan; Eilber, Ursula; Wang-Gohrke, Shan; Odunsi, Kunle; Sucheston-Campbell, Lara E; Friel, Grace; Lurie, Galina; Killeen, Jeffrey L; Wilkens, Lynne R; Goodman, Marc T; Runnebaum, Ingo; Hillemanns, Peter A; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Edwards, Robert P; Ness, Roberta B; Moysich, Kirsten B; du Bois, Andreas; Heitz, Florian; Harter, Philipp; Kommoss, Stefan; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Jensen, Allan; Kjaer, Susanne Krüger; Høgdall, Estrid; Peissel, Bernard; Bonanni, Bernardo; Bernard, Loris; Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A; Cunningham, Julie M; Larson, Melissa C; Fogarty, Zachary C; Kalli, Kimberly R; Liang, Dong; Lu, Karen H; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A; Dao, Fanny; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Marks, Jeffrey R; Akushevich, Lucy; Cramer, Daniel W; Schildkraut, Joellen; Terry, Kathryn L; Poole, Elizabeth M; Stampfer, Meir; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Bjorge, Line; Salvesen, Helga B; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Pejovic, Tanja; Bean, Yukie; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Górski, Bohdan; Gronwald, Jacek; Menkiszak, Janusz; Høgdall, Claus K; Lundvall, Lene; Nedergaard, Lotte; Engelholm, Svend Aage; Dicks, Ed; Tyrer, Jonathan; Campbell, Ian; McNeish, Iain; Paul, James; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Cai, Hui; Shu, Xiao-Ou; Teten, Rachel T; Sutphen, Rebecca; McLaughlin, John R; Narod, Steven A; Phelan, Catherine M; Monteiro, Alvaro N; Fenstermacher, David; Lin, Hui-Yi; Permuth, Jennifer B; Sellers, Thomas A; Chen, Y Ann; Tsai, Ya-Yu; Chen, Zhihua; Gentry-Maharaj, Aleksandra; Gayther, Simon A; Ramus, Susan J; Menon, Usha; Wu, Anna H; Pearce, Celeste L; Van Den Berg, David; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul DP; Song, Honglin; Winship, Ingrid; Chenevix-Trench, Georgia; Giles, Graham G; Tavtigian, Sean V; Easton, Doug F; Milne, Roger L

    2016-01-01

    Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important. PMID:27595995

  16. Chronic PARP-1 inhibition reduces carotid vessel remodeling and oxidative damage of the dorsal hippocampus in spontaneously hypertensive rats

    PubMed Central

    Eros, Krisztian; Magyar, Klara; Deres, Laszlo; Skazel, Arpad; Riba, Adam; Vamos, Zoltan; Kalai, Tamas; Gallyas, Ferenc; Sumegi, Balazs; Toth, Kalman

    2017-01-01

    Vascular remodeling during chronic hypertension may impair the supply of tissues with oxygen, glucose and other compounds, potentially unleashing deleterious effects. In this study, we used Spontaneously Hypertensive Rats and normotensive Wistar-Kyoto rats with or without pharmacological inhibition of poly(ADP-ribose)polymerase-1 by an experimental compound L-2286, to evaluate carotid artery remodeling and consequent damage of neuronal tissue during hypertension. We observed elevated oxidative stress and profound thickening of the vascular wall with fibrotic tissue accumulation induced by elevated blood pressure. 32 weeks of L-2286 treatment attenuated these processes by modulating mitogen activated protein kinase phosphatase-1 cellular levels in carotid arteries. In hypertensive animals, vascular inflammation and endothelial dysfunction was observed by NF-κB nuclear accumulation and impaired vasodilation to acetylcholine, respectively. Pharmacological poly(ADP-ribose)polymerase-1 inhibition interfered in these processes and mitigated Apoptosis Inducing Factor dependent cell death events, thus improved structural and functional alterations of carotid arteries, without affecting blood pressure. Chronic poly(ADP-ribose)polymerase-1 inhibition protected neuronal tissue against oxidative damage, assessed by nitrotyrosine, 4-hydroxinonenal and 8-oxoguanosine immunohistochemistry in the area of Cornu ammonis 1 of the dorsal hippocampus in hypertensive rats. In this area, extensive pyramidal cell loss was also attenuated by treatment with lowered poly(ADP-ribose)polymer formation. It also preserved the structure of fissural arteries and attenuated perivascular white matter lesions and reactive astrogliosis in hypertensive rats. These data support the premise in which chronic poly(ADP-ribose)polymerase-1 inhibition has beneficial effects on hypertension related tissue damage both in vascular tissue and in the hippocampus by altering signaling events, reducing oxidative

  17. Collaboration of MLLT1/ENL, Polycomb and ATM for transcription and genome integrity.

    PubMed

    Ui, Ayako; Yasui, Akira

    2016-04-25

    Polycomb group (PcG) repress, whereas Trithorax group (TrxG) activate transcription for tissue development and cellular proliferation, and misregulation of these factors is often associated with cancer. ENL (MLLT1) and AF9 (MLLT3) are fusion partners of Mixed Lineage Leukemia (MLL), TrxG proteins, and are factors in Super Elongation Complex (SEC). SEC controls transcriptional elongation to release RNA polymerase II, paused around transcription start site. In MLL rearranged leukemia, several components of SEC have been found as MLL-fusion partners and the control of transcriptional elongation is misregulated leading to tumorigenesis in MLL-SEC fused Leukemia. It has been suggested that unexpected collaboration of ENL/AF9-MLL and PcG are involved in tumorigenesis in leukemia. Recently, we found that the collaboration of ENL/AF9 and PcG led to a novel mechanism of transcriptional switch from elongation to repression under ATM-signaling for genome integrity. Activated ATM phosphorylates ENL/AF9 in SEC, and the phosphorylated ENL/AF9 binds BMI1 and RING1B, a heterodimeric E3-ubiquitin-ligase complex in Polycomb Repressive complex 1 (PRC1), and recruits PRC1 at transcriptional elongation sites to rapidly repress transcription. The ENL/AF9 in SEC- and PcG-mediated transcriptional repression promotes DSB repair near transcription sites. The implication of this is that the collaboration of ENL/AF9 in SEC and PcG ensures a rapid response of transcriptional switching from elongation to repression to neighboring genotoxic stresses for DSB repair. Therefore, these results suggested that the collaboration of ENL/AF9 and PcG in transcriptional control is required to maintain genome integrity and may be link to the MLL-ENL/AF9 leukemia.

