Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers

Abstract

To cite this article: Pavlina Dolezelova, Katerina Cetkovska, Karen H Vousden & Stjepan Uldrijan (2012) Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers, Cell Cycle, 11:5,[953][954][955][956][957][958][959][960][961][962]

Dysfunction of the MDM2/p53 axis is linked to premature aging

“…Consistent with the study mentioned above (27), we showed that ectopically expressed MDM2 with the antiterminating mutation is defective in its ability to degrade both ectopic and endogenous p53 in U2OS cells (Supplemental Figure 2, B and C). In fact, expression of mutant MDM2 led to increased levels of p53 protein in either case.…”

“…Previous cell-based transfection studies have shown that the highly conserved extreme C-terminus of MDM2 is essential for its oligomerization and E3 ubiquitin ligase activity (25,26). In addition, a more recent study showed that the same MDM2 variant, when ectopically expressed, is unable to degrade coexpressed p53 in vitro (27).…”

“…Reports that defective E3 ligase activity due to mutations or extensions in the extreme C terminus of MDM2 can be partially rescued by coexpression of the MDM2 homolog MDMX could explain the viability of the Tyr487Ala mouse in comparison with the Cys462Ala mouse (25)(26)(27). However, since MDM2 variants with mutations in the last 5 amino acids of MDM2 share characteristic properties with those of antiterminating MDM2 mutations, it is surprising that the Tyr487Ala mouse does not display some segmental progeroid characteristics (25)(26)(27). We speculate that key differences between our index patient and Tyr487Ala mice could account for the different phenotypes.…”

The p53–Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans

“…S9A,B). Consistent with other C ′ -terminal RING domain-containing proteins (Dolezelova et al 2012), there are exactly 13 amino acids following the final cysteine residue, and, as with HDM2 (Fang et al 2000), there are seven critical cysteine residues that are conserved for ubiquitin ligation activity and p53 degradation (Supplemental Fig. S10).…”

Limiting the power of p53 through the ubiquitin proteasome pathway

“…However, recent studies have also implicated the extreme C-terminal amino acids of Mdm2 in E3 ligase function (Uldrijan et al 2007). Mutations of cysteine residues in human MDM2 (C447, C462, or C475) that are critical for the structure of the RING domain (Sharp et al 1999;Argentini et al 2000;Fang et al 2000) or changes in the C-terminal tail length by either deletion of five amino acids or extension of five residues (by bypassing the stop codon) substantially inhibit its E3 ligase activity (Poyurovsky et al 2010;Dolezelova et al 2012). Another important feature of the Mdm2 RING domain is that it interacts with an Mdm2-related protein, Mdm4 (Sharp et al 1999;Tanimura et al 1999).…”