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Molecular and Cellular Biology, November 2004, p. 10058-10071, Vol. 24, No. 22
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.22.10058-10071.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Silvia Fernández de Mattos,1 Abdelkader Essafi,1 Inês Soeiro,1 Alexandra M. Pietersen,2 Kim U. Birkenkamp,2 Corinne S. Edwards,1 Anthony Martino,3,{dagger} Brad H. Nelson,3 Julia M. Francis,4 Marius C. Jones,4 Jan J. Brosens,4 Paul J. Coffer,2 and Eric W.-F. Lam1*

Cancer Research-UK Laboratories, Department of Cancer Medicine, Imperial College London,1 Institute of Reproductive and Developmental Biology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom,4 Department of Pulmonary Diseases, University Medical Center, Utrecht, The Netherlands,2 British Columbia Cancer Agency, Victoria, British Columbia, Canada3

Received 8 March 2004/ Returned for modification 31 March 2004/ Accepted 26 August 2004

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.

* Corresponding author. Mailing address: Cancer Research-UK Laboratories, Department of Cancer Medicine, Section of Cancer Cell Biology, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom. Phone: 44-20-8383-5829. Fax: 44-20-8383-5830. E-mail: eric.lam{at}imperial.ac.uk.

{dagger} Present address: Biosystems Research Department, Sandia National Laboratories, Livermore, CA 94551.

Molecular and Cellular Biology, November 2004, p. 10058-10071, Vol. 24, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.22.10058-10071.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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