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31.
A large-scale RNAi screen in human cells identifies new components of the p53 pathway 总被引:3,自引:0,他引:3
Berns K Hijmans EM Mullenders J Brummelkamp TR Velds A Heimerikx M Kerkhoven RM Madiredjo M Nijkamp W Weigelt B Agami R Ge W Cavet G Linsley PS Beijersbergen RL Bernards R 《Nature》2004,428(6981):431-437
RNA interference (RNAi) is a powerful new tool with which to perform loss-of-function genetic screens in lower organisms and can greatly facilitate the identification of components of cellular signalling pathways. In mammalian cells, such screens have been hampered by a lack of suitable tools that can be used on a large scale. We and others have recently developed expression vectors to direct the synthesis of short hairpin RNAs (shRNAs) that act as short interfering RNA (siRNA)-like molecules to stably suppress gene expression. Here we report the construction of a set of retroviral vectors encoding 23,742 distinct shRNAs, which target 7,914 different human genes for suppression. We use this RNAi library in human cells to identify one known and five new modulators of p53-dependent proliferation arrest. Suppression of these genes confers resistance to both p53-dependent and p19ARF-dependent proliferation arrest, and abolishes a DNA-damage-induced G1 cell-cycle arrest. Furthermore, we describe siRNA bar-code screens to rapidly identify individual siRNA vectors associated with a specific phenotype. These new tools will greatly facilitate large-scale loss-of-function genetic screens in mammalian cells. 相似文献
32.
LKB1 modulates lung cancer differentiation and metastasis 总被引:1,自引:0,他引:1
Ji H Ramsey MR Hayes DN Fan C McNamara K Kozlowski P Torrice C Wu MC Shimamura T Perera SA Liang MC Cai D Naumov GN Bao L Contreras CM Li D Chen L Krishnamurthy J Koivunen J Chirieac LR Padera RF Bronson RT Lindeman NI Christiani DC Lin X Shapiro GI Jänne PA Johnson BE Meyerson M Kwiatkowski DJ Castrillon DH Bardeesy N Sharpless NE Wong KK 《Nature》2007,448(7155):807-810
Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis. 相似文献
33.
The genome of woodland strawberry (Fragaria vesca) 总被引:3,自引:0,他引:3
Shulaev V Sargent DJ Crowhurst RN Mockler TC Folkerts O Delcher AL Jaiswal P Mockaitis K Liston A Mane SP Burns P Davis TM Slovin JP Bassil N Hellens RP Evans C Harkins T Kodira C Desany B Crasta OR Jensen RV Allan AC Michael TP Setubal JC Celton JM Rees DJ Williams KP Holt SH Ruiz Rojas JJ Chatterjee M Liu B Silva H Meisel L Adato A Filichkin SA Troggio M Viola R Ashman TL Wang H Dharmawardhana P Elser J Raja R Priest HD Bryant DW Fox SE Givan SA Wilhelm LJ Naithani S Christoffels A Salama DY 《Nature genetics》2011,43(2):109-116
34.
Müller T Hess MW Schiefermeier N Pfaller K Ebner HL Heinz-Erian P Ponstingl H Partsch J Röllinghoff B Köhler H Berger T Lenhartz H Schlenck B Houwen RJ Taylor CJ Zoller H Lechner S Goulet O Utermann G Ruemmele FM Huber LA Janecke AR 《Nature genetics》2008,40(10):1163-1165
Following homozygosity mapping in a single kindred, we identified nonsense and missense mutations in MYO5B, encoding type Vb myosin motor protein, in individuals with microvillus inclusion disease (MVID). MVID is characterized by lack of microvilli on the surface of enterocytes and occurrence of intracellular vacuolar structures containing microvilli. In addition, mislocalization of transferrin receptor in MVID enterocytes suggests that MYO5B deficiency causes defective trafficking of apical and basolateral proteins in MVID. 相似文献
35.
