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排序方式: 共有1939条查询结果,搜索用时 531 毫秒
61.
Antoni Camins Javier G. Pizarro Daniel Alvira Javier Gutierrez-Cuesta Aurelio Vazquez de la Torre Jaume Folch Francesc X. Sureda Ester Verdaguer Felix Junyent Joaquín Jordán Isidre Ferrer Mercè Pallàs 《Cellular and molecular life sciences : CMLS》2010,67(22):3865-3882
In the present study we demonstrated that neurotoxin MPP+-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP+-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson’s disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G0/G1 cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP+ leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP+ and cell-cycle re-entry through retinoblastoma protein phosphorylation. 相似文献
62.
Alcázar R García AV Kronholm I de Meaux J Koornneef M Parker JE Reymond M 《Nature genetics》2010,42(12):1135-1139
Accumulation of genetic incompatibilities within species can lead to reproductive isolation and, potentially, speciation. In this study, we show that allelic variation at SRF3 (Strubbelig Receptor Family 3), encoding a receptor-like kinase, conditions the occurrence of incompatibility between Arabidopsis thaliana accessions. The geographical distribution of SRF3 alleles reveals that allelic forms causing epistatic incompatibility with a Landsberg erecta allele at the RPP1 resistance locus are present in A. thaliana accessions in central Asia. Incompatible SRF3 alleles condition for an enhanced early immune response to pathogens as compared to the resistance-dampening effect of compatible SRF3 forms in isogenic backgrounds. Variation in disease susceptibility suggests a basis for the molecular patterns of a recent selective sweep detected at the SRF3 locus in central Asian populations. 相似文献
63.
van der Meijden PE Feijge MA Swieringa F Gilio K Nergiz-Unal R Hamulyák K Heemskerk JW 《Cellular and molecular life sciences : CMLS》2012,69(20):3481-3492
The fibrin(ogen) receptor, integrin α(IIb)β(3), has a well-established role in platelet spreading, aggregation and clot retraction. How α(IIb)β(3) contributes to platelet-dependent coagulation is less well resolved. Here, we demonstrate that the potent suppressing effect of clinically used α(IIb)β(3) blockers on tissue factor-induced thrombin generation is linked to diminished platelet Ca(2+) responses and phosphatidylserine (PS) exposure. The same blockers suppress these responses in platelets stimulated with collagen and thrombin receptor agonists, whereas added fibrinogen potentiates these responses. In platelets spreading on fibrinogen, outside-in α(IIb)β(3) signaling similarly enhances thrombin-induced Ca(2+) rises and PS exposure. These responses are reduced in α(IIb)β(3)-deficient platelets from patients with Glanzmann's thrombasthenia. Furthermore, the contribution of α(IIb)β(3) to tissue factor-induced platelet Ca(2+) rises, PS exposure and thrombin generation in plasma are fully dependent on Syk kinase activity. Tyrosine phosphorylation analysis confirms a key role of Syk activation, which is largely but not exclusively dependent on α(IIb)β(3) activation. It is concluded that the majority of tissue factor-induced procoagulant activity of platelets relies on Syk activation and ensuing Ca(2+) signal generation, and furthermore that a considerable part of Syk activation relies on α(IIb)β(3) signaling. These results hence point to a novel role of Syk in integrin-dependent thrombin generation. 相似文献
64.
Postel-Vinay S Véron AS Tirode F Pierron G Reynaud S Kovar H Oberlin O Lapouble E Ballet S Lucchesi C Kontny U González-Neira A Picci P Alonso J Patino-Garcia A de Paillerets BB Laud K Dina C Froguel P Clavel-Chapelon F Doz F Michon J Chanock SJ Thomas G Cox DG Delattre O 《Nature genetics》2012,44(3):323-327
Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2. 相似文献
65.
A mixed-model approach for genome-wide association studies of correlated traits in structured populations 总被引:1,自引:0,他引:1
Genome-wide association studies (GWAS) are a standard approach for studying the genetics of natural variation. A major concern in GWAS is the need to account for the complicated dependence structure of the data, both between loci as well as between individuals. Mixed models have emerged as a general and flexible approach for correcting for population structure in GWAS. Here, we extend this linear mixed-model approach to carry out GWAS of correlated phenotypes, deriving a fully parameterized multi-trait mixed model (MTMM) that considers both the within-trait and between-trait variance components simultaneously for multiple traits. We apply this to data from a human cohort for correlated blood lipid traits from the Northern Finland Birth Cohort 1966 and show greatly increased power to detect pleiotropic loci that affect more than one blood lipid trait. We also apply this approach to an Arabidopsis thaliana data set for flowering measurements in two different locations, identifying loci whose effect depends on the environment. 相似文献
66.