  18. ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans

    PubMed Central

    Hathcock, Karen S.; Padilla-Nash, Hesed M.; Camps, Jordi; Shin, Dong-Mi; Triner, Daniel; Shaffer, Arthur L.; Maul, Robert W.; Steinberg, Seth M.; Gearhart, Patricia J.; Staudt, Louis M.; Morse, Herbert C.; Ried, Thomas

    2015-01-01

    The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M+ B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell–like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-κB, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-κB activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors. PMID:26400962

  19. ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress.

    PubMed

    Wu, Zhao-Hui; Wong, Ee Tsin; Shi, Yuling; Niu, Jixiao; Chen, Zhijian; Miyamoto, Shigeki; Tergaonkar, Vinay

    2010-10-08

    Activation of the transcription factor NF-κB by multiple genotoxic stimuli modulates cancer cell survival. This response is mediated by a conserved pathway involving the nuclear ATM kinase and cytoplasmic IκB kinase (IKK); however, the molecular link between them remains incompletely understood. Here we show that ATM activates the IKK kinase TAK1 in a manner dependent on IKKγ/NEMO and ELKS (a protein rich in glutamate, leucine, lysine, and serine). K63-linked polyubiquitination of ELKS, dependent on the ubiquitin ligase XIAP and the conjugating enzyme UBC13, allows ELKS association with TAK1 via its ubiquitin-binding subunits TAB2/3. Although NEMO mutants defective in ubiquitin binding permit ATM-dependent TAK1 activation, they block NEMO association with ELKS and IKK activation. Thus, ATM- and NEMO-dependent ubiquitination of ELKS leads to the ubiquitin-dependent assembly of TAK1/TAB2/3 and NEMO/IKK complexes, resulting in IKK and NF-κB activation following genotoxic stimuli.

  20. Non-redundant Functions of ATM and DNA-PKcs in Response to DNA Double-Strand Breaks.

    PubMed

    Caron, Pierre; Choudjaye, Jonathan; Clouaire, Thomas; Bugler, Béatrix; Daburon, Virginie; Aguirrebengoa, Marion; Mangeat, Thomas; Iacovoni, Jason S; Álvarez-Quilón, Alejandro; Cortés-Ledesma, Felipe; Legube, Gaëlle

    2015-11-24

    DNA double-strand breaks (DSBs) elicit the so-called DNA damage response (DDR), largely relying on ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PKcs), two members of the PI3K-like kinase family, whose respective functions during the sequential steps of the DDR remains controversial. Using the DIvA system (DSB inducible via AsiSI) combined with high-resolution mapping and advanced microscopy, we uncovered that both ATM and DNA-PKcs spread in cis on a confined region surrounding DSBs, independently of the pathway used for repair. However, once recruited, these kinases exhibit non-overlapping functions on end joining and γH2AX domain establishment. More specifically, we found that ATM is required to ensure the association of multiple DSBs within "repair foci." Our results suggest that ATM acts not only on chromatin marks but also on higher-order chromatin organization to ensure repair accuracy and survival.

  1. Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model

    PubMed Central

    Lee, Andrew J.; Cunningham, Alex P.; Tischkowitz, Marc; Simard, Jacques; Pharoah, Paul D.; Easton, Douglas F.; Antoniou, Antonis C.

    2016-01-01

    Purpose The proliferation of gene-panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2 and ATM. Methods The BC incidence was modelled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2 and ATM and other unobserved genetic effects using segregation analysis methods. Results The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH-burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive-testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly. Conclusions The model may be a valuable tool for counselling women who have undergone gene-panel testing for providing consistent risks and harmonizing their clinical management. A web-application can be used to obtain BC- risks in clinical practice (http://ccge.medschl.cam.ac.uk/boadicea/). PMID:27464310

  2. Non-redundant Functions of ATM and DNA-PKcs in Response to DNA Double-Strand Breaks

    PubMed Central

    Caron, Pierre; Choudjaye, Jonathan; Clouaire, Thomas; Bugler, Béatrix; Daburon, Virginie; Aguirrebengoa, Marion; Mangeat, Thomas; Iacovoni, Jason S.; Álvarez-Quilón, Alejandro; Cortés-Ledesma, Felipe; Legube, Gaëlle

    2015-01-01

    Summary DNA double-strand breaks (DSBs) elicit the so-called DNA damage response (DDR), largely relying on ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PKcs), two members of the PI3K-like kinase family, whose respective functions during the sequential steps of the DDR remains controversial. Using the DIvA system (DSB inducible via AsiSI) combined with high-resolution mapping and advanced microscopy, we uncovered that both ATM and DNA-PKcs spread in cis on a confined region surrounding DSBs, independently of the pathway used for repair. However, once recruited, these kinases exhibit non-overlapping functions on end joining and γH2AX domain establishment. More specifically, we found that ATM is required to ensure the association of multiple DSBs within “repair foci.” Our results suggest that ATM acts not only on chromatin marks but also on higher-order chromatin organization to ensure repair accuracy and survival. PMID:26586426

  3. TP53 and ATM mRNA expression in skin and skeletal muscle after low-level laser exposure.

    PubMed

    Guedes de Almeida, Luciana; Silva Sergio, Luiz Philippe da; de Paoli, Flavia; Mencalha, Andre Luiz; da Fonseca, Adenilson de Souza

    2017-02-16

    Low-level lasers are widespread in regenerative medicine, but the molecular mechanisms involved in their biological effects are not fully understood, particularly those on DNA stability. Therefore, this study aimed to investigate mRNA expression of genes related to DNA genomic stability in skin and skeletal muscle tissue from Wistar rats exposed to low-level red and infrared lasers. For this, TP53 (Tumor Protein 53) and ATM (Ataxia Telangiectasia Mutated gene) mRNA expressions were evaluated by real-time quantitative PCR (RT-qPCR) technique 24 hours after low-level red and infrared laser exposure. Our data showed that relative TP53 mRNA expression was not significantly altered in both tissues exposed to lasers. For ATM, relative mRNA expression in skin tissue was not significantly altered, but in muscle tissue, laser exposure increased relative ATM mRNA expression. Low-level red and infrared laser radiations alter ATM mRNA expression related to DNA stability in skeletal muscle tissue.

  4. Performance analysis of ATM ABR service under self-similar traffic in the presence of background VBR traffic

    SciTech Connect

    Benke, G. |; Brandt, J.; Chen, H.; Dastangoo, S.; Miller, G.J.