Genome sequencing reveals insights into physiology and longevity of the naked mole rat 总被引:1,自引:0,他引:1
Kim EB Fang X Fushan AA Huang Z Lobanov AV Han L Marino SM Sun X Turanov AA Yang P Yim SH Zhao X Kasaikina MV Stoletzki N Peng C Polak P Xiong Z Kiezun A Zhu Y Chen Y Kryukov GV Zhang Q Peshkin L Yang L Bronson RT Buffenstein R Wang B Han C Li Q Chen L Zhao W Sunyaev SR Park TJ Zhang G Wang J Gladyshev VN 《Nature》2011,479(7372):223-227
36.
Roderick V.N.MELNIK 《中国科学:技术科学》2010,(4)
Reversible large electric-field-induced strain caused by reversible orientation switchings in BaTiO3 is modeled using the Landau's theory of phase transition.A triple well free energy function is constructed.Each of its minima is associated with one of the polarization orientations involved.Nonlinear constitutive laws accounting for reversible orientation switchings and electrostriction effects are obtained by using thermodynamic equilibrium conditions.Hysteretic dynamics of onedimensional structures is des... 相似文献
37.
High-conductance voltage- and Ca(2+)-activated K(+) channels function in many physiological processes that link cell membrane voltage and intracellular Ca(2+) concentration, including neuronal electrical activity, skeletal and smooth muscle contraction, and hair cell tuning. Like other voltage-dependent K(+) channels, Ca(2+)-activated K(+) channels open when the cell membrane depolarizes, but in contrast to other voltage-dependent K(+) channels, they also open when intracellular Ca(2+) concentrations rise. Channel opening by Ca(2+) is made possible by a structure called the gating ring, which is located in the cytoplasm. Recent structural studies have defined the Ca(2+)-free, closed, conformation of the gating ring, but the Ca(2+)-bound, open, conformation is not yet known. Here we present the Ca(2+)-bound conformation of the gating ring. This structure shows how one layer of the gating ring, in response to the binding of Ca(2+), opens like the petals of a flower. The degree to which it opens explains how Ca(2+) binding can open the transmembrane pore. These findings present a molecular basis for Ca(2+) activation of K(+) channels and suggest new possibilities for targeting the gating ring to treat conditions such as asthma and hypertension. 相似文献
38.
Efficient generation and mapping of recessive developmental mutations using ENU mutagenesis 总被引:12,自引:0,他引:12
Herron BJ Lu W Rao C Liu S Peters H Bronson RT Justice MJ McDonald JD Beier DR 《Nature genetics》2002,30(2):185-189
Treatment with N-ethyl-N-nitrosourea (ENU) efficiently generates single-nucleotide mutations in mice. Along with the renewed interest in this approach, much attention has been given recently to large screens with broad aims; however, more finely focused studies have proven very productive as well. Here we show how mutagenesis together with genetic mapping can facilitate the rapid characterization of recessive loci required for normal embryonic development. We screened third-generation progeny of mutagenized mice at embryonic day (E) 18.5 for abnormalities of organogenesis. We ascertained 15 monogenic mutations in the 54 families that were comprehensively analyzed. We carried out the experiment as an outcross, which facilitated the genetic mapping of the mutations by haplotype analysis. We mapped seven of the mutations and identified the affected locus in two lines. Using a hierarchical approach, it is possible to maximize the efficiency of this analysis so that it can be carried out easily with modest infrastructure and resources. 相似文献
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40.
大叶白麻叶化学成分的研究 总被引:1,自引:0,他引:1
从大叶白麻[poacynumhendersonii(Hookf)woodson]叶中分得2个木脂素类化舍物,经理化常数测定和光谱分析,分别鉴定为(-)-丁香脂素[(-)-Syringaresino1]和( )-松脂素-4-O-β-D-葡萄糖甙[( )-Pinoresionol-4-0-β-D-glucopyranoside]. 相似文献