Abstract
CD40, a tumor necrosis factor receptor family member, is expressed on B lymphocytes. Interaction between CD40 and its ligand (CD40L), expressed on activated T lymphocytes, is critical for B cell survival. Here, we demonstrate that CD40 signals B cell survival in part via transcriptional activation of the RelB NF-kappaB subunit. CD40L treatment of chronic lymphocytic leukemia cells induced levels of relB mRNA. Similarly, CD40L-mediated rescue of WEHI 231 B lymphoma cells from apoptosis induced upon B cell receptor (surface IgM) engagement led to increased relB mRNA levels. Recently, we characterized a new de novo synthesis pathway for the RelB NF-kappaB subunit, induced by the cytomegalovirus IE1 protein, in which binding of p50/p65 NF-kappaB and c-Jun/Fra-2 AP-1 complexes to the relB promoter works in synergy to potently activate transcription (Wang, X., and Sonenshein, G. E. (2005) J. Virol. 79, 95-105). CD40L treatment of WEHI 231 cells caused induction of AP-1 family members Fra-2, c-Jun, JunD, and JunB. Cotransfection of Fra-2 with the Jun AP-1 subunits and p50/c-Rel NF-kappaB led to synergistic activation of the relB promoter. Ectopic expression of relB or RelB knockdown using small interfering RNA demonstrated the important role of this subunit in control of WEHI 231 cell survival and implicated activation of the anti-apoptotic factors Survivin and manganese superoxide dismutase. Thus, CD40 engagement of transformed B cells activates relB gene transcription via a process we have termed the de novo RelB synthesis pathway, which protects these cells from apoptosis.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis / physiology*
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B-Lymphocytes / cytology
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B-Lymphocytes / physiology*
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CD40 Antigens / genetics
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CD40 Antigens / metabolism*
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CD40 Ligand / genetics
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CD40 Ligand / metabolism*
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Cell Line, Tumor
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Fos-Related Antigen-2 / genetics
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Fos-Related Antigen-2 / metabolism
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Gene Expression Regulation
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Humans
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Inhibitor of Apoptosis Proteins
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / immunology
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Mice
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction / physiology*
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Survivin
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Transcription Factor RelB / genetics
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Transcription Factor RelB / metabolism*
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Transcription, Genetic
Substances
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BIRC5 protein, human
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CD40 Antigens
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Fos-Related Antigen-2
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Protein Subunits
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Proto-Oncogene Proteins c-jun
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RELB protein, human
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RNA, Messenger
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RNA, Small Interfering
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Survivin
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Transcription Factor AP-1
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CD40 Ligand
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Transcription Factor RelB
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Superoxide Dismutase
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JNK Mitogen-Activated Protein Kinases