    1996-05-01

    Recent empirical studies of traffic measurements of packet switched networks have demonstrated that actual network traffic is self-similar, or long range dependent, in nature. That is, the measured traffic is bursty over a wide range of time intervals. Furthermore, the emergence of high-speed network backbones demands the study of accurate models of aggregated traffic to assess network performance. This paper provides a method for generation of self-similar traffic, which can be used to drive network simulation models. The authors present the results of a simulation study of a two-node ATM network configuration that supports the ATM Forum`s Available Bit Rate (ABR) service. In this study, the authors compare the state of the queue at the source router at the edge of the ATM network under both Poisson and self-similar traffic loading. These findings indicate an order of magnitude increase in queue length for self-similar traffic loading as compared to Poisson loading. Moreover, when background VBR traffic is present, self-similar ABR traffic causes more congestion at the ATM switches than does Poisson traffic.

  5. Training of Evaluators in the Third World: Implementation of the Action Training Model (ATM) in Kenya and Botswana.

    ERIC Educational Resources Information Center

    Bhola, H. S.

    The Action Training Model (ATM) was developed for the delivery of evaluation training to development workers in Kenya and Botswana and implemented under the aegis of the German Foundation for International Development. Training of evaluators is a challenge in any context, but in the Third World environment, evaluation training offers special…

  6. Mobile phone signal exposure triggers a hormesis-like effect in Atm+/+ and Atm−/− mouse embryonic fibroblasts

    PubMed Central

    Sun, Chuan; Wei, Xiaoxia; Fei, Yue; Su, Liling; Zhao, Xinyuan; Chen, Guangdi; Xu, Zhengping

    2016-01-01

    Radiofrequency electromagnetic fields (RF-EMFs) have been classified by the International Agency for Research on Cancer as possible carcinogens to humans; however, this conclusion is based on limited epidemiological findings and lacks solid support from experimental studies. In particular, there are no consistent data regarding the genotoxicity of RF-EMFs. Ataxia telangiectasia mutated (ATM) is recognised as a chief guardian of genomic stability. To address the debate on whether RF-EMFs are genotoxic, we compared the effects of 1,800 MHz RF-EMF exposure on genomic DNA in mouse embryonic fibroblasts (MEFs) with proficient (Atm+/+) or deficient (Atm−/−) ATM. In Atm+/+ MEFs, RF-EMF exposure for 1 h at an average special absorption rate of 4.0 W/kg induced significant DNA single-strand breaks (SSBs) and activated the SSB repair mechanism. This effect reduced the DNA damage to less than that of the background level after 36 hours of exposure. In the Atm−/− MEFs, the same RF-EMF exposure for 12 h induced both SSBs and double-strand breaks and activated the two repair processes, which also reduced the DNA damage to less than the control level after prolonged exposure. The observed phenomenon is similar to the hormesis of a toxic substance at a low dose. To the best of our knowledge, this study is the first to report a hormesis-like effect of an RF-EMF. PMID:27857169

  7. A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease.

    PubMed

    Tidball, Andrew M; Bryan, Miles R; Uhouse, Michael A; Kumar, Kevin K; Aboud, Asad A; Feist, Jack E; Ess, Kevin C; Neely, M Diana; Aschner, Michael; Bowman, Aaron B

    2015-04-01

    The essential micronutrient manganese is enriched in brain, especially in the basal ganglia. We sought to identify neuronal signaling pathways responsive to neurologically relevant manganese levels, as previous data suggested that alterations in striatal manganese handling occur in Huntington's disease (HD) models. We found that p53 phosphorylation at serine 15 is the most responsive cell signaling event to manganese exposure (of 18 tested) in human neuroprogenitors and a mouse striatal cell line. Manganese-dependent activation of p53 was severely diminished in HD cells. Inhibitors of ataxia telangiectasia mutated (ATM) kinase decreased manganese-dependent phosphorylation of p53. Likewise, analysis of ATM autophosphorylation and additional ATM kinase targets, H2AX and CHK2, support a role for ATM in the activation of p53 by manganese and that a defect in this process occurs in HD. Furthermore, the deficit in Mn-dependent activation of ATM kinase in HD neuroprogenitors was highly selective, as DNA damage and oxidative injury, canonical activators of ATM, did not show similar deficits. We assessed cellular manganese handling to test for correlations with the ATM-p53 pathway, and we observed reduced Mn accumulation in HD human neuroprogenitors and HD mouse striatal cells at manganese exposures associated with altered p53 activation. To determine if this phenotype contributes to the deficit in manganese-dependent ATM activation, we used pharmacological manipulation to equalize manganese levels between HD and control mouse striatal cells and rescued the ATM-p53 signaling deficit. Collectively, our data demonstrate selective alterations in manganese biology in cellular models of HD manifest in ATM-p53 signaling.

  8. Measurement of Atmospheric Black Carbon Concentrations, [BC]atm, in the Arctic Region from ~1700 to 2013

    NASA Astrophysics Data System (ADS)

    Husain, L.; Sarkar, S.; Jyethi, D. S.; Ruppel, M.; Dutkiewicz, V. A.

    2015-12-01

    Atmospheric black carbon (BC) aerosols play a key role in Earth's climate through direct and indirect effects. Due to a lack of long-term BC data, climate models are used to estimate BC based on fuel inventories, which have large uncertainties. Hence, long term BC data is needed to verify global models. We report here the first measurements of atmospheric BC concentrations, [BC]atm, from ~1700 to 2013 using sediments from Finnish lakes, Saanajarvi (SJ)(690 44' N, 200 52' E), and Vuoskojarvi (VJ)(69044'N, 26057'E). The cores were collected from the deepest parts of the lakes using a HTH gravity corer, sliced in 0.25 cm sections; freeze dried, and ages determined using 210Pb dating method. The BC was chemically separated, and [BC] determined by the thermal optical method. The [BC] varied from 50 to 1140µg/gdry weight in SJ; and 20 to 130µg/gdry weight in VJ. Husain et al.,(JGR, vol 113, D13102,doi:10.1029/2007JD009398, 2008) showed that the atmospheric deposition of BC into lake sediments depends on the characteristic of individual lakes, BC washout ratios, precipitation intensity, and sedimentation rates. The deposition rate, K, for a lake is defined by, [BC]sed = K[BC]atm where [BC]sed, is the concentration of BC in the sediment. We have measured [BC]atm from 1970 to 2010 in Kevo, Finland, where VJ and SJ are located. The [BC]atm from Kevo, and [BC]sed from VJ, and SJ were used to determine K for each of the lake. Owing to the availability of the long term atmospheric BC data from 1970 to 2010 multiple measurements of K were made, and provided a high measure of precision. The mean values of K for VJ, and SJ were 226 ± 60, and 830 ± 290 (m3air/ gdry weight). The K values were used to determine [BC]atm for the years before 1970. The [BC]atm from 2013 to 2006 was 82ng/m3. It increased slowly reaching a peak value of about 947 ± 322 ng/m3.The concentrations decreased subsequently to 244 ± 83ng/m3 in 1920, and changed little ~ 1774.The lowest concentration, 77

  9. ATM protein is indispensable to repair complex-type DNA double strand breaks induced by high LET heavy ion irradiation.

