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  • Original Paper
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Regulation of Pax3 transcriptional activity by SUMO-1-modified PML

Oncogene volume 20, pages 1–9 (2001)Cite this article

Abstract

Pax3 is an evolutionarily conserved transcription factor that plays a major role in a variety of developmental processes. Mutations in Pax3 lead to severe malformations as seen in human Waardenburg syndrome and in the Splotch mutant mice. The transcriptional activity of Pax3 was recently shown to be repressed by Daxx whereas the oncogenic fusion protein Pax3-FKHR is unresponsive to this repressive action. Here we demonstrate that Daxx-mediated repression of Pax3 can be inhibited by the nuclear body (NB)-associated protein PML. Interestingly, this suppression of Daxx properties correlates with its recruitment to the NBs. Factors such as arsenicals and interferons that enhance NB formation, trigger both the targeting of Daxx to these nuclear structures and the relief of the repressive activity of Daxx. Conversely, lack of structurally intact NBs profoundly impairs Pax3 transcriptional activity, likely by increasing the pool of available nucleoplasmic Daxx. Moreover, a PML mutant that can not be modified by the ubiquitin-related SUMO-1 modifier is no more able to interact with Daxx. Consistently, such a mutant fails both to inhibit the Daxx repressing effect on Pax3 and to induce its accumulation into the NBs. Taken together, these results argue that SUMO-1 modified PML can derepress Pax3 transcriptional activity through sequestration of the Daxx repressor into the NBs and suggest a role for these nuclear structures in the transcriptional control by Pax proteins.

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Acknowledgements

We greatly acknowledge Andrew Hollenbach and Gerald Grosveld for helpful discussion and for the gift of antibodies and expression vectors. We are indebted to Paul Freemont, Roel van Driel, Alexander Ishov and Gerd Maul for providing reagents used in these experiments. We wish to thank Emmanuelle Perret for excellent help with confocal microscopy. We thank Pierre Tiollais for support, and all members of our group for stimulating discussions and for providing reagents. This work was supported by grants from the Association pour la Recherche contre le Cancer, the European Economic Community (Biomed 2, PCRD), and the Association for International Cancer Research. F Lehembre was supported by a fellowship from la Fondation pour la Recherche Medicale. S Müller was supported by a fellowship from the Association for International Cancer Research.

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  1. Unité de Recombinaison et Expression Génétique, INSERM U 163, Institut Pasteur, 28 rue du Dr Roux, Paris, 75724, Cedex 15, France

    François Lehembre, Stefan Müller & Anne Dejean

  2. Department of Human Genetics and Molecular Biology Program, Memorial Sloan-kettering Cancer Center, Cornel University, New York, 10021, NY, USA

    Pier Paolo Pandolfi

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  1. François Lehembre
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Lehembre, F., Müller, S., Pandolfi, P. et al. Regulation of Pax3 transcriptional activity by SUMO-1-modified PML. Oncogene 20, 1–9 (2001). https://doi.org/10.1038/sj.onc.1204063

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