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

Mol Cell Biol. 2004 Nov;24(22):10058-71. doi: 10.1128/MCB.24.22.10058-10071.2004.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Benzamides
  • Binding Sites / genetics
  • Cell Line
  • Cyclin D2
  • Cyclins / genetics*
  • Cyclins / metabolism
  • DNA, Complementary / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Imatinib Mesylate
  • Milk Proteins / genetics
  • Milk Proteins / metabolism*
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Piperazines / pharmacology
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-6
  • Pyrimidines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • STAT5 Transcription Factor
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects

Substances

  • BCL6 protein, human
  • Benzamides
  • CCND2 protein, human
  • Cyclin D2
  • Cyclins
  • DNA, Complementary
  • DNA-Binding Proteins
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Milk Proteins
  • Nuclear Proteins
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-6
  • Pyrimidines
  • RNA, Messenger
  • RNA, Small Interfering
  • STAT5 Transcription Factor
  • Trans-Activators
  • Transcription Factors
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl