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Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy 总被引:20,自引:0,他引:20
Gerull B Heuser A Wichter T Paul M Basson CT McDermott DA Lerman BB Markowitz SM Ellinor PT MacRae CA Peters S Grossmann KS Drenckhahn J Michely B Sasse-Klaassen S Birchmeier W Dietz R Breithardt G Schulze-Bahr E Thierfelder L 《Nature genetics》2004,36(11):1162-1164
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations. 相似文献
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Physical forces can activate colon cancer cell adhesion, critical for metastasis. Paxillin is phosphorylated by FAK and required
for pressure-stimulated adhesion. However, whether paxillin acts as an inert scaffolding protein or whether paxillin phosphorylation
is required is unknown. Transfection with paxillin point-phosphorylation mutants demonstrated that phosphorylation at tyrosines
31 and 118 together is necessary for pressure-stimulated adhesion. We further evaluated potential paxillin partners. Reducing
the adaptor protein Crk or the focal adhesion protein p130Cas blocked pressure-stimulated adhesion. Furthermore, Crk and p130Cas both displayed increased co-immunoprecipitation with paxillin in response to increased pressure, except in cells transfected
with a Y31Y118 paxillin mutant. Inhibiting the small GTPase Rac1 also abolished pressure-stimulated adhesion, and reducing
paxillin by siRNA blocked Rac1 phosphorylation by pressure. Thus, paxillin phosphorylation at tyrosines 31 and 118 together
is necessary for pressure-induced adhesion. Paxillin, Crk and Cas form a trimeric complex that activates Rac1 and mediates
this effect.
Received 21 January 2008; received after revision 4 March 2008; accepted 19 March 2008 相似文献
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The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans 总被引:159,自引:0,他引:159
Reinhart BJ Slack FJ Basson M Pasquinelli AE Bettinger JC Rougvie AE Horvitz HR Ruvkun G 《Nature》2000,403(6772):901-906
The C. elegans heterochronic gene pathway consists of a cascade of regulatory genes that are temporally controlled to specify the timing of developmental events. Mutations in heterochronic genes cause temporal transformations in cell fates in which stage-specific events are omitted or reiterated. Here we show that let-7 is a heterochronic switch gene. Loss of let-7 gene activity causes reiteration of larval cell fates during the adult stage, whereas increased let-7 gene dosage causes precocious expression of adult fates during larval stages. let-7 encodes a temporally regulated 21-nucleotide RNA that is complementary to elements in the 3' untranslated regions of the heterochronic genes lin-14, lin-28, lin-41, lin-42 and daf-12, indicating that expression of these genes may be directly controlled by let-7. A reporter gene bearing the lin-41 3' untranslated region is temporally regulated in a let-7-dependent manner. A second regulatory RNA, lin-4, negatively regulates lin-14 and lin-28 through RNA-RNA interactions with their 3' untranslated regions. We propose that the sequential stage-specific expression of the lin-4 and let-7 regulatory RNAs triggers transitions in the complement of heterochronic regulatory proteins to coordinate developmental timing. 相似文献
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Economou AD Ohazama A Porntaveetus T Sharpe PT Kondo S Basson MA Gritli-Linde A Cobourne MT Green JB 《Nature genetics》2012,44(3):348-351
We present direct evidence of an activator-inhibitor system in the generation of the regularly spaced transverse ridges of the palate. We show that new ridges, called rugae, that are marked by stripes of expression of Shh (encoding Sonic hedgehog), appear at two growth zones where the space between previously laid rugae increases. However, inter-rugal growth is not absolutely required: new stripes of Shh expression still appeared when growth was inhibited. Furthermore, when a ruga was excised, new Shh expression appeared not at the cut edge but as bifurcating stripes branching from the neighboring stripe of Shh expression, diagnostic of a Turing-type reaction-diffusion mechanism. Genetic and inhibitor experiments identified fibroblast growth factor (FGF) and Shh as components of an activator-inhibitor pair in this system. These findings demonstrate a reaction-diffusion mechanism that is likely to be widely relevant in vertebrate development. 相似文献
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