Letter abstract
Nature Cell Biology 8, 855 - 862 (2006)
Published online: 16 July 2006 | doi:10.1038/ncb1442
Critical role for Daxx in regulating Mdm2
Jun Tang1,7, Li-Ke Qu1,7, Jianke Zhang2, Wenge Wang3, Jennifer S. Michaelson4, Yan Y. Degenhardt5,6, Wafik S. El-Deiry3 & Xiaolu Yang1
The tumour suppressor p53 induces apoptosis or cell-cycle arrest in response to genotoxic and other stresses1, 2. In unstressed cells, the anti-proliferative effects of p53 are restrained by mouse double minute 2 (Mdm2), a ubiquitin ligase (E3) that promotes p53 ubiquitination and degradation3. Mdm2 also mediates its own degradation through auto-ubiquitination. It is unclear how the cis- and trans-E3 activities of Mdm2, which have opposing effects on cell fate, are differentially regulated. Here, we show that death domain-associated protein (Daxx)4 is required for Mdm2 stability. Downregulation of Daxx decreases Mdm2 levels, whereas overexpression of Daxx strongly stabilizes Mdm2. Daxx simultaneously binds to Mdm2 and the deubiquitinase Hausp, and it mediates the stabilizing effect of Hausp on Mdm2. In addition, Daxx enhances the intrinsic E3 activity of Mdm2 towards p53. On DNA damage, Daxx dissociates from Mdm2, which correlates with Mdm2 self-degradation. These findings reveal that Daxx modulates the function of Mdm2 at multiple levels and suggest that the disruption of the Mdm2–Daxx interaction may be important for p53 activation in response to DNA damage.
- Abramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19104, USA.
- Departments of Medicine, Genetics and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
- Department of Exploratory Science, Biogen Idec, Cambridge, MA 02142, USA.
- Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
- Current address: TMG/Human Biomarker Center-PA, GlaxoSmithKline, King of Prussia, PA 19406, USA.
- These authors contributed equally to this work.
Correspondence to: Xiaolu Yang1 e-mail: xyang@mail.med.upenn.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Balancing Mdm2 ? a Daxx?HAUSP matterNature Cell Biology News and Views (01 Aug 2006)
HAUSP hunting the FOX(O)Nature Cell Biology News and Views (01 Oct 2006)
RESEARCH
The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2?DAXX?HAUSP complexThe EMBO Journal Article (09 Jul 2008)
The deubiquitinylation and localization of PTEN are regulated by a HAUSP?PML networkNature Letters to Editor (09 Oct 2008)
See all 23 matches for Research
