Journal
MOLECULAR IMMUNOLOGY
Volume 43, Issue 12, Pages 1965-1971Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2005.11.017
Keywords
Bcl-6; Mad1; Blimp-1; B cell
Categories
Funding
- NIAID NIH HHS [AI07285, AI45012, AI37123] Funding Source: Medline
- NICHD NIH HHS [HD36293] Funding Source: Medline
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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-L 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 BcI-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 immunciprecipitation assays with anti-Mad1 Ab demonstrated in vivo interaction of Mad1 with the BcI-6 promoter region. The findings suggest that Mad I is a transcriptional repressor of Bcl-6. (c) 2005 Elsevier Ltd. All rights reserved.
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