BCL-6 negatively regulates expression of the NF-kappaB1 p105/p50 subunit.
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-kappaB 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-kappaB1 in vitro and in vivo, and repress NF-kappaB1 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-kappaB1 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-kappaB inhibitors, e.g., N-tosyl-l-phenylalanine chloromethyl ketone and SN50, a result that is consistent with increased nuclear kappaB-binding activity of p50 homodimer and p50/p65 heterodimer. Our results demonstrate that BCL-6 can negatively regulate NF-kappaB1 expression, thereby inhibiting NF-kappaB-mediated cellular functions.
Li
Zhiping
Z
Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Wang
Xing
X
Yu
Raymond Yick-Loi
RY
Ding
B Belinda
BB
Yu
J Jessica
JJ
Dai
Xu-Ming
XM
Naganuma
Akira
A
Stanley
E Richard
ER
Ye
B Hilda
BH
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D016393:Lymphoma, B-Cell / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D014157:Transcription Factors