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Polyhomeotic has a tumor suppressor activity mediated by repression of Notch signaling

Nature Genetics volume 41, pages 1076–1082 (2009)Cite this article

Abstract

Polycomb Group (PcG) proteins silence critical developmental genes and modulate cell proliferation. Using the Drosophila melanogaster eye as a model system, we show that cells with mutations in the gene locus (ph) that encodes the PcG protein Polyhomeotic (PH) overproliferate and lose both the ability to differentiate and their normal polarity. They invade the neighboring tissues and, when combined with an activated form of the Ras proto-oncogene, they trigger the formation of metastases. PcG proteins bind to multiple genes in the Notch pathway and control their transcription as well as Notch signaling. The massive cell-autonomous overproliferation of ph mutant cell clones can be rescued by ectopic expression of a dominant negative form of Notch or by RNA interference (RNAi)-mediated repression of Notch. Conversely, overexpression of ph induces a small-eye phenotype that is rescued by activation of Notch signaling. These data show that ph is a tumor suppressor locus that controls cellular proliferation by silencing multiple Notch signaling components.

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Figure 1: The ph505 null mutation induces massive overgrowth during larval and adult stages.
Figure 2: ph505 mutant cells in eye discs escape normal cell cycle exit.
Figure 3: Loss of ph disrupts epithelial polarity.
Figure 4: ph mutation induces malignant tumors.
Figure 5: Components of the Notch signaling pathway are directly repressed by PcG proteins to regulate eye tissue growth.
Figure 6: ph overexpression induces small-eye phenotypes in a Notch-dependent manner.

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Acknowledgements

We are grateful to N. Azpiazu, M. Dominguez, F. Maschat, J. Treisman, L. Jan, S. Artavanis-Tsakonas, J.-M. Dura, Y.N. Jan, J. Müller, M. O'Connor, F. Schweisguth, T. Xu, the Bloomington Stock Center (Indiana University) and the Developmental Studies Hybridoma Bank (University of Iowa) for fly stocks and antibodies (see Supplementary Acknowledgments for details). We thank C. Cazevieille, N. Lautredou and C. Duperray for technical assistance. We also thank F. Bantignies for his contribution on PC foci analysis, T. Sexton for critical reading of the manuscript and members of the Cavalli lab for discussion. G.C.'s research was supported by grants from the CNRS, the Human Frontier Science Program Organization, the European Union FP6 (Network of Excellence the Epigenome and STREP 3D Genome), the Agence Nationale de la Recherche, the Association pour la Recherche sur le Cancer, the Fondation pour la Recherche Médicale and the Ministère de l'Enseignement Supérieur.

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Authors and Affiliations

  1. Institut de Génétique Humaine, Centre Nationale de la Recherche Scientifique, Montpellier, France

    Anne-Marie Martinez, Bernd Schuettengruber, Samy Sakr & Giacomo Cavalli

  2. Faculté des Sciences, Université de Montpellier 2, Montpellier, France

    Anne-Marie Martinez

  3. Cell Division Group, Institute for Research in Biomedicine and Institució Catalana de Recerca i Estudis Avançats, Parc Científic Barcelona, Barcelona, Spain

    Ana Janic & Cayetano Gonzalez

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  1. Anne-Marie Martinez
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Contributions

A.-M.M. and G.C. designed experiments and wrote the manuscript. A.-M.M. and S.S. did clonal analysis and immunostaining experiments. B.S. performed RT-PCR and ChIP experiments. A.J. and C.G. performed transplantation experiments. All authors discussed the text of the manuscript.

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Correspondence to Anne-Marie Martinez or Giacomo Cavalli.

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Supplementary Acknowledgments, Supplementary Figures 1–15 and Supplementary Tables 1 and 2 (PDF 4454 kb)

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Martinez, AM., Schuettengruber, B., Sakr, S. et al. Polyhomeotic has a tumor suppressor activity mediated by repression of Notch signaling. Nat Genet 41, 1076–1082 (2009). https://doi.org/10.1038/ng.414

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