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Anske Van den Abbeele Sarah De Clercq Ariane De Ganck Veerle De Corte Berlinda Van Loo Sameh Hamdy Soror Vasundara Srinivasan Jan Steyaert Joël Vandekerckhove Jan Gettemans 《Cellular and molecular life sciences : CMLS》2010,67(9):1519-1535
RNA interference has tremendously advanced our understanding of gene function but recent reports have exposed undesirable
side-effects. Recombinant Camelid single-domain antibodies (VHHs) provide an attractive means for studying protein function without affecting gene expression.
We raised VHHs against gelsolin (GsnVHHs), a multifunctional actin-binding protein that controls cellular actin organization
and migration. GsnVHH-induced delocalization of gelsolin to mitochondria or the nucleus in mammalian cells reveals distinct
subpopulations including free gelsolin and actin-bound gelsolin complexes. GsnVHH 13 specifically recognizes Ca2+-activated gelsolin (K
d ~10 nM) while GsnVHH 11 binds gelsolin irrespective of Ca2+ (K
d ~5 nM) but completely blocks its interaction with G-actin. Both GsnVHHs trace gelsolin in membrane ruffles of EGF-stimulated
MCF-7 cells and delay cell migration without affecting F-actin severing/capping or actin nucleation activities by gelsolin.
We conclude that VHHs represent a potent way of blocking structural proteins and that actin nucleation by gelsolin is more
complex than previously anticipated. 相似文献
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The induction of associative synaptic plasticity in the mammalian central nervous system classically depends on coincident presynaptic and postsynaptic activity. According to this principle, associative homosynaptic long-term potentiation (LTP) of excitatory synaptic transmission can be induced only if synaptic release occurs during postsynaptic depolarization. In contrast, heterosynaptic plasticity in mammals is considered to rely on activity-independent, non-associative processes. Here we describe a novel mechanism underlying the induction of associative LTP in the lateral amygdala (LA). Simultaneous activation of converging cortical and thalamic afferents specifically induced associative, N-methyl-D-aspartate (NMDA)-receptor-dependent LTP at cortical, but not at thalamic, inputs. Surprisingly, the induction of associative LTP at cortical inputs was completely independent of postsynaptic activity, including depolarization, postsynaptic NMDA receptor activation or an increase in postsynaptic Ca2+ concentration, and did not require network activity. LTP expression was mediated by a persistent increase in the presynaptic probability of release at cortical afferents. Our study shows the presynaptic induction and expression of heterosynaptic and associative synaptic plasticity on simultaneous activity of converging afferents. Our data indicate that input specificity of associative LTP can be determined exclusively by presynaptic properties. 相似文献
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Kote-Jarai Z Olama AA Giles GG Severi G Schleutker J Weischer M Campa D Riboli E Key T Gronberg H Hunter DJ Kraft P Thun MJ Ingles S Chanock S Albanes D Hayes RB Neal DE Hamdy FC Donovan JL Pharoah P Schumacher F Henderson BE Stanford JL Ostrander EA Sorensen KD Dörk T Andriole G Dickinson JL Cybulski C Lubinski J Spurdle A Clements JA Chambers S Aitken J Gardiner RA Thibodeau SN Schaid D John EM Maier C Vogel W Cooney KA Park JY Cannon-Albright L Brenner H Habuchi T Zhang HW Lu YJ Kaneva R 《Nature genetics》2011,43(8):785-791
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified. 相似文献
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Eeles RA Kote-Jarai Z Giles GG Olama AA Guy M Jugurnauth SK Mulholland S Leongamornlert DA Edwards SM Morrison J Field HI Southey MC Severi G Donovan JL Hamdy FC Dearnaley DP Muir KR Smith C Bagnato M Ardern-Jones AT Hall AL O'Brien LT Gehr-Swain BN Wilkinson RA Cox A Lewis S Brown PM Jhavar SG Tymrakiewicz M Lophatananon A Bryant SL;UK Genetic Prostate Cancer Study Collaborators;British Association of Urological Surgeons' Section of Oncology;UK ProtecT Study Collaborators Horwich A Huddart RA 《Nature genetics》2008,40(3):316-321
Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at =60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 x 10(-8) to P = 8.7 x 10(-29)). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3. 相似文献
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