Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53*

By Shengyun Fang, J. P. Jensen, R. Ludwig, Karen H. Vousden, A. Weissman. Journal of Biological Chemistry, 2000

1,139 citations recorded by the source corpus.

Mdm2 has been shown to regulate p53 stability by targeting the p53 protein for proteasomal degradation. We now report that Mdm2 is a ubiquitin protein ligase (E3) for p53 and that its activity is dependent on its RING finger. Furthermore, we show that Mdm2 mediates its own ubiquitination in a RING finger-dependent manner, which requires no eukaryotic proteins other than ubiquitin-activating enzyme (E1) and an ubiquitin-conjugating enzyme (E2). It is apparent, therefore, that Mdm2 manifests an intrinsic capacity to mediate ubiquitination. Mutation of putative zinc coordination residues abrogated this activity, as did chelation of divalent cations. After cation chelation, the full activity could be restored by addition of zinc. We further demonstrate that the degradation of p53 and Mdm2 in cells requires additional potential zinc-coordinating residues beyond those required for the intrinsic activity of Mdm2 in vitro. Replacement of the Mdm2 RING with that of another protein (Praja1) reconstituted ubiquitination and proteasomal degradation of Mdm2. However, this RING was ineffective in ubiquitination and proteasomal targeting of p53, suggesting that there may be specificity at the level of the RING in the recognition of heterologous substrates.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/3b6a4cded80f6fd3560978765e9ec0530a9fc7fc

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Citations in the corpus

The complexity of p53 stabilization and activation (2006, background): “MDM2 is an E3 ubiquitin ligase capable of targeted ubiquitination of p53 but it also self-ubiquitinates.(54) Exposure of cells to stress reduces sumoylation of MDM2, and causes an increase in self-ubiquitination and degradation, thus favouring p53 stabilization.”
RING finger proteins: mediators of ubiquitin ligase activity. (2000, background): “Similarly, the E3 activity of Mdm2 toward to Ub conjugation, interact with E2 and substrate, facili- p53 and itself has now been determined to be due to tating formation of isopeptide bonds between the C its atypical C-terminal RING (Fang et al., 2000; Honda terminus of Ub and lysines (Lys) either o”
Cellular response to oxidative stress: Signaling for suicide and survival * (2002, background): “Serine-20 phosphorylation is important for p53 stabilization because this modification interferes with p53’s association with its inhibitor, Mdm2, a primary mediator of p53 degradation (Fang et al., 2000).”
Malignant astrocytic glioma: genetics, biology, and paths to treatment. (2007, background): “…cell line, and then later found to be a key negative regulator of p53 during normal development and in tumorigenesis (Fakharzadeh et al. 1991; Momand et al. 1992; Oliner et al. 1993; Jones et al. 1995; Montes de Oca Luna et al. 1995; Honda et al. 1997; Fang et al. 2000; Honda and Yasuda 2000).”
Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. (2004, background): “These ubiquitination as well as the ubiquitination of p53 (Fang et al., 2000; Honda and Yasuda, 2000).data show that a key activity of Mdm2 in homeostatic tissues is to inhibit the growth-suppressing effects of p53.”
The MDM2-p53 interaction. (2003, background): “MDM2 harbors a self- and p53-specific E3 ubiquitin ligase activity within its evolutionarily conserved COOH terminal RING finger domain (Zinc-binding), and its RING finger is critical for its E3 ligase activity (21).”
RING domain E3 ubiquitin ligases. (2009, background): “Prominent examples include ubiquitination of p53 by Mdm2 (83) and histone H2B by Bre1-Rad6 (84, 85).”