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dc.contributor.authorSakamaki, Kazuhiroja
dc.contributor.authorIwabe, Naoyukija
dc.contributor.authorIwata, Hiroakija
dc.contributor.authorImai, Kenichiroja
dc.contributor.authorTakagi, Chiyoja
dc.contributor.authorChiba, Kumikoja
dc.contributor.authorShukunami, Chisaja
dc.contributor.authorTomii, Kentaroja
dc.contributor.authorUeno, Naotoja
dc.contributor.alternative酒巻, 和弘ja
dc.date.accessioned2015-09-29T04:12:19Z-
dc.date.available2015-09-29T04:12:19Z-
dc.date.issued2015-09-
dc.identifier.issn2405-5808ja
dc.identifier.urihttp://hdl.handle.net/2433/199933-
dc.description.abstractCellular FLICE-like inhibitory protein (c-FLIP, gene symbol CFLAR) was first identified as a negative regulator of death receptor-mediated apoptosis in mammals. To understand the ubiquity and diversity of the c-FLIP protein subfamily during evolution, c-FLIP orthologs were identified from a comprehensive range of vertebrates, including birds, amphibians, and fish, and were characterized by combining experimental and computational analysis. Predictions of three-dimensional protein structures and molecular phylogenetic analysis indicated that the conserved structural features of c-FLIP proteins are all derived from an ancestral caspase-8, although they rapidly diverged from the subfamily consisting of caspases-8, -10, and -18. The functional role of the c-FLIP subfamily members is nearly ubiquitous throughout vertebrates. Exogenous expression of non-mammalian c-FLIP proteins in cultured mammalian cells suppressed death receptor-mediated apoptosis, implying that all of these proteins possess anti-apoptotic activity. Furthermore, non-mammalian c-FLIP proteins induced NF-κB activation much like their mammalian counterparts. The CFLAR mRNAs were synthesized during frog and fish embryogenesis. Overexpression of a truncated mutant of c-FLIP in the Xenopus laevis embryos by mRNA microinjection caused thorax edema and abnormal constriction of the abdomen. Depletion of cflar transcripts in zebrafish resulted in developmental abnormalities accompanied by edema and irregular red blood cell flow. Thus, our results demonstrate that c-FLIP/CFLAR is conserved in both protein structure and function in several vertebrate species, and suggest a significant role of c-FLIP in embryonic development.ja
dc.format.mimetypeapplication/pdfja
dc.language.isoengja
dc.publisherElsevier B.V.ja
dc.rights© 2015 The Authors. Published by Elsevier B.V.ja
dc.rightsThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).ja
dc.subjectApoptosisja
dc.subjectCaspase-8ja
dc.subjectEmbryogenesisja
dc.subjectEvolutionja
dc.subjectNF-κBja
dc.subjectPseudocatalytic triadja
dc.titleConservation of structure and function in vertebrate c-FLIP proteins despite rapid evolutionary changeja
dc.type.niitypeJournal Articleja
dc.identifier.jtitleBiochemistry and Biophysics Reportsja
dc.identifier.volume3ja
dc.identifier.spage175ja
dc.identifier.epage189ja
dc.relation.doi10.1016/j.bbrep.2015.08.005ja
dc.textversionpublisherja
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