1. Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase
- Author
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James J. Steinhardt, Carlos Rodriguez, Ari L. Landon, Ronald Tesoriero, Brandon R. Bruns, Matthew J. Bradley, Thomas M. Scalea, Krystyna Mazan-Mamczarz, Stacy Shackelford, Ronald B. Gartenhaus, Ferenc Livak, Simone Houng, Raymond J. Peroutka, Raymond Fang, Qing Chen, Nader Hanna, Deborah M. Stein, Bojie Dai, Rolf N. Barth, Joseph Rabin, Mark D. Kligman, Jason Pasley, Carol Robles, and Joseph J. DuBose
- Subjects
Untranslated region ,Adult ,Immunology ,Blotting, Western ,Receptors, Antigen, B-Cell ,RNA-binding protein ,Biology ,Biochemistry ,DEAD-box RNA Helicases ,hemic and lymphatic diseases ,Cell Line, Tumor ,Protein biosynthesis ,Humans ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Aged ,Aged, 80 and over ,B-Lymphocytes ,Lymphoid Neoplasia ,Reverse Transcriptase Polymerase Chain Reaction ,breakpoint cluster region ,RNA-Binding Proteins ,Ribosomal Protein S6 Kinases, 70-kDa ,Translation (biology) ,Cell Biology ,Hematology ,Middle Aged ,B-Cell CLL-Lymphoma 10 Protein ,RNA Helicase A ,BCL10 ,Triterpenes ,Neoplasm Proteins ,CARD Signaling Adaptor Proteins ,Guanylate Cyclase ,Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ,eIF4A ,Caspases ,Protein Biosynthesis ,Eukaryotic Initiation Factor-4A ,Cancer research ,Lymphoma, Large B-Cell, Diffuse ,5' Untranslated Regions ,Apoptosis Regulatory Proteins ,Signal Transduction - 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.
- Published
- 2014