FoxO3a and BCR-ABL Regulate cyclin D2 Transcription through a STAT5/BCL6-Dependent Mechanism

S Fernández de Mattos, A Essafi, I Soeiro… - … and cellular biology, 2004 - Taylor & Francis
S Fernández de Mattos, A Essafi, I Soeiro, AM Pietersen, KU Birkenkamp, CS Edwards…
Molecular and cellular biology, 2004Taylor & Francis
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 …
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.
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