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Overexpressed BCL6 (LAZ3) oncoprotein triggers apoptosis, delays S phase progression and associates with replication foci

Abstract

One of the most frequent genetic abnormalities associated with non Hodgkin lymphoma is the structural alteration of the 5′ non coding/regulatory region of the BCL6 (LAZ3) protooncogene. BCL6 encodes a POZ/Zn finger protein, a structure similar to that of many Drosophila developmental regulators and to another protein involved in a human hematopoietic malignancy, PLZF. BCL6 is a sequence specific transcriptional repressor controlling germinal center formation and T cell dependent immune response. Although the expression of BCL6 negatively correlates with cellular proliferation in different cell types, the influence of BCL6 on cell growth and survival is currently unknown so that the way its deregulation may contribute to cancer remains elusive. To directly address this issue, we used a tetracycline-regulated system in human U2OS osteosarcoma cells and thus found that BCL6 mediates growth suppression associated with impaired S phase progression and apoptosis. Interestingly, overexpressed BCL6 can colocalize with sites of ongoing DNA synthesis, suggesting that it may directly interfere with S phase initiation and/or progression. In contrast, the isolated Zn finger region of BCL6, which binds BCL6 target sequence but lacks transcriptional repression activity, slows, but does not suppress, U2OS cell growth, is less efficient at delaying S phase progression, and does not trigger apoptosis. Thus, for a large part, the effects of BCL6 overexpression on cell growth and survival depend on its ability to engage protein/protein interactions with itself and/or its transcriptional corepressors. That BCL6 restricts cell growth suggests that its deregulation upon structural alterations may alleviate negative controls on the cell cycle and cell survival.

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Acknowledgements

We are indebted to Tim Bestor for his insightful suggestions. We thank Hermann Bujard, Dominique Leprince and Patrick Martin for the gift of different plasmids used in this study. Anne Fernandez for the anti-Cyclin A antibody, and Olga Lefebvre, Patrick Martin, Gilles Carnac and Marcel Koken for many comments and support throughout this work. We are also grateful to Martial Flactif from the Service d'Imagerie Cellulaire of the IFR 22 for the confocal microscopy, and to Geraldine Buffenoir and Rodolphe Vereecque for their help. Catherine Lindon is a recipient of a fellowship from Association Française contre les Myopathies (AFM) and Frédérique Quignon is supported by grants from Association pour la Recherche contre le Cancer (ARC) and Fondation pour la Recherche Médicale (FRM). This work is supported by grants from INSERM, CNRS, Ligue Nationale contre le Cancer and ARC and Fondation de France.

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Albagli, O., Lantoine, D., Quief, S. et al. Overexpressed BCL6 (LAZ3) oncoprotein triggers apoptosis, delays S phase progression and associates with replication foci. Oncogene 18, 5063–5075 (1999). https://doi.org/10.1038/sj.onc.1202892

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Keywords

  • BCL6(LAZ3) protooncogene
  • tetracycline regulated expression
  • cell cycle
  • DNA replication
  • growth suppression
  • apoptosis

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