An efficient multi-locus mixed-model approach for genome-wide association studies in structured populations 总被引:2,自引:0,他引:2
Segura V Vilhjálmsson BJ Platt A Korte A Seren Ü Long Q Nordborg M 《Nature genetics》2012,44(7):825-830
Population structure causes genome-wide linkage disequilibrium between unlinked loci, leading to statistical confounding in genome-wide association studies. Mixed models have been shown to handle the confounding effects of a diffuse background of large numbers of loci of small effect well, but they do not always account for loci of larger effect. Here we propose a multi-locus mixed model as a general method for mapping complex traits in structured populations. Simulations suggest that our method outperforms existing methods in terms of power as well as false discovery rate. We apply our method to human and Arabidopsis thaliana data, identifying new associations and evidence for allelic heterogeneity. We also show how a priori knowledge from an A. thaliana linkage mapping study can be integrated into our method using a Bayesian approach. Our implementation is computationally efficient, making the analysis of large data sets (n > 10,000) practicable. 相似文献
67.
Gutiérrez-López MD Gilsanz A Yáñez-Mó M Ovalle S Lafuente EM Domínguez C Monk PN González-Alvaro I Sánchez-Madrid F Cabañas C 《Cellular and molecular life sciences : CMLS》2011,68(19):3275-3292
ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell
surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important
biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report
here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ
proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association
between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert
negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against
its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction,
negatively regulates the sheddase activity of ADAM17. 相似文献
68.
69.
Biegel E Schmidt S González JM Müller V 《Cellular and molecular life sciences : CMLS》2011,68(4):613-634
Microbes have a fascinating repertoire of bioenergetic enzymes and a huge variety of electron transport chains to cope with
very different environmental conditions, such as different oxygen concentrations, different electron acceptors, pH and salinity.
However, all these electron transport chains cover the redox span from NADH + H+ as the most negative donor to oxygen/H2O as the most positive acceptor or increments thereof. The redox range more negative than −320 mV has been largely ignored.
Here, we have summarized the recent data that unraveled a novel ion-motive electron transport chain, the Rnf complex, that
energetically couples the cellular ferredoxin to the pyridine nucleotide pool. The energetics of the complex and its biochemistry,
as well as its evolution and cellular function in different microbes, is discussed. 相似文献
70.
Thomae AW Baltin J Pich D Deutsch MJ Ravasz M Zeller K Gossen M Hammerschmidt W Schepers A 《Cellular and molecular life sciences : CMLS》2011,68(22):3741-3756
In eukaryotes, binding of the six-subunit origin recognition complex (ORC) to DNA provides an interactive platform for the
sequential assembly of pre-replicative complexes. This process licenses replication origins competent for the subsequent initiation
step. Here, we analyze the contribution of human Orc6, the smallest subunit of ORC, to DNA binding and pre-replicative complex
formation. We show that Orc6 not only interacts with Orc1–Orc5 but also with the initiation factor Cdc6. Biochemical and imaging
experiments reveal that this interaction is required for licensing DNA replication competent. Furthermore, we demonstrate
that Orc6 contributes to the interaction of ORC with the chaperone protein HMGA1a (high mobility group protein A1a). Binding
of human ORC to replication origins is not specified at the level of DNA sequence and the functional organization of origins
is poorly understood. We have identified HMGA1a as one factor that might direct ORC to AT-rich heterochromatic regions. The
systematic analysis of the interaction between ORC and HMGA1a revealed that Orc6 interacts with the acidic C-terminus of HMGA1a
and also with its AT-hooks. Both domains support autonomous replication if targeted to DNA templates. As such, Orc6 functions
at different stages of the replication initiation process. Orc6 can interact with ORC chaperone proteins such as HMGA1a to
facilitate chromatin binding of ORC and is also an essential factor for pre-RC formation. 相似文献