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A ribosomal protein L23-nucleophosmin circuit coordinates Miz1 function with cell growth

Nature Cell Biology volume 10, pages 1051–1061 (2008)Cite this article

Abstract

The Myc-associated zinc-finger protein, Miz1, is a negative regulator of cell proliferation and induces expression of the cell-cycle inhibitors p15Ink4b and p21Cip1. Here we identify the ribosomal protein L23 as a negative regulator of Miz1-dependent transactivation. L23 exerts this function by retaining nucleophosmin, an essential co-activator of Miz1 required for Miz1-induced cell-cycle arrest, in the nucleolus. Mutant forms of nucleophosmin found in acute myeloid leukaemia fail to co-activate Miz1 and re-localize it to the cytosol. As L23 is encoded by a direct target gene of Myc, this regulatory circuit may provide a feedback mechanism that links translation of Myc target genes and cell growth to Miz1-dependent cell-cycle arrest.

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Figure 1: Identification of L23 as a negative regulator of Miz1 function.
Figure 2: Depletion of endogenous L23 activates target genes of Miz1.
Figure 3: Nucleophosmin is a co-activator of Miz1.
Figure 4: Nucleophosmin interacts with the POZ-domain of Miz1.
Figure 5: L23 and Myc disrupt the complex between Miz1 and nucleophosmin.
Figure 6: Nucleophosmin is an essential co-activator of Miz1.
Figure 7: Mutant alleles of nucleophosmin fail to co-activate Miz1.
Figure 8: A potential feedback loop monitors translation of Myc target genes.

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Acknowledgements

This study was supported by grants from the Deutsche Forschungsgemeinschaft through the Transregio 17 (Ras-dependent Pathways in Human Tumorigenesis) and the Research Group Chromatin-mediated Biological Decisions. The authors thank Katrien Berns and Rene Bernards for help with retroviral cloning techniques and Bianca Jebavy and Doris Dobrin for excellent technical support.

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Authors and Affiliations

  1. Institute for Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Str.2, Marburg, 35033

    Michael Wanzel, Annika C. Russ & Martin Eilers

  2. Germany

    Michael Wanzel, Annika C. Russ & Martin Eilers

  3. Biotech Research and Innovation Centre (BRIC), Copenhagen Biocenter,

    Daniela Kleine-Kohlbrecher

  4. Ole Maaløes Vej 5, Copenhagen N, DK-2200, Denmark

    Daniela Kleine-Kohlbrecher

  5. Department of Experimental Oncology, Instituto Europeo di Oncologia, Via Ripamonti 435

    Emanuela Colombo & Pier-Guiseppe Pelicci

  6. Milan, 20141, Italy

    Emanuela Colombo & Pier-Guiseppe Pelicci

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  1. Michael Wanzel
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Contributions

M.W., A.C.R and D.K.K. performed the experiments; E.C. and P.-G.P provided reagents and advice; M.W. and M.E. analysed the data and planned the project.

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Correspondence to Martin Eilers.

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Supplementary Figures S1, S2, S3, S4, S5, S6, S7, S8 and Supplementary Table S1 (PDF 1507 kb)

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Wanzel, M., Russ, A., Kleine-Kohlbrecher, D. et al. A ribosomal protein L23-nucleophosmin circuit coordinates Miz1 function with cell growth. Nat Cell Biol 10, 1051–1061 (2008). https://doi.org/10.1038/ncb1764

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