Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage

DOI Web Site 被引用文献5件
  • Yaron Pereg
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Dganit Shkedy
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Petra de Graaf
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Erik Meulmeester
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Marina Edelson-Averbukh
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Mogjiborahman Salek
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Sharon Biton
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Amina F. A. S. Teunisse
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Wolf D. Lehmann
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Aart G. Jochemsen
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • Yosef Shiloh
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Molecular and Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands; and Central Spectroscopy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

書誌事項

公開日
2005-03-23
DOI
  • 10.1073/pnas.0408595102
公開者
Proceedings of the National Academy of Sciences

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説明

<jats:p>Maintenance of genomic stability depends on the DNA damage response, an extensive signaling network that is activated by DNA lesions such as double-strand breaks (DSBs). The primary activator of the mammalian DSB response is the nuclear protein kinase ataxia–telangiectasia, mutated (ATM), which phosphorylates key players in various arms of this network. The activation and stabilization of the p53 protein play a major role in the DNA damage response and are mediated by ATM-dependent posttranslational modifications of p53 and Mdm2, a ubiquitin ligase of p53. p53's response to DNA damage also depends on Mdm2-dependent proteolysis of Mdmx, a homologue of Mdm2 that represses p53's transactivation function. Here we show that efficient damage-induced degradation of human Hdmx depends on functional ATM and at least three sites on the Hdmx that are phosphorylated in response to DSBs. One of these sites, S403, is a direct ATM target. Accordingly, each of these sites is important for Hdm2-mediated ubiquitination of Hdmx after DSB induction. These results demonstrate a sophisticated mechanism whereby ATM fine-tunes the optimal activation of p53 by simultaneously modifying each player in the process.</jats:p>

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