Mad1 is a transcriptional repressor of Bcl-6

Mol Immunol. 2006 May;43(12):1965-71. doi: 10.1016/j.molimm.2005.11.017. Epub 2006 Jan 19.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Binding Sites
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Leukemia, B-Cell / genetics
  • Leukemia, B-Cell / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotides, Antisense / pharmacology
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-6 / genetics*
  • Proto-Oncogene Proteins c-bcl-6 / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Spleen / cytology
  • Spleen / immunology

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Mad protein, mouse
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins