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)

Abstract

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
Volume24
Issue number22
DOIs
Publication statusPublished - Nov 2004

Keywords

  • 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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