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排序方式: 共有138条查询结果,搜索用时 156 毫秒
61.
Crasta K Ganem NJ Dagher R Lantermann AB Ivanova EV Pan Y Nezi L Protopopov A Chowdhury D Pellman D 《Nature》2012,482(7383):53-58
The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement. 相似文献
62.
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups 总被引:1,自引:0,他引:1
Curtis C Shah SP Chin SF Turashvili G Rueda OM Dunning MJ Speed D Lynch AG Samarajiwa S Yuan Y Gräf S Ha G Haffari G Bashashati A Russell R McKinney S;METABRIC Group Langerød A Green A Provenzano E Wishart G Pinder S Watson P Markowetz F Murphy L Ellis I Purushotham A Børresen-Dale AL Brenton JD Tavaré S Caldas C Aparicio S 《Nature》2012,486(7403):346-352
63.
Berger MF Hodis E Heffernan TP Deribe YL Lawrence MS Protopopov A Ivanova E Watson IR Nickerson E Ghosh P Zhang H Zeid R Ren X Cibulskis K Sivachenko AY Wagle N Sucker A Sougnez C Onofrio R Ambrogio L Auclair D Fennell T Carter SL Drier Y Stojanov P Singer MA Voet D Jing R Saksena G Barretina J Ramos AH Pugh TJ Stransky N Parkin M Winckler W Mahan S Ardlie K Baldwin J Wargo J Schadendorf D Meyerson M Gabriel SB Golub TR Wagner SN Lander ES Getz G Chin L Garraway LA 《Nature》2012,485(7399):502-506
Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma. 相似文献
64.
Summary Amantadine, like amphetamine, exerts a depletory effect upon noradrenaline containing vesicles of the adrenal medulla. The microtubular system seems to play a role in the releasing process.The authors want to thank Dr. Diaz-Flores Feo for his help and advice in the accomplishment of this study. 相似文献
65.
The human APOBEC3G (apolipoprotein B messenger-RNA-editing enzyme, catalytic polypeptide-like 3G) protein is a single-strand DNA deaminase that inhibits the replication of human immunodeficiency virus-1 (HIV-1), other retroviruses and retrotransposons. APOBEC3G anti-viral activity is circumvented by most retroelements, such as through degradation by HIV-1 Vif. APOBEC3G is a member of a family of polynucleotide cytosine deaminases, several of which also target distinct physiological substrates. For instance, APOBEC1 edits APOB mRNA and AID deaminates antibody gene DNA. Although structures of other family members exist, none of these proteins has elicited polynucleotide cytosine deaminase or anti-viral activity. Here we report a solution structure of the human APOBEC3G catalytic domain. Five alpha-helices, including two that form the zinc-coordinating active site, are arranged over a hydrophobic platform consisting of five beta-strands. NMR DNA titration experiments, computational modelling, phylogenetic conservation and Escherichia coli-based activity assays combine to suggest a DNA-binding model in which a brim of positively charged residues positions the target cytosine for catalysis. The structure of the APOBEC3G catalytic domain will help us to understand functions of other family members and interactions that occur with pathogenic proteins such as HIV-1 Vif. 相似文献
66.
Elena Rapizzi Maria Letizia Taddei Tania Fiaschi Chiara Donati Paola Bruni Paola Chiarugi 《Cellular and molecular life sciences : CMLS》2009,66(19):3207-3218
Sphingosine 1-phosphate (S1P) is a bioactive lipid that acts through a family of G-protein-coupled receptors. Herein, we report
evidence of a novel redox-based cross-talk between S1P and insulin signaling pathways. In skeletal muscle cells S1P, through
engagement of its S1P2 receptor, is found to produce a transient burst of reactive oxygen species through a calcium-dependent activation of the
small GTPase Rac1. S1P-induced redox-signaling is sensed by protein tyrosine phosphatase-1B, the main negative regulator of
insulin receptor phosphorylation, which undergoes oxidation and enzymatic inhibition. This redox-based inhibition of the phosphatase
provokes a ligand-independent trans-phosphorylation of insulin receptor and a strong increase in glucose uptake. Our results propose a new role of S1P, recognizing
the lipid as an insulin-mimetic cue and pointing at reactive oxygen species as critical regulators of the cross-talk between
S1P and insulin pathways. Any possible implication of S1P-directed insulin signaling in diabetes and insulin resistance remains
to be established. 相似文献
67.
Abd El-Aziz MM Barragan I O'Driscoll CA Goodstadt L Prigmore E Borrego S Mena M Pieras JI El-Ashry MF Safieh LA Shah A Cheetham ME Carter NP Chakarova C Ponting CP Bhattacharya SS Antinolo G 《Nature genetics》2008,40(11):1285-1287
Using a positional cloning approach supported by comparative genomics, we have identified a previously unreported gene, EYS, at the RP25 locus on chromosome 6q12 commonly mutated in autosomal recessive retinitis pigmentosa. Spanning over 2 Mb, this is the largest eye-specific gene identified so far. EYS is independently disrupted in four other mammalian lineages, including that of rodents, but is well conserved from Drosophila to man and is likely to have a role in the modeling of retinal architecture. 相似文献
68.
Renna MD Oyadeyi AS Bossi E Kottra G Peres A 《Cellular and molecular life sciences : CMLS》2011,68(17):2961-2975
The functional and structural basis of reverse operation of PepT1 has been studied in Xenopus oocytes expressing the wild-type
and mutated forms of this protein. Using brief pulses from a negative holding potential, wild-type and Arg282 mutants exhibit
outward currents in the presence of Gly-Gln. The reversal potential of these currents is affected by both pH and substrate
concentration, confirming coupled transport in the wild type and in the mutants as well. Long-lasting voltage and current-clamp
experiments show that the outward currents are only temporary, and reflect accumulation and/or depletion effects near the
membrane. The ability to operate in reverse mode was confirmed in all isoforms by intracellular injection of substrate. The
role of Arg282 and Asp341 in the reverse transport was also investigated using charged substrates. Positive Lys-Gly (but not
Gly-Lys) showed enhanced transport currents in the Arg282 mutants. In contrast, negative Gly-Asp and Asp-Gly elicited modest
currents in all isoforms. 相似文献
69.