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Akt and 14-3-3η regulate Miz1 to control cell-cycle arrest after DNA damage

Nature Cell Biology volume 7, pages 30–41 (2005)Cite this article

Abstract

The transcription factor Miz1 is required for DNA-damage-induced cell-cycle arrest. We have now identified 14-3-3η as a gene that inhibits Miz1 function through interaction with its DNA binding domain. Binding of 14-3-3η to Miz1 depends on phosphorylation by Akt and regulates the recovery of cells from arrest after DNA damage. Miz1 has two functions in response to DNA damage: first, it is required for upregulation of a large group of genes, a function that is regulated by c-Myc, but not by 14-3-3η; second, Miz1 represses the expression of many genes in response to DNA damage in an Akt- and 14-3-3η-regulated manner.

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Figure 1: Miz1 is required for DNA-damage-induced cell-cycle arrest in both rodent and human cells.
Figure 2: Identification of genes that regulate Miz1 function.
Figure 3: 14-3-3η is a negative regulator of Miz1.
Figure 4: 14-3-3η binds to Miz1 and inhibits binding of Miz1 to DNA.
Figure 5: Akt phosphorylates Miz1 at Ser 428 in vitro.
Figure 6: Phosphorylation of Miz1 by Akt in vivo.
Figure 7: Cells expressing Miz1S428A are hypersensitive to DNA damage.
Figure 8: 14-3-3η and Miz1 coordinately regulate gene expression after DNA damage in a PI3K-dependent manner.

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Acknowledgements

This study was supported by grants from the Deutsche Forschungsgemeinschaft, The European Union and the Thyssen-Stiftung to M.E. We thank B. Jebavy and M. Neuhaus for expert technical assistance, M. Krause (MPI for Biochemistry, Munich) and B. Samans (Phillips University, Marburg) for performing and evaluating the microarray experiments, H. Hermeking and J. Daut for the gift of reagents and J. Downward (Cancer Research UK, London) for help with the analysis of phosphorylation sites on Miz1.

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Author notes

  1. Michael Wanzel, Daniela Kleine-Kohlbrecher and Steffi Herold: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Molecular Biology and Tumor Research (IMT), University of Marburg, Emil-Mannkopff-Strasse 2, Marburg, 35033, Germany

    Michael Wanzel, Daniela Kleine-Kohlbrecher, Steffi Herold, Andreas Hock & Martin Eilers

  2. Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands

    Katrien Berns

  3. Friedrich Miescher Institute, Novartis Research Foundation, Maulbeerstrasse 66, Basel, CH 4058, Switzerland

    Jongsun Park & Brian Hemmings

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  1. Michael Wanzel
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Correspondence to Martin Eilers.

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Wanzel, M., Kleine-Kohlbrecher, D., Herold, S. et al. Akt and 14-3-3η regulate Miz1 to control cell-cycle arrest after DNA damage. Nat Cell Biol 7, 30–41 (2005). https://doi.org/10.1038/ncb1202

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