Mad1 is a transcriptional repressor of Bcl-6.
Bcl-6, a major regulator of B lymphocyte function that contributes to neoplastic transformation of B cells, is expressed in activated germinal center (GC) B cells and down-regulated during terminal differentiation to plasma cells. Regulation of Bcl-6 expression is incompletely characterized. Terminal B cell differentiation is associated with down-regulation of Bcl-6, activation of Blimp-1, modulation of Myc, and specifically with the up-regulation of the Mad1 and Mad4 transcription factors, which play a critical role in cell differentiation and cell cycle regulation. Because the Mad E-box consensus binding site is present in the upstream promoter of Bcl-6, we investigated whether Bcl-6 may be under control of the Mad1 transcription factor. Anti-sense Mad1 oligonucleotides abrogated the down-regulation of Bcl-6 expression that occurred during in vitro differentiation of mouse splenic B cells induced by dextran-conjugated anti-IgD Ab and IL-5. Transduction of the WEHI 231 B cell line with retroviruses expressing Mad1 down-regulated Bcl-6 expression. Expression of the 5' upstream promoter region of Bcl-6 was down-regulated by co-expression of Mad1. Last, chromatin immunoprecipitation assays with anti-Mad1 Ab demonstrated in vivo interaction of Mad1 with the Bcl-6 promoter region. The findings suggest that Mad1 is a transcriptional repressor of Bcl-6.
Lee
Sang C
SC
Center for Human Genetics and Molecular Pediatric Disease, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Bottaro
Andrea
A
Chen
Luojing
L
Insel
Richard A
RA
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499479:Mad protein, mouse; D016376:Oligonucleotides, Antisense; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins