排序方式: 共有109条查询结果,搜索用时 15 毫秒
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iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53 总被引:6,自引:0,他引:6
Bergamaschi D Samuels Y Sullivan A Zvelebil M Breyssens H Bisso A Del Sal G Syed N Smith P Gasco M Crook T Lu X 《Nature genetics》2006,38(10):1133-1141
iASPP is one of the most evolutionarily conserved inhibitors of p53, whereas ASPP1 and ASPP2 are activators of p53. We show here that, in addition to the DNA-binding domain, the ASPP family members also bind to the proline-rich region of p53, which contains the most common p53 polymorphism at codon 72. Furthermore, the ASPP family members, particularly iASPP, bind to and regulate the activity of p53Pro72 more efficiently than that of p53Arg72. Hence, escape from negative regulation by iASPP is a newly identified mechanism by which p53Arg72 activates apoptosis more efficiently than p53Pro72. 相似文献
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Spectrin mutations cause spinocerebellar ataxia type 5 总被引:12,自引:0,他引:12
Ikeda Y Dick KA Weatherspoon MR Gincel D Armbrust KR Dalton JC Stevanin G Dürr A Zühlke C Bürk K Clark HB Brice A Rothstein JD Schut LJ Day JW Ranum LP 《Nature genetics》2006,38(2):184-190
We have discovered that beta-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in an 11-generation American kindred descended from President Lincoln's grandparents and two additional families. Two families have separate in-frame deletions of 39 and 15 bp, and a third family has a mutation in the actin/ARP1 binding region. Beta-III spectrin is highly expressed in Purkinje cells and has been shown to stabilize the glutamate transporter EAAT4 at the surface of the plasma membrane. We found marked differences in EAAT4 and GluRdelta2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant beta-III spectrin stabilizes EAAT4 at the plasma membrane. Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling. 相似文献
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Engen JR Wales TE Hochrein JM Meyn MA Banu Ozkan S Bahar I Smithgall TE 《Cellular and molecular life sciences : CMLS》2008,65(19):3058-3073
Src-family kinases are modular signaling proteins involved in a diverse array of cellular processes. All members of the Src
family share the same domain organization, with modular SH3, SH2 and kinase domains followed by a C-terminal negative regulatory
tail. X-ray crystallographic analyses of several Src family members have revealed critical roles for the SH3 and SH2 domains
in the down-regulation of the kinase domain. This review focuses on biological, biophysical, and computational studies that
reveal conformationally distinct active states within this unique kinase family.
Received 10 March 2008; received after revision 17 May 2008; accepted 21 May 2008 相似文献
96.
Population genomics of human gene expression 总被引:1,自引:0,他引:1
Stranger BE Nica AC Forrest MS Dimas A Bird CP Beazley C Ingle CE Dunning M Flicek P Koller D Montgomery S Tavaré S Deloukas P Dermitzakis ET 《Nature genetics》2007,39(10):1217-1224
Genetic variation influences gene expression, and this variation in gene expression can be efficiently mapped to specific genomic regions and variants. Here we have used gene expression profiling of Epstein-Barr virus-transformed lymphoblastoid cell lines of all 270 individuals genotyped in the HapMap Consortium to elucidate the detailed features of genetic variation underlying gene expression variation. We find that gene expression is heritable and that differentiation between populations is in agreement with earlier small-scale studies. A detailed association analysis of over 2.2 million common SNPs per population (5% frequency in HapMap) with gene expression identified at least 1,348 genes with association signals in cis and at least 180 in trans. Replication in at least one independent population was achieved for 37% of cis signals and 15% of trans signals, respectively. Our results strongly support an abundance of cis-regulatory variation in the human genome. Detection of trans effects is limited but suggests that regulatory variation may be the key primary effect contributing to phenotypic variation in humans. We also explore several methodologies that improve the current state of analysis of gene expression variation. 相似文献
97.
Morison IM Cramer Bordé EM Cheesman EJ Cheong PL Holyoake AJ Fichelson S Weeks RJ Lo A Davies SM Wilbanks SM Fagerlund RD Ludgate MW da Silva Tatley FM Coker MS Bockett NA Hughes G Pippig DA Smith MP Capron C Ledgerwood EC 《Nature genetics》2008,40(4):387-389
We report the first identified mutation in the gene encoding human cytochrome c (CYCS). Glycine 41, invariant throughout eukaryotes, is substituted by serine in a family with autosomal dominant thrombocytopenia caused by dysregulated platelet formation. The mutation yields a cytochrome c variant with enhanced apoptotic activity in vitro. Notably, the family has no other phenotypic indication of abnormal apoptosis, implying that cytochrome c activity is not a critical regulator of most physiological apoptosis. 相似文献
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de Pontual L Yao E Callier P Faivre L Drouin V Cariou S Van Haeringen A Geneviève D Goldenberg A Oufadem M Manouvrier S Munnich A Vidigal JA Vekemans M Lyonnet S Henrion-Caude A Ventura A Amiel J 《Nature genetics》2011,43(10):1026-1030
MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17~92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17~92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17~92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17~92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans. 相似文献
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Hunt KA Zhernakova A Turner G Heap GA Franke L Bruinenberg M Romanos J Dinesen LC Ryan AW Panesar D Gwilliam R Takeuchi F McLaren WM Holmes GK Howdle PD Walters JR Sanders DS Playford RJ Trynka G Mulder CJ Mearin ML Verbeek WH Trimble V Stevens FM O'Morain C Kennedy NP Kelleher D Pennington DJ Strachan DP McArdle WL Mein CA Wapenaar MC Deloukas P McGinnis R McManus R Wijmenga C van Heel DA 《Nature genetics》2008,40(4):395-402
Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways. 相似文献