    NASA Astrophysics Data System (ADS)

    Sekine, Emiko; Yu, Dong; Fujimori, Akira; Anzai, Kazunori; Okayasu, Ryuichi

    ATM (ataxia telangiectasia-mutated) protein responsible for a rare genetic disease with hyperradiosensitivity, is the one of the earliest repair proteins sensing DNA double-strand breaks (DSB). ATM is known to phosphorylate DNA repair proteins such as MRN complex (Mre11, Rad50 and NBS1), 53BP1, Artemis, Brca1, gamma-H2AX, and MDC. We studied the interactions between ATM and DNA-PKcs, a crucial NHEJ repair protein, after cells exposure to high and low LET irradiation. Normal human (HFL III, MRC5VA) and AT homozygote (AT2KY, AT5BIVA, AT3BIVA) cells were irradiated with X-rays and high LET radiation (carbon ions: 290MeV/n initial energy at 70 keV/um, and iron ions: 500MeV/n initial energy at 200KeV/um), and several critical end points were examined. AT cells with high LET irradiation showed a significantly higher radiosensitivity when compared with normal cells. The behavior of DNA DSB repair was monitored by immuno-fluorescence techniques using DNA-PKcs (pThr2609, pSer2056) and ATM (pSer1981) antibodies. In normal cells, the phosphorylation of DNA-PKcs was clearly detected after high LET irradiation, though the peak of phosphorylation was delayed when compared to X-irradiation. In contrast, almost no DNA-PKcs phosphorylation foci were detected in AT cells irradiated with high LET radiation. A similar result was also observed in normal cells treated with 10 uM ATM kinase specific inhibitor (KU55933) one hour before irradiation. These data suggest that the phosphorylation of DNA-PKcs with low LET X-rays is mostly ATM-independent, and the phosphorylation of DNA-PKcs with high LET radiation seems to require ATM probably due to its complex nature of DSB induced. Our study indicates that high LET heavy ion irradiation which we can observe in the space environment would provide a useful tool to study the fundamental mechanism associated with DNA DSB repair.

  10. Differential Processing of Low and High LET Radiation Induced DNA Damage: Investigation of Switch from ATM to ATR Signaling

    NASA Technical Reports Server (NTRS)

    Saha, Janapriya; Wang, Minli; Hada, Megumi; Cucinotta, Francis A.

    2011-01-01

    The members of the phosphatidylinositol kinase-like kinase family of proteins namely ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) are directly responsible for the maintenance of genomic integrity by mounting DDR through signaling and facilitating the recruitment of repair factors at the sites of DNA damage along with coordinating the deployment of cell cycle checkpoints to permit repair by phosphorylating Checkpoint kinase Chk1, Chk2 and p53. High LET radiation from GCR (Galactic Cosmic Rays) consisting mainly of protons and high energy and charged (HZE) particles from SPE (Solar Particle Event) pose a major health risk for astronauts on their space flight missions. The determination of these risks and the design of potential safeguards require sound knowledge of the biological consequences of lesion induction and the capability of the cells to counter them. We here strive to determine the coordination of ATM and ATR kinases at the break sites directly affecting checkpoint signaling and DNA repair and whether differential processing of breaks induced by low and high LET radiation leads to possible augmentation of swap of these damage sensors at the sites of DNA damage. Exposure of cells to IR triggers rapid autophosphorylation of serine-1981 that causes dimer dissociation and initiates monomer formation of ATM. ATM kinase activity depends on the disruption of the dimer, which allows access and phosphorylation of downstream ATM substrates like Chk2. Evidence suggests that ATM is activated by the alterations in higher-order chromatin structure although direct binding of ATM to DSB ends may be a crucial step in its activation. On the other hand, in case of ATR, RPA (replication protein A)-coated ssDNA (single-stranded DNA) generated as a result of stalled DNA replication or during processing of chromosomal lesions is crucial for the localization of ATR to sites of DNA damage in association with ATR-interacting protein (ATRIP). Although the

  11. First six months of clinical usage of an ATM network link between two Veterans Affairs Medical Centers

    NASA Astrophysics Data System (ADS)

    Duerinckx, Andre J.; Gentili, Amilcare; El-Saden, Suzie; Harmon, Craig; Kenagy, John J.; Grant, Edward G.

    1998-07-01

    Purpose/Background: Asynchronous transfer mode (ATM) network technology has recently been used for high speed transmission of radiological images between hospitals and inside hospitals. However, the number of clinical sites which routinely use this technology is limited. The purpose of this study was to analyze the very early impact of an ATM link between a large tertiary referral center and small peripheral clinic on cost and clinical practice. Methodology: An ATM link using 155 bps (OC3) technology was installed between the West Los Angeles VA Medical Center and the Sepulveda VA, a large outpatient facility which provides full service radiological services. The West Los Angeles VA Medical Center is a large tertiary referral center with sub-specialist radiologist. The clinical impact of this ATM link between a large full-scale DICOM-3 compliant PACS system at the West LA VA on a smaller PACS system at the Sepulveda VA was evaluated. Results: The ability to freely exchange complicated MRI and CT studies between a tertiary referral center and a clinic could have a direct impact on patient care. Over the last six months, all and CT studies from Sepulveda VA were readily available via the ATM connection to all radiologists at the West LA VA. On average the workload at the Sepulveda VA in CT and MRI was about one tenth of the same workload at West LA VA, thus creating interesting possibilities for sharing or radiologist resources. Conclusions: Although our preliminary data and work loads have been too limited to draw any final conclusions yet, we feel that future results will show that the ability to provide immediate and fast interactive consultation between general radiologists in a large outpatient facility and sub- specialists at a tertiary referral center can have an impact upon the quality of patient care.

  12. Genome stability of Arabidopsis atm, ku80 and rad51b mutants: somatic and transgenerational responses to stress.

    PubMed

    Yao, Youli; Bilichak, Andriy; Titov, Viktor; Golubov, Andrey; Kovalchuk, Igor

    2013-06-01

    DNA double-strand breaks (DSBs) can be repaired via two main mechanisms: non-homologous end joining (NHEJ) and homologous recombination (HR). Our previous work showed that exposure to abiotic stresses resulted in an increase in point mutation frequency (PMF) and homologous recombination frequency (HRF), and these changes were heritable. We hypothesized that mutants impaired in DSB recognition and repair would also be deficient in somatic and transgenerational changes in PMF and HRF. To test this hypothesis, we analyzed the genome stability of the Arabidopsis thaliana mutants deficient in ATM (communication between DNA strand break recognition and the repair machinery), KU80 (deficient in NHEJ) and RAD51B (deficient in HR repair) genes. We found that all three mutants exhibited higher levels of DSBs. Plants impaired in ATM had a lower spontaneous PMF and HRF, whereas ku80 plants had higher frequencies. Plants impaired in RAD51B had a lower HRF. HRF in wild-type, atm and rad51b plants increased in response to several abiotic stressors, whereas it did not increase in ku80 plants. The progeny of stressed wild-type and ku80 plants exhibited an increase in HRF in response to all stresses, and the increase was higher in ku80 plants. The progeny of atm plants showed an increase in HRF only when the parental generation was exposed to cold or flood, whereas the progeny of rad51b plants completely lacked a transgenerational increase in HRF. Our experiments showed that mutants impaired in the recognition and repair of DSBs exhibited changes in the efficiency of DNA repair as reflected by changes in strand breaks, point mutation and HRF. They also showed that the HR RAD51B protein and the protein ATM that recognized damaged DNA might play an important role in transgenerational changes in HRF.

  13. ATM Polymorphisms Predict Severe Radiation Pneumonitis in Patients With Non-Small Cell Lung Cancer Treated With Definitive Radiation Therapy

    SciTech Connect

    Xiong, Huihua; Liao, Zhongxing; Liu, Zhensheng; Xu, Ting; Wang, Qiming; Liu, Hongliang; Komaki, Ritsuko; Gomez, Daniel; Wang, Li-E; Wei, Qingyi

    2013-03-15

    Purpose: The ataxia telangiectasia mutated (ATM) gene mediates detection and repair of DNA damage. We investigated associations between ATM polymorphisms and severe radiation-induced pneumonitis (RP). Methods and Materials: We genotyped 3 potentially functional single nucleotide polymorphisms (SNPs) of ATM (rs1801516 [D1853N/5557G>A], rs189037 [-111G>A] and rs228590) in 362 patients with non-small cell lung cancer (NSCLC), who received definitive (chemo)radiation therapy. The cumulative severe RP probabilities by genotypes were evaluated using the Kaplan-Meier analysis. The associations between severe RP risk and genotypes were assessed by both logistic regression analysis and Cox proportional hazard model with time to event considered. Results: Of 362 patients (72.4% of non-Hispanic whites), 56 (15.5%) experienced grade ≥3 RP. Patients carrying ATM rs189037 AG/GG or rs228590 TT/CT genotypes or rs189037G/rs228590T/rs1801516G (G-T-G) haplotype had a lower risk of severe RP (rs189037: GG/AG vs AA, adjusted hazard ratio [HR] = 0.49, 95% confidence interval [CI], 0.29-0.83, P=.009; rs228590: TT/CT vs CC, HR=0.57, 95% CI, 0.33-0.97, P=.036; haplotype: G-T-G vs A-C-G, HR=0.52, 95% CI, 0.35-0.79, P=.002). Such positive findings remained in non-Hispanic whites. Conclusions: ATM polymorphisms may serve as biomarkers for susceptibility to severe RP in non-Hispanic whites. Large prospective studies are required to confirm our findings.

  14. Advanced oxidation protein products induce intestine epithelial cell death through a redox-dependent, c-jun N-terminal kinase and poly (ADP-ribose) polymerase-1-mediated pathway.

    PubMed

    Xie, F; Sun, S; Xu, A; Zheng, S; Xue, M; Wu, P; Zeng, J H; Bai, L

    2014-01-16

    Advanced oxidation protein products (AOPPs), a novel protein marker of oxidative damage, have been confirmed to accumulate in patients with inflammatory bowel disease (IBD), as well as those with diabetes and chronic kidney disease. However, the role of AOPPs in the intestinal epithelium remains unclear. This study was designed to investigate whether AOPPs have an effect on intestinal epithelial cell (IEC) death and intestinal injury. Immortalized rat intestinal epithelial (IEC-6) cells and normal Sprague Dawley rats were treated with AOPP-albumin prepared by incubation of rat serum albumin (RSA) with hypochlorous acid. Epithelial cell death, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit activity, reactive oxygen species (ROS) generation, apoptosis-related protein expression, and c-jun N-terminal kinase (JNK) phosphorylation were detected both in vivo and in vitro. In addition, we measured AOPPs deposition and IEC death in 23 subjects with Crohn's disease (CD). Extracellular AOPP-RSA accumulation induced apoptosis in IEC-6 cultures. The triggering effect of AOPPs was mainly mediated by a redox-dependent pathway, including NADPH oxidase-derived ROS generation, JNK phosphorylation, and poly (ADP-ribose) polymerase-1 (PARP-1) activation. Chronic AOPP-RSA administration to normal rats resulted in AOPPs deposition in the villous epithelial cells and in inflammatory cells in the lamina propria. These changes were companied with IEC death, inflammatory cellular infiltration, and intestinal injury. Both cell death and intestinal injury were ameliorated by chronic treatment with apocynin. Furthermore, AOPPs deposition was also observed in IECs and inflammatory cells in the lamina propria of patients with CD. The high immunoreactive score of AOPPs showed increased apoptosis. Our results demonstrate that AOPPs trigger IEC death and intestinal tissue injury via a redox-mediated pathway. These data suggest that AOPPs may represent a novel pathogenic factor

  15. The role of hydrogen peroxide and nitric oxide in the induction of plant-encoded RNA-dependent RNA polymerase 1 in the basal defense against Tobacco mosaic virus.

    PubMed

    Liao, Yang-Wen-Ke; Sun, Zeng-Hui; Zhou, Yan-Hong; Shi, Kai; Li, Xin; Zhang, Guan-Qun; Xia, Xiao-Jian; Chen, Zhi-Xiang; Yu, Jing-Quan

    2013-01-01

    Plant RNA-dependent RNA Polymerase 1 (RDR1) is an important element of the RNA silencing pathway in the plant defense against viruses. RDR1 expression can be elicited by viral infection and salicylic acid (SA), but the mechanisms of signaling during this process remains undefined. The involvement of hydrogen peroxide (H2O2) and nitric oxide (NO) in RDR1 induction in the compatible interactions between Tobacco mosaic tobamovirus (TMV) and Nicotiana tabacum, Nicotiana benthamiana, and Arabidopsis thaliana was examined. TMV inoculation onto the lower leaves of N. tabacum induced the rapid accumulation of H2O2 and NO followed by the increased accumulation of RDR1 transcripts in the non-inoculated upper leaves. Pretreatment with exogenous H2O2 and NO on upper leaf led to increased RDR1 expression and systemic TMV resistance. Conversely, dimethylthiourea (an H2O2 scavenger) and 2-(4-carboxyphenyl)- 4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (an NO scavenger) partly blocked TMV- and SA-induced RDR1 expression and increased TMV susceptibility, whereas pretreatment with exogenous H2O2 and NO failed to diminish TMV infection in N. benthamiana plants with naturally occurring RDR1 loss-of-function. Furthermore, in N. tabacum and A. thaliana, TMV-induced H2O2 accumulation was NO-dependent, whereas NO generation was not affected by H2O2. These results suggest that, in response to TMV infection, H2O2 acts downstream of NO to mediate induction of RDR1, which plays a critical role in strengthening RNA silencing to restrict systemic viral infection.

  16. The Aspergillus nidulans uvsB gene encodes an ATM-related kinase required for multiple facets of the DNA damage response.

    PubMed Central

    Hofmann, A F; Harris, S D

    2000-01-01

    In Aspergillus nidulans, uvsB and uvsD belong to the same epistasis group of DNA repair mutants. Recent observations suggest that these genes are likely to control cell cycle checkpoint responses to DNA damage and incomplete replication. Consistent with this notion, we show here that UVSB is a member of the conserved family of ATM-related kinases. Phenotypic characterization of uvsB mutants shows that they possess defects in additional aspects of the DNA damage response besides checkpoint control, including inhibition of septum formation, regulation of gene expression, and induced mutagenesis. The musN227 mutation partially suppresses the poor growth and DNA damage sensitivity of uvsB mutants. Although musN227 partially suppresses several uvsB defects, it does not restore checkpoint function to uvsB mutants. Notably, the failure of uvsB mutants to restrain septum formation in the presence of DNA damage is suppressed by the musN227 mutation. We propose that UVSB functions as the central regulator of the A. nidulans DNA damage response, whereas MUSN promotes recovery by modulating a subset of the response. PMID:10747054

  17. Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer.

    PubMed

    Menendez, Javier A; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Martin-Castillo, Begoña; Joven, Jorge; Vellon, Luciano; Vazquez-Martin, Alejandro

    2011-11-01

    By activating the ataxia telangiectasia mutated (ATM)-mediated DNA Damage Response (DDR), the AMPK agonist metformin might sensitize cells against further damage, thus mimicking the precancerous stimulus that induces an intrinsic barrier against carcinogenesis. Herein, we present the new hypothesis that metformin might function as a tissue sweeper of pre-malignant cells before they gain stem cell/tumor initiating properties. Because enhanced glycolysis (the Warburg effect) plays a causal role in the gain of stem-like properties of tumor-initiating cells by protecting them from the pro-senescent effects of mitochondrial respiration-induced oxidative stress, metformin's ability to disrupt the glycolytic metabotype may generate a cellular phenotype that is metabolically protected against immortalization. The bioenergetic crisis imposed by metformin, which may involve enhanced mitochondrial biogenesis and oxidative stress, can lower the threshold for cellular senescence by pre-activating an ATM-dependent pseudo-DDR. This allows an accelerated onset of cellular senescence in response to additional oncogenic stresses. By pushing cancer cells to use oxidative phosphorylation instead of glycolysis, metformin can rescue cell surface major histocompatibility complex class I (MHC-I) expression that is downregulated by oncogenic transformation, a crucial adaptation of tumor cells to avoid the adaptive immune response by cytotoxic T-lymphocytes (CTLs). Aside from restoration of tumor immunosurveillance at the cell-autonomous level, metformin can activate a senescence-associated secretory phenotype (SASP) to reinforce senescence growth arrest, which might trigger an immune-mediated clearance of the senescent cells in a non-cell-autonomous manner. By diminishing the probability of escape from the senescence anti-tumor barrier, the net effect of metformin should be a significant decrease in the accumulation of dysfunctional, pre-malignant cells in tissues, including those with the

  18. Low Ki67/high ATM protein expression in malignant tumors predicts favorable prognosis in a retrospective study of early stage hormone receptor positive breast cancer

    PubMed Central

    Feng, Xiaolan; Li, Haocheng; Kornaga, Elizabeth N.; Dean, Michelle; Lees-Miller, Susan P.; Riabowol, Karl; Magliocco, Anthony M.; Morris, Don; Watson, Peter H.; Enwere, Emeka K.; Bebb, Gwyn; Paterson, Alexander

    2016-01-01

    Introduction This study was designed to investigate the combined influence of ATM and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (< 4 cm) and fewer than four positive lymph nodes. Methods 532 formalin-fixed paraffin-embedded specimens of resected primary breast tumors were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using fluorescence and brightfield immunohistochemistry respectively, and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome. Results Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up (p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively (p = 0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status (p = 0.02). Conclusions These data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC. PMID:27741524

  19. Simultaneous depletion of Atm and Mdl rebalances cytosolic Fe-S cluster assembly but not heme import into the mitochondrion of Trypanosoma brucei.

    PubMed

    Horáková, Eva; Changmai, Piya; Paris, Zdeněk; Salmon, Didier; Lukeš, Julius

    2015-11-01

    ABC transporter mitochondrial 1 (Atm1) and multidrug resistance-like 1 (Mdl) are mitochondrial ABC transporters. Although Atm1 was recently suggested to transport different forms of glutathione from the mitochondrion, which are used for iron-sulfur (Fe-S) cluster maturation in the cytosol, the function of Mdl remains elusive. In Trypanosoma brucei, we identified one homolog of each of these genes, TbAtm and TbMdl, which were downregulated either separately or simultaneously using RNA interference. Individual depletion of TbAtm and TbMdl led to limited growth defects. In cells downregulated for TbAtm, the enzymatic activities of the Fe-S cluster proteins aconitase and fumarase significantly decreased in the cytosol but not in the mitochondrion. Downregulation of TbMdl did not cause any change in activities of the Fe-S proteins. Unexpectedly, the simultaneous downregulation of TbAtm and TbMdl did not result in any growth defect, nor were the Fe-S cluster protein activities altered in either the cytosolic or mitochondrial compartments. Additionally, TbAtm and TbMdl were able to partially restore the growth of the Saccharomyces cerevisiae Δatm1 and Δmdl2 null mutants, respectively. Because T. brucei completely lost the heme b biosynthesis pathway, this cofactor has to be obtained from the host. Based on our results, TbMdl is a candidate for mitochondrial import of heme b, which was markedly decreased in both TbMdl and TbAtm + TbMdl knockdowns. Moreover, the levels of heme a were strongly decreased in the same knockdowns, suggesting that TbMdl plays a key role in heme a biosynthesis, thus affecting the overall heme homeostasis in T. brucei.

