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  • Original Article
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PML4 induces differentiation by Myc destabilization

Oncogene volume 26, pages 3415–3422 (2007)Cite this article

Abstract

Opposing functions like oncogene and tumor suppressions have been established for c-Myc and promyelocytic leukemia (PML) protein, respectively. Myc is known to inhibit differentiation of hematopoietic precursor cells, and here we report that PML promotes cell differentiation. We further demonstrate that PML and Myc form a complex in vivo. The interaction of the two proteins leads to the destabilization of Myc in a manner dependent on the really interesting new gene (RING) domain of PML. Although several PML isoforms are able to interact with Myc, the ability to destabilize Myc is specific for PML4. Importantly, the PML-induced destabilization resulted in a reduction of promoter-bound Myc on Myc-repressed genes. Thereby, PML induced the re-activation of Myc-repressed target genes including the tumor suppressive genes of the cell cycle inhibitors cdkn1a/p21 and cdkn2b/p15. Together, these results establish PML-mediated destabilization of Myc and the derepression of cell cycle inhibitor genes as an important regulatory mechanism that allows cell differentiation and prevents aberrant proliferation driven by uncontrolled Myc activity.

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Abbreviations

aa:

amino acids

RARα:

retinoic acid receptor alpha

HA:

hemagglutinin

PML:

promyelocytic leukemia protein

TGFβ:

transforming growth factor beta

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Acknowledgements

We thank KS Chang, Y Haupt, M Oren, B Amati, F Fuks, W Tansey, S Salghetti, M Edel, D Tenen, M Eilers, D Bowmann, S Jentsch and J Seoane for providing reagents. We gratefully acknowledge Hoffmann-LaRoche (Switzerland) for providing 1α,25-dihydroxyvitamin D3. We thank B Amati, PG Pelicci, T Graf, J Seoane and members of the Di Croce laboratory for helpful discussions. This work was supported by grants from ‘Fundació La Marató TV3’ and the Spanish Consolider (Ministerio de Educacion y Ciencia). MB was supported by Fellowships from the European Molecular Biology Organisation and Deutsche Forschungsgesellschaft; IU by an FPI fellowship and SM by the Deutsche Forschungsgemeinschaft and the German Israeli Foundation for Development and Scientific Research.

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Authors and Affiliations

  1. Centre de Regulació Genòmica (CRG)/PRBB and Universitat Pompeu Fabra, Barcelona, Spain

    M Buschbeck, I Uribesalgo, A Gutierrez & L Di Croce

  2. Max-Planck-Institute of Biochemistry, Martinsried, Germany

    A Ledl & S Muller

  3. European Institute of Oncology (IEO), Milan, Italy

    S Minucci

  4. Centre de Regulació Genòmica (CRG) and Institució Catalana de Recerca i Estudis Avançats (ICREA), Spain

    L Di Croce

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  1. M Buschbeck
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  2. I Uribesalgo
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  6. S Muller
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  7. L Di Croce
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Correspondence to L Di Croce.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Buschbeck, M., Uribesalgo, I., Ledl, A. et al. PML4 induces differentiation by Myc destabilization. Oncogene 26, 3415–3422 (2007). https://doi.org/10.1038/sj.onc.1210128

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