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B1 p105/p50 Subunit1
Departments of
*
Cell Biology and
Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461; and
Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-Ku, Sendai, Japan
BCL-6 is a transcription repressor frequently deregulated in non-Hodgkin’s B cell lymphomas. Its activity is also critical to germinal center development and balanced Th1/Th2 differentiation. Previous studies have suggested that NF-
B activity is suppressed in germinal center and lymphoma B cells that express high levels of BCL-6, and yet the reason for this is unknown. We report in this study that BCL-6 can bind to three sequence motifs in the 5' regulatory region of NF-B1 in vitro and in vivo, and repress NF-B1 transcription both in reporter assays and in lymphoma B cell lines. BCL-6–/– mice further confirm the biological relevance of BCL-6-dependent regulation of NF-B1 because BCL-6 inactivation caused notable increase in p105/p50 proteins in several cell types. Among these, BCL-6–/– macrophage cell lines displayed a hyperproliferation phenotype that can be reversed by NF-B inhibitors, e.g., N-tosyl-L-phenylalanine chloromethyl ketone and SN50, a result that is consistent with increased nuclear B-binding activity of p50 homodimer and p50/p65 heterodimer. Our results demonstrate that BCL-6 can negatively regulate NF-B1 expression, thereby inhibiting NF-B-mediated cellular functions.
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