FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism

Silvia Fernández de Mattos, Abdelkader Essafi, Inês Soeiro, Alexandra M Pietersen, Kim U Birkenkamp, Corinne S Edwards, Anthony Martino, Brad H Nelson, Julia M Francis, Marius C Jones, Jan J Brosens, Paul J Coffer, Eric W-F Lam

Research output: Contribution to journalArticle (Academic Journal)peer-review

141 Citations (Scopus)


Cell cycle arrest by FoxO transcription factors involves transcriptional repression of cyclin D, although the exact mechanism remains unclear. In this study, we used the BCR-ABL-expressing cell line BV173 as a model system to investigate the mechanisms whereby FoxO3a regulates cyclin D2 expression. Inhibition of BCR-ABL by STI571 results in down-regulation of cyclin D2 expression, activation of FoxO3a activity, and up-regulation of BCL6 expression. Using reporter gene assays, we demonstrate that STI571, FoxO3a, and BCL6 can repress cyclin D2 transcription through a STAT5/BCL6 site located within the cyclin D2 promoter. We propose that BCR-ABL inhibition leads to FoxO3a activation, which in turn induces the expression of BCL6, culminating in the repression of cyclin D2 transcription through this STAT5/BCL6 site. This process was verified by mobility shift and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to accumulation of BCL6 and down-regulation of cyclin D2 at protein and mRNA levels. Furthermore, silencing of FoxO3a and BCL6 in BCR-ABL-expressing cells abolishes STI571-mediated effects on cyclin D2. This report establishes the signaling events whereby BCR-ABL signals are relayed to cyclin D2 to mediate cell cycle progression and defines a potential mechanism by which FoxO proteins regulate cyclin D2 expression.

Original languageEnglish
Pages (from-to)10058-71
Number of pages14
JournalMolecular and Cellular Biology
Issue number22
Publication statusPublished - Nov 2004


  • Base Sequence
  • Benzamides
  • Binding Sites
  • Cell Line
  • Cyclin D2
  • Cyclins
  • DNA, Complementary
  • DNA-Binding Proteins
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Fusion Proteins, bcr-abl
  • Humans
  • Imatinib Mesylate
  • Milk Proteins
  • Nuclear Proteins
  • Phosphorylation
  • Piperazines
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-6
  • Pyrimidines
  • RNA, Messenger
  • RNA, Small Interfering
  • STAT5 Transcription Factor
  • Signal Transduction
  • Trans-Activators
  • Transcription Factors
  • Transcription, Genetic
  • Journal Article
  • Research Support, Non-U.S. Gov't

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