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ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response 总被引:48,自引:0,他引:48
Wu X Ranganathan V Weisman DS Heine WF Ciccone DN O'Neill TB Crick KE Pierce KA Lane WS Rathbun G Livingston DM Weaver DT 《Nature》2000,405(6785):477-482
Nijmegen breakage syndrome (NBS) is characterized by extreme radiation sensitivity, chromosomal instability and cancer. The phenotypes are similar to those of ataxia telangiectasia mutated (ATM) disease, where there is a deficiency in a protein kinase that is activated by DNA damage, indicating that the Nbs and Atm proteins may participate in common pathways. Here we report that Nbs is specifically phosphorylated in response to gamma-radiation, ultraviolet light and exposure to hydroxyurea. Phosphorylation of Nbs mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, Nbs was phosphorylated on many serine residues, of which S343, S397 and S615 were phosphorylated by Atm in vitro. At least two of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated Atm-dependent phosphorylation. Reconstituting NBS cells with a mutant form of Nbs that cannot be phosphorylated at selected, ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. Thus, phosphorylation of Nbs by Atm is critical for certain responses of human cells to DNA damage. 相似文献
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艾摩尔 《华东师范大学学报(自然科学版)》2004,2004(1):40-44
在二次损失函数下,作者研究了多元线性模型协方差矩阵的MINQUE估计和简单估计的比较问题,其中多元线性模型的设计矩阵和离散矩阵可以不满秩,得到了一个充分和必要条件。 相似文献
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Crow YJ Hayward BE Parmar R Robins P Leitch A Ali M Black DN van Bokhoven H Brunner HG Hamel BC Corry PC Cowan FM Frints SG Klepper J Livingston JH Lynch SA Massey RF Meritet JF Michaud JL Ponsot G Voit T Lebon P Bonthron DT Jackson AP Barnes DE Lindahl T 《Nature genetics》2006,38(8):917-920
Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response. 相似文献
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Xia B Dorsman JC Ameziane N de Vries Y Rooimans MA Sheng Q Pals G Errami A Gluckman E Llera J Wang W Livingston DM Joenje H de Winter JP 《Nature genetics》2007,39(2):159-161
The Fanconi anemia and BRCA networks are considered interconnected, as BRCA2 gene defects have been discovered in individuals with Fanconi anemia subtype D1. Here we show that a defect in the BRCA2-interacting protein PALB2 is associated with Fanconi anemia in an individual with a new subtype. PALB2-deficient cells showed hypersensitivity to cross-linking agents and lacked chromatin-bound BRCA2; these defects were corrected upon ectopic expression of PALB2 or by spontaneous reversion. 相似文献
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心肌宁冲剂按1.75g/kg,0.875g/kg剂量,每天早晚分两次灌胃给药,连续7天,均能明显对抗垂体后叶素所诱发的大鼠急性心肌缺血的心电图改变。 相似文献
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A recurrent mutation in PALB2 in Finnish cancer families 总被引:1,自引:0,他引:1
Erkko H Xia B Nikkilä J Schleutker J Syrjäkoski K Mannermaa A Kallioniemi A Pylkäs K Karppinen SM Rapakko K Miron A Sheng Q Li G Mattila H Bell DW Haber DA Grip M Reiman M Jukkola-Vuorinen A Mustonen A Kere J Aaltonen LA Kosma VM Kataja V Soini Y Drapkin RI Livingston DM Winqvist R 《Nature》2007,446(7133):316-319
BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified. The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development. 相似文献
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New records for bushy-tailed wood rat ( Neotoma cinerea ) on the White Mountains of eastern California increase the elevation from which this animal is known on the White Mountains, outside of human habitation, from 3,120 to 3,648 m. These records, coupled with archaeological data, suggest that the isolated bouldery outcrops occupied by bushy-tailed wood rats above timberline here are true habitat islands, occasionally colonized by dispersing individuals and characterized by frequent local extinction. 相似文献
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Infectious C-type virus isolated from a baboon placenta 总被引:60,自引:0,他引:60
R E Benveniste M M Lieber D M Livingston C J Sherr G J Todaro S S Kalter 《Nature》1974,248(443):17-20
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该文通过34只罗猴头颈实验研究,从中决定罗猴的颅脑损伤容限.当颅脑受到冲击时,颅壳发生局部变形瞬间,大脑亦发生变形,致使颅内压升高.利用这些结果来确定它的损伤机制,以模拟宇航员在冲击载荷下的创伤分析模型,将有助于进行临床创伤治疗和宇航弹射时的防护. 相似文献