title: Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase.
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.
authors.affiliation: Department of Medicine.
authors.forename: James J
authors.initials: JJ
authors.lastname: Steinhardt
authors.affiliation: Department of Medicine.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Peroutka
authors.affiliation: Department of Medicine.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Mazan-Mamczarz
authors.affiliation: Department of Pathology, and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Medicine.
authors.forename: Simone
authors.initials: S
authors.lastname: Houng
authors.affiliation: Department of Microbiology and Immunology, Marlene & Stewart Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD;
authors.forename: Carol
authors.initials: C
authors.lastname: Robles
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Rolf N
authors.initials: RN
authors.lastname: Barth
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Joseph
authors.initials: J
authors.lastname: DuBose
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Brandon
authors.initials: B
authors.lastname: Bruns
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Ronald
authors.initials: R
authors.lastname: Tesoriero
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stein
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Raymond
authors.initials: R
authors.lastname: Fang
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Nader
authors.initials: N
authors.lastname: Hanna
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Jason
authors.initials: J
authors.lastname: Pasley
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Kligman
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bradley
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rabin
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Stacy
authors.initials: S
authors.lastname: Shackelford
authors.affiliation: Department of Medicine.
authors.forename: Bojie
authors.initials: B
authors.lastname: Dai
authors.affiliation: Department of Medicine.
authors.forename: Ari L
authors.initials: AL
authors.lastname: Landon
authors.affiliation: R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Scalea
authors.affiliation: Department of Microbiology and Immunology, Marlene & Stewart Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD;
authors.forename: Ferenc
authors.initials: F
authors.lastname: Livak
authors.affiliation: Department of Medicine, Veterans Administration Medical Center, Baltimore, MD.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Gartenhaus
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014315:Triterpenes / Q000494:pharmacology; D001572:Benzofurans
chemical_list: D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D020169:Caspases; D053487:DEAD-box RNA Helicases; D039601:Eukaryotic Initiation Factor-4A; D006162:Guanylate Cyclase; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D011947:Receptors, Antigen, B-Cell; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D014315:Triterpenes; C118591:BCL10 protein, human; C114487:PDCD4 protein, human; C489897:silvestrol; D001572:Benzofurans; C400109:MALT1 protein, human; C426242:CARD11 protein, human