| Cap-independent translation promotes C. elegans germ cell apoptosis through Apaf-1/CED-4 in a caspase-dependent mechanism. | |
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MedLine Citation:
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PMID: 21909434 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Apoptosis is a natural process during animal development for the programmed removal of superfluous cells. During apoptosis general protein synthesis is reduced, but the synthesis of cell death proteins is enhanced. Selective translation has been attributed to modification of the protein synthesis machinery to disrupt cap-dependent mRNA translation and induce a cap-independent mechanism. We have previously shown that disruption of the balance between cap-dependent and cap-independent C. elegans eIF4G isoforms (IFG-1 p170 and p130) by RNA interference promotes apoptosis in developing oocytes. Germ cell apoptosis was accompanied by the appearance of the Apaf-1 homolog, CED-4. Here we show that IFG-1 p170 is a native substrate of the worm executioner caspase, CED-3, just as mammalian eIF4GI is cleaved by caspase-3. Loss of Bcl-2 function (ced-9ts) in worms induced p170 cleavage in vivo, coincident with extensive germ cell apoptosis. Truncation of IFG-1 occurred at a single site that separates the cap-binding and ribosome-associated domains. Site-directed mutagenesis indicated that CED-3 processes IFG-1 at a non-canonical motif, TTTD(456). Coincidentally, the recognition site was located 65 amino acids downstream of the newly mapped IFG-1 p130 start site suggesting that both forms support cap-independent initiation. Genetic evidence confirmed that apoptosis induced by loss of ifg-1 p170 mRNA was caspase (ced-3) and apoptosome (ced-4/Apaf-1) dependent. These findings support a new paradigm in which modal changes in protein synthesis act as a physiological signal to initiate cell death, rather than occur merely as downstream consequences of the apoptotic event. |
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Authors:
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Vince Contreras; Andrew J Friday; J Kaitlin Morrison; Enhui Hao; Brett D Keiper |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-09-01 |
Journal Detail:
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Title: PloS one Volume: 6 ISSN: 1932-6203 ISO Abbreviation: PLoS ONE Publication Date: 2011 |
Date Detail:
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Created Date: 2011-09-12 Completed Date: 2012-01-05 Revised Date: 2012-04-26 |
Medline Journal Info:
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Nlm Unique ID: 101285081 Medline TA: PLoS One Country: United States |
Other Details:
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Languages: eng Pagination: e24444 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, United States of America. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Apoptosomes / metabolism Apoptotic Protease-Activating Factor 1 / metabolism Aspartic Acid / metabolism Base Sequence Binding Sites Biocatalysis Caenorhabditis elegans / cytology*, metabolism Caenorhabditis elegans Proteins / metabolism* Calcium-Binding Proteins / metabolism* Caspase 3 / metabolism* Caspases / metabolism Eukaryotic Initiation Factor-4G / metabolism Germ Cells / cytology*, metabolism Humans Molecular Sequence Data Protein Biosynthesis* Protein Isoforms / metabolism Proto-Oncogene Proteins c-bcl-2 / metabolism RNA Caps / metabolism* Recombinant Proteins / metabolism Substrate Specificity |
| Chemical | |
Reg. No./Substance:
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0/Apoptosomes; 0/Apoptotic Protease-Activating Factor 1; 0/Caenorhabditis elegans Proteins; 0/Calcium-Binding Proteins; 0/Ced-4 protein, C elegans; 0/Ced-9 protein, C elegans; 0/Eukaryotic Initiation Factor-4G; 0/Protein Isoforms; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA Caps; 0/Recombinant Proteins; 56-84-8/Aspartic Acid; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases; EC 3.4.22.-/ced-3 protein, C elegans |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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