Critical role for Daxx in regulating Mdm2

• Published in: Nature cell biology Vol. 8; no. 8; pp. 855 - 862
• Main Authors: Yang, Xiaolu, Tang, Jun, Qu, Li-Ke, Zhang, Jianke, Wang, Wenge, Michaelson, Jennifer S, Degenhardt, Yan Y, El-Deiry, Wafik S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.08.2006
• Subjects: Animals; Apoptosis; Blotting, Western; Cancer research; Carrier Proteins - genetics; Carrier Proteins - metabolism; Carrier Proteins - physiology; Cell Line; Degradation; Deoxyribonucleic acid; DNA; DNA Damage; Endopeptidases - metabolism; Genetic aspects; Genetic regulation; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HCT116 Cells; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Intracellular Signaling Peptides and Proteins - physiology; Kinases; Medical research; Medicine; Mice; Microscopy, Fluorescence; Models, Biological; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Physiological aspects; Protein Binding; Proteins; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; RNA Interference; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ubiquitin - metabolism; Ubiquitin Thiolesterase; Ubiquitin-proteasome system; Ubiquitin-Specific Peptidase 7; United States; United States > US
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb1442

The tumour suppressor p53 induces apoptosis or cell-cycle arrest in response to genotoxic and other stresses. 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 degradation. 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) 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.