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

Silvia Fernández de Mattos1, Abdelkader Essafi, Inês Soeiro

  • 1Cancer Research-UK Laboratories, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.

Molecular and Cellular Biology
|October 29, 2004
PubMed

Insights

FoxO transcription factors repress cyclin D2, a key cell cycle regulator. BCR-ABL inhibition activates FoxO3a, inducing BCL6, which represses cyclin D2 transcription via a specific promoter site.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Transcription Factor Function

Background:

  • FoxO transcription factors are known to induce cell cycle arrest by repressing cyclin D, but the precise molecular mechanisms are not fully understood.
  • The BCR-ABL oncoprotein drives cell proliferation, and its inhibition is a therapeutic strategy in certain cancers.

Purpose of the Study:

  • To elucidate the mechanism by which FoxO3a transcription factor regulates cyclin D2 expression in BCR-ABL-expressing cells.
  • To investigate the role of BCL6 in the FoxO3a-mediated repression of cyclin D2.

Main Methods:

  • Utilized the BCR-ABL-expressing cell line BV173.
  • Employed reporter gene assays, mobility shift assays, and chromatin immunoprecipitation analyses.
  • Investigated the effects of BCR-ABL inhibition (STI571), FoxO3a activation, and BCL6 modulation.

Main Results:

  • BCR-ABL inhibition by STI571 led to decreased cyclin D2 expression, activated FoxO3a, and increased BCL6 expression.
  • FoxO3a and BCL6 were shown to repress cyclin D2 transcription through a specific STAT5/BCL6 binding site in the promoter.
  • Conditional FoxO3a activation resulted in BCL6 accumulation and reduced cyclin D2 levels; FoxO3a and BCL6 silencing abrogated STI571 effects.

Conclusions:

  • BCR-ABL inhibition triggers FoxO3a activation, which upregulates BCL6, ultimately repressing cyclin D2 transcription via a defined promoter element.
  • This study defines a signaling pathway linking BCR-ABL to cyclin D2 repression, mediated by FoxO3a and BCL6, impacting cell cycle progression.
  • Establishes a novel mechanism for FoxO-mediated regulation of cyclin D2 expression.

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