  20. Gamma-radiation-induced ATM-dependent signalling in human T-lymphocyte leukemic cells, MOLT-4.

    PubMed

    Tichý, Ales; Záskodová, Darina; Rezácová, Martina; Vávrová, Jirina; Vokurková, Doris; Pejchal, Jaroslav; Vilasová, Zdena; Cerman, Jaroslav; Osterreicher, Jan

    2007-01-01

    ATM kinase (ATM) is essential for activation of cell cycle check points and DNA repair in response to ionizing radiation (IR). In this work we studied the molecular mechanisms regulating DNA repair and cell death in human T-lymphocyte leukemic cells, MOLT-4. Apoptosis was evaluated by flow-cytometric detection of annexin V. Early apoptotic cells were determined as sub-G1 cells and late apoptotic cells were determined as APO2.7-positive ones. Proteins involved in ATM signalling pathway were analysed by Western-blotting. We observed a rapid (0.5 h) phosphorylation of ATM declining after 6 h after irradiation by all the doses studied (1.5, 3.0, and 7.5 Gy). Checkpoint kinase-2 (Chk-2) was also phosphorylated after 0.5 h but its phosphorylated form persisted 4, 2, and 1 h after the doses of 1.5, 3.0, and 7.5 Gy, respectively. The amount of p53 protein and its form phosphorylated on Ser-392 increased 1 h after irradiation (1-10 Gy). The lethal dose of 7.5 Gy caused an immediate induction and phosphorylation of p53 after 0.5 h post-irradiation. At the time of phosphorylation of p53, we found simultaneous phosphorylation of the oncoprotein Mdm2 on Ser-166. Neither ATM nor its downstream targets showed a dose-dependent response after 1 h when irradiated by the doses of 1-10 Gy. MOLT-4 cells were very sensitive to the effect of IR. Even low doses, such as 1.5 Gy, induced apoptosis 16 h after irradiation (evaluated according to the cleavage of nuclear lamin B to a 48-kDa fragment). IR-induced molecular signalling after exposure to all the tested doses was triggered by rapid phosphorylation of ATM and Chk-2. Subsequent induction of p53 protein and its phosphorylation was accompanied by concomitant phosphorylation of its negative regulator, oncoprotein Mdm2, and followed by induction of apoptosis.

  1. Distributed medical services within the ATM-based Berlin regional test bed

    NASA Astrophysics Data System (ADS)

    Thiel, Andreas; Bernarding, Johannes; Krauss, Manfred; Schulz, Sandra; Tolxdorff, Thomas

    1996-05-01

    The ATM-based Metropolitan Area Network (MAN) of Berlin connects two university hospitals (Benjamin Franklin University Hospital and Charite) with the computer resources of the Technical University of Berlin (TUB). Distributed new medical services have been implemented and will be evaluated within the highspeed MAN of Berlin. The network with its data transmission rates of up to 155 Mbit/s renders these medical services externally available to practicing physicians. Resource and application sharing is demonstrated by the use of two software systems. The first software system is an interactive 3D reconstruction tool (3D- Medbild), based on a client-server mechanism. This structure allows the use of high- performance computers at the TUB from the low-level workstations in the hospitals. A second software system, RAMSES, utilizes a tissue database of Magnetic Resonance Images. For the remote control of the software, the developed applications use standards such as DICOM 3.0 and features of the World Wide Web. Data security concepts are being tested and integrated for the needs of the sensitive medical data. The highspeed network is the necessary prerequisite for the clinical evaluation of data in a joint teleconference. The transmission of digitized real-time sequences such as video and ultrasound and the interactive manipulation of data are made possible by Multi Media tools.

  2. Tele-ultrasound using ATM over a T-1 satellite connection

    NASA Astrophysics Data System (ADS)

    Williamson, Morgan P.; Suitor, Charles T.; de Treville, Robert E.; Freckleton, Michael W.; Kinsey, Van; Goeringer, Fred; Lyche, David K.; Hunter, Bruce; Jennings, Neal E.; Shelton, Philip D.; Marcy, Jon; Poore, Tom; North, Jack

    1996-04-01

    In September 1995 the United States military conducted a demonstration project to provide live ultrasound video and diagnostic DICOM still images using GTE's asynchronous transfer mode (ATM) technologies over an Orion T-1 satellite link. Still images were frame-grabbed from a Diasonics ultrasound and sent to the ALI Wide Area Network system. A group of diagnostic images was then sent in DICOM 3.0 format over a virtual ethernet satellite link from Chantilly, Virginia to Dayton, Ohio. These images came across a DICOM gateway into the Medical Diagnostic Imaging Support (MDIS) System. Live video from the ultrasound was also routed through a CLI Radiance VTC over the satellite to a VTC in Ohio. The video bandwidth was progressively narrowed with two radiologists determining the minimal acceptable bandwidth for detecting test objects in a phantom. The radiologists accepted live video ultrasound at bandwidths as low as 384 kbps from the hands of an experienced ultrasonographer located hundreds of miles away. DICOM still images were sent uncompressed and were of acceptable image quality when viewed on the MDIS system. The technology demonstrated holds great promise for both deployed U.S. Military Forces and civil uses of remote radiology. Detailed network drawings and videotapes of the ultrasound examinations at the remote site are provided.

  3. The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways.

    PubMed

    Sobeck, Alexandra; Stone, Stacie; Landais, Igor; de Graaf, Bendert; Hoatlin, Maureen E

    2009-09-18

    Genomic stability requires a functional Fanconi anemia (FA) pathway composed of an upstream "core complex" (FA proteins A/B/C/E/F/G/L/M) that mediates monoubiquitination of the downstream targets FANCD2 and FANCI. Unique among FA core complex members, FANCM has processing activities toward replication-associated DNA structures, suggesting a vital role for FANCM during replication. Using Xenopus egg extracts, we analyzed the functions of FANCM in replication and the DNA damage response. xFANCM binds chromatin in a replication-dependent manner and is phosphorylated in response to DNA damage structures. Chromatin binding and DNA damage-induced phosphorylation of xFANCM are mediated in part by the downstream FA pathway protein FANCD2. Moreover, phosphorylation and chromatin recruitment of FANCM is regulated by two mayor players in the DNA damage response: the cell cycle checkpoint kinases ATR and ATM. Our results indicate that functions of FANCM are controlled by FA- and non-FA pathways in the DNA damage response.

  4. Buffer allocation in an ATM switch with output buffer and speed constraints

    NASA Astrophysics Data System (ADS)

    Gupta, Anil K.; Georganas, N. D.

