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Acetylation inactivates the transcriptional repressor BCL6.

The proto-oncogene BCL6 encodes a BTB/POZ-zinc finger transcriptional repressor that is necessary for germinal-center formation and has been implicated in the pathogenesis of B-cell lymphomas. Here we show that the co-activator p300 binds and acetylates BCL6 in vivo and inhibits its function. Acetylation disrupts the ability of BCL6 to recruit histone deacetylases (HDACs), thereby hindering its capacity to repress transcription and to induce cell transformation. BCL6 is acetylated under physiologic conditions in normal germinal-center B cells and in germinal center-derived B-cell tumors. Treatment with specific inhibitors shows that levels of acetylation of BCL6 are controlled by both HDAC-dependent and SIR2-dependent pathways. Pharmacological inhibition of these pathways leads to the accumulation of the inactive acetylated BCL6 and to cell-cycle arrest and apoptosis in B-cell lymphoma cells. These results identify a new mechanism of regulation of the proto-oncogene BCL6 with potential for therapeutic exploitation. Furthermore, these findings provide a new mechanism by which acetylation can promote transcription not only by modifying histones and activating transcriptional activators, but also by inhibiting transcriptional repressors.

Pubmed ID: 12402037

Authors

  • Bereshchenko OR
  • Gu W
  • Dalla-Favera R

Journal

Nature genetics

Publication Data

December 28, 2002

Associated Grants

None

Mesh Terms

  • Acetylation
  • Acetyltransferases
  • Amino Acid Substitution
  • Animals
  • B-Lymphocytes
  • Cell Cycle Proteins
  • Cell Line
  • Cells, Cultured
  • DNA-Binding Proteins
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors
  • Gene Expression Regulation
  • Genes, Reporter
  • Histone Acetyltransferases
  • Histone Deacetylases
  • Humans
  • Hydroxamic Acids
  • Luciferases
  • Point Mutation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Rats
  • Repressor Proteins
  • Transcription Factors
  • Transcription, Genetic
  • p300-CBP Transcription Factors