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Caspase-8, an initiator caspase involved in lymphocyte apoptosis, is paradoxically required for lymphocyte proliferation. It is not understood how caspase-8 is controlled during antigenic signaling to allow for activation while averting the triggering of apoptosis. Here, we show that caspase-8 undergoes limited activation upon antigenic stimulation, and this activation is dependent on the paracaspase MALT1. The paracaspase domain of MALT1, in a protease-independent manner, induces caspase-8 activation through direct association. MALT1 diminishes the activation of apoptotic effector caspases, but it does not alter the activity of caspase-8 toward c-FLIP(L), which is required for antigenic signaling. Mutants of MALT1 that fail to activate caspase-8 and permit c-FLIP(L) cleavage cannot facilitate NF-kappaB activation or IL-2 induction. Our results reveal a mechanism that utilizes a protease potentially deadly to the cell for proliferative signaling and demonstrate a functional connection between the caspase and paracaspase families to enable nonapoptotic processes. 相似文献
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Searching for signals of evolutionary selection in 168 genes related to immune function 总被引:5,自引:0,他引:5
Walsh EC Sabeti P Hutcheson HB Fry B Schaffner SF de Bakker PI Varilly P Palma AA Roy J Cooper R Winkler C Zeng Y de The G Lander ES O'Brien S Altshuler D 《Human genetics》2006,119(1-2):92-102
Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing
immune function. We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms
across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from
Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency
(MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH). Six of the 168
genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent
data from the International HapMap Project. These analyses identify two loci involved in immune function that are candidates
for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection
in genome-wide polymorphism data.
Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.
Emily C. Walsh, Pardis Sabeti, Holli B. Hutcheson, and Ben Fry have contributed equally to this work and Stephen O’Brien and
David Altshuler have jointly supervised this project 相似文献
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