Abstract
Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5' untranslated region (UTR). Oncogenes with complex 5'UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5'UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G(+) splenic B cells, from which most DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM(+) B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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5' Untranslated Regions / genetics
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Adult
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Aged
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Aged, 80 and over
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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B-Cell CLL-Lymphoma 10 Protein
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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Blotting, Western
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / metabolism*
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Caspases / genetics
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Caspases / metabolism
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Cell Line, Tumor
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Cells, Cultured
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DEAD-box RNA Helicases / antagonists & inhibitors
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / metabolism*
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Eukaryotic Initiation Factor-4A / antagonists & inhibitors
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Eukaryotic Initiation Factor-4A / genetics
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Eukaryotic Initiation Factor-4A / metabolism*
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Guanylate Cyclase / genetics
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Guanylate Cyclase / metabolism*
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Humans
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Lymphoma, Large B-Cell, Diffuse / pathology
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Middle Aged
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Protein Biosynthesis / drug effects
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Receptors, Antigen, B-Cell / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Triterpenes / pharmacology
Substances
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5' Untranslated Regions
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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B-Cell CLL-Lymphoma 10 Protein
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BCL10 protein, human
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CARD Signaling Adaptor Proteins
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Neoplasm Proteins
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PDCD4 protein, human
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RNA-Binding Proteins
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Receptors, Antigen, B-Cell
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Triterpenes
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silvestrol
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Ribosomal Protein S6 Kinases, 70-kDa
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Eukaryotic Initiation Factor-4A
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Caspases
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MALT1 protein, human
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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DEAD-box RNA Helicases
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CARD11 protein, human
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Guanylate Cyclase