    A synchronous nonblocking N times N switch for asynchronous transfer mode (ATM) networks or high speed packet switching networks transporting fixed length packets called cells is considered. Such a switch with output queuing achieves the optimal performance, however it requires the switch fabric to work at the speed of N. In practice the switch may operate L times faster than the input/output trunk. It is assumed that queues at each output port have a limited buffer space and whenever an output queue is full, the back-pressure is applied and the packets are retained at the head of the input queues. The upper bound on the packet loss probability at the input queues in such a switch are computed. To achieve a given packet loss rate, the switch with L equals 2 requires almost the same amount of input and output buffers as with L equals 4 up to 70 percent input load, but as the load increases beyond 70 percent the switch with L equals 4 would require more output buffers and less input buffers in comparison with a switch operating at L equals 2. The performance of a switch with L equals 3 is very similar to that for L equals 4 and is not considered.

  5. Results from CrIS/ATMS Obtained Using an AIRS "Version-6 like" Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena

    2015-01-01

    We tested and evaluated Version-6.22 AIRS and Version-6.22 CrIS products on a single day, December 4, 2013, and compared results to those derived using AIRS Version-6. AIRS and CrIS Version-6.22 O3(p) and q(p) products are both superior to those of AIRS Version-6All AIRS and CrIS products agree reasonably well with each other. CrIS Version-6.22 T(p) and q(p) results are slightly poorer than AIRS over land, especially under very cloudy conditions. Both AIRS and CrIS Version-6.22 run now at JPL. Our short term plans are to analyze many common months at JPL in the near future using Version-6.22 or a further improved algorithm to assess the compatibility of AIRS and CrIS monthly mean products and their interannual differences. Updates to the calibration of both CrIS and ATMS are still being finalized. JPL plans, in collaboration with the Goddard DISC, to reprocess all AIRS data using a still to be finalized Version-7 retrieval algorithm, and to reprocess all recalibrated CrISATMS data using Version-7 as well.

  6. Results from CrIS/ATMS Obtained Using an AIRS "Version-6 Like" Retrieval Algorithm

    NASA Technical Reports Server (NTRS)

    Susskind, Joel; Kouvaris, Louis; Iredell, Lena

    2015-01-01

    We have tested and evaluated Version-6.22 AIRS and Version-6.22 CrIS products on a single day, December 4, 2013, and compared results to those derived using AIRS Version-6. AIRS and CrIS Version-6.22 O3(p) and q(p) products are both superior to those of AIRS Version-6All AIRS and CrIS products agree reasonably well with each other CrIS Version-6.22 T(p) and q(p) results are slightly poorer than AIRS under very cloudy conditions. Both AIRS and CrIS Version-6.22 run now at JPL. Our short term plans are to analyze many common months at JPL in the near future using Version-6.22 or a further improved algorithm to assess the compatibility of AIRS and CrIS monthly mean products and their interannual differencesUpdates to the calibration of both CrIS and ATMS are still being finalized. JPL plans, in collaboration with the Goddard DISC, to reprocess all AIRS data using a still to be finalized Version-7 retrieval algorithm, and to reprocess all recalibrated CrISATMS data using Version-7 as well.

  7. A new type of mutation causes a splicing defect in ATM.

    PubMed

    Pagani, Franco; Buratti, Emanuele; Stuani, Cristiana; Bendix, Regina; Dörk, Thilo; Baralle, Francisco E

    2002-04-01

    Disease-causing splicing mutations described in the literature primarily produce changes in splice sites and, to a lesser extent, variations in exon-regulatory sequences such as the enhancer elements. The gene ATM is mutated in individuals with ataxia-telangiectasia; we have identified the aberrant inclusion of a cryptic exon of 65 bp in one affected individual with a deletion of four nucleotides (GTAA) in intron 20. The deletion is located 12 bp downstream and 53 bp upstream from the 5' and 3' ends of the cryptic exon, respectively. Through analysis of the splicing defect using a hybrid minigene system, we identified a new intron-splicing processing element (ISPE) complementary to U1 snRNA, the RNA component of the U1 small nuclear ribonucleoprotein (snRNP). This element mediates accurate intron processing and interacts specifically with U1 snRNP particles. The 4-nt deletion completely abolished this interaction, causing activation of the cryptic exon. On the basis of this analysis, we describe a new type of U1 snRNP binding site in an intron that is essential for accurate intron removal. Deletion of this sequence is directly involved in the splicing processing defect.

  8. An Alu-derived intronic splicing enhancer facilitates intronic processing and modulates aberrant splicing in ATM.

    PubMed

    Pastor, Tibor; Talotti, Gabriele; Lewandowska, Marzena Anna; Pagani, Franco

    2009-11-01

    We have previously reported a natural GTAA deletion within an intronic splicing processing element (ISPE) of the ataxia telangiectasia mutated (ATM) gene that disrupts a non-canonical U1 snRNP interaction and activates the excision of the upstream portion of the intron. The resulting pre-mRNA splicing intermediate is then processed to a cryptic exon, whose aberrant inclusion in the final mRNA is responsible for ataxia telangiectasia. We show here that the last 40 bases of a downstream intronic antisense Alu repeat are required for the activation of the cryptic exon by the ISPE deletion. Evaluation of the pre-mRNA splicing intermediate by a hybrid minigene assay indicates that the identified intronic splicing enhancer represents a novel class of enhancers that facilitates processing of splicing intermediates possibly by recruiting U1 snRNP to defective donor sites. In the absence of this element, the splicing intermediate accumulates and is not further processed to generate the cryptic exon. Our results indicate that Alu-derived sequences can provide intronic splicing regulatory elements that facilitate pre-mRNA processing and potentially affect the severity of disease-causing splicing mutations.

  9. Reduced cost alternatives to premise wiring using ATM and microcellular technologies

    NASA Technical Reports Server (NTRS)

    Gejji, Raghvendra R.

    1993-01-01

    The cost of premises wiring keeps increasing due to personnel moves, new equipment, capacity upgrades etc. It would be desirable to have a wireless interface from the workstations to the fixed network, so as to minimize the wiring changes needed. New technologies such as microcellular personal communication systems are promising to bring down the cost of wireless communication. Another promising technology is Code Division Multiple Access (CDMA), which could dramatically increase the bandwidth available for wireless connections. In addition, Asynchronous Transfer Mode (ATM) technology is emerging as a technique for integrated management of voice, data, and video traffic on a single network. The focus of this investigation will be to assess the future utility of these new technologies for reducing the premise wiring cost at KSC. One of the issues to be studied is the cost comparison of 'old' versus 'new,' especially as time and technology progress. An additional issue for closer study is a feasible time-line for progress in technological capability.