The Arf tumor suppressor protein inhibits Miz1 to suppress cell adhesion and induce apoptosis |
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| Authors: | Barbara Herkert Anne Dwertmann Steffi Herold Mona Abed Jean-Francois Naud Florian Finkernagel Gregory S. Harms Amir Orian Michael Wanzel Martin Eilers |
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| Affiliation: | 1.Theodor-Boveri-Institute, and 2.Rudolf-Virchow-Center, University of Würzburg, D-97070 Würzburg, Germany;3.Center for Vascular and Cancer Biology, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel;4.Institute of Molecular Biology and Tumor Research, University of Marburg, D-35033 Marburg, Germany |
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| Abstract: | Oncogenic stress induces expression of the alternate reading frame (Arf) tumor suppressor protein. Arf then stabilizes p53, which leads to cell cycle arrest or apoptosis. The mechanisms that distinguish both outcomes are incompletely understood. In this study, we show that Arf interacts with the Myc-associated zinc finger protein Miz1. Binding of Arf disrupts the interaction of Miz1 with its coactivator, nucleophosmin, induces the sumoylation of Miz1, and facilitates the assembly of a heterochromatic complex that contains Myc and trimethylated H3K9 in addition to Miz1. Arf-dependent assembly of this complex leads to the repression of multiple genes involved in cell adhesion and signal transduction and induces apoptosis. Our data point to a tumor-suppressive pathway that weakens cell–cell and cell–matrix interactions in response to expression of Arf and that may thereby facilitate the elimination of cells harboring an oncogenic mutation. |
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