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BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells

Nature Immunology volume 6, pages 1054–1060 (2005)Cite this article

Abstract

The BCL6 proto-oncogene encodes a transcriptional repressor that is required for germinal center formation and has been linked to lymphomagenesis. BCL6 functions by directly binding to specific DNA sequences and suppressing the transcription of target genes. Here we report an alternative mechanism by which BCL6 controls the transcription of genes lacking a BCL6 binding site and show that this mechanism was required for the prevention of tumor suppressor p53–independent cell cycle arrest in germinal center B cells. BCL6 interacted with the transcriptional activator Miz-1 and, via Miz-1, bound to the promoter and suppressed transcription of the cell cycle arrest gene CDKN1A. Through this mechanism, BCL6 may facilitate the proliferative expansion of germinal centers during the normal immune response and, when deregulated, the pathological expansion of B cell lymphomas.

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Figure 1: Identification of candidates BCL6 target genes.
Figure 2: BCL6 interacts with Miz-1.
Figure 3: BCL6 is recruited to the CDKN1A promoter by Miz-1.
Figure 4: BCL6 actively suppresses Miz-1-dependent activation of the CDKN1A gene.
Figure 5: Suppression of BCL6 by siRNA induces CDKN1A mRNA and protein expression and cell cycle retardation in B cells.
Figure 6: Constitutive expression of BCL6 in B cells suppresses DNA damage–induced CDKN1A expression and protects B cells from DNA damage–induced cell cycle arrest.

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Acknowledgements

We thank J. Seoane and J. Massague (Sloan Kettering Memorial Cancer Center, New York, New York) for advice and for the Miz-1 construct; R. Tjian (University of California, Berkeley, California) for anti-Miz-1; and A. Iavarone and R. Baer for advice, discussions and critically reading the manuscript. Supported by the National Institutes of Health (R.D.-F. and R.T.P.) and the American-Italian Cancer Foundation (K.B.).

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Author notes

  1. Ryan T Phan

    Present address: Children's Hospital, Center for Blood Research, Harvard University Medical School, Boston, Massachusetts, 02115, USA

  2. Huifeng Niu

    Present address: Roche Institute of Molecular Biology, Nutley, New Jersey, 07110, USA

Authors and Affiliations

  1. Department of Pathology, Department of Genetics and Development and the Herbert Irving Comprehensive Cancer Center, Institute for Cancer Genetics, Columbia University, New York, 10032, New York, USA

    Ryan T Phan, Masumichi Saito, Katia Basso, Huifeng Niu & Riccardo Dalla-Favera

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Correspondence to Riccardo Dalla-Favera.

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Phan, R., Saito, M., Basso, K. et al. BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells. Nat Immunol 6, 1054–1060 (2005). https://doi.org/10.1038/ni1245

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