Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells

Abdelkader Essafi, Silvia Fernández de Mattos, Yasmin A M Hassen, Inês Soeiro, Ghulam J Mufti, N Shaun B Thomas, René H Medema, Eric W-F Lam

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

239 Citations (Scopus)

Abstract

In this study, we have used the human BV173 and the mouse BaF3/Bcr-Abl-expressing cell lines as model systems to investigate the molecular mechanisms whereby STI571 and FoxO3a regulate Bim expression and apoptosis. FoxO3a lies downstream of Bcr-Abl signalling and is constitutively phosphorylated in the Bcr-Abl-positive BV173 and BaF3/Bcr-Abl cells. Inhibition of Bcr-Abl kinase by STI571 results in FoxO3a activation, induction of Bim expression and apoptosis. Using reporter gene assays, we demonstrate that STI571 and FoxO3a activate Bim transcription through a FoxO-binding site (FHRE) located within the promoter. This was verified by DNA pull-down and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to induction of Bim expression and apoptosis. Conversely, silencing of FoxO3a in Bcr-Abl-expressing cells abolishes STI571-mediated Bim induction and apoptosis. Together, the results presented clearly confirm FoxO3a as a key regulator of apoptosis induced by STI571, and show that Bim is a direct transcriptional target of FoxO3a that mediates the STI571-induced apoptosis. Thus, STI571 induces an accumulation of FoxO3a activity which in turn binds directly to an FHRE in the promoter to activate Bim expression and apoptosis.

Original languageEnglish
Pages (from-to)2317-29
Number of pages13
JournalOncogene
Volume24
Issue number14
DOIs
Publication statusPublished - 31 Mar 2005

Keywords

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Base Sequence
  • Bcl-2-Like Protein 11
  • Benzamides
  • Carrier Proteins
  • Cell Line
  • Cell Line, Tumor
  • DNA
  • DNA-Binding Proteins
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Fusion Proteins, bcr-abl
  • Humans
  • Imatinib Mesylate
  • Membrane Proteins
  • Mice
  • Molecular Sequence Data
  • Piperazines
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins
  • Pyrimidines
  • RNA, Small Interfering
  • Transcription Factors
  • Transcription, Genetic
  • Journal Article
  • Research Support, Non-U.S. Gov't

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