Mutant p53 Sequestration of the MDM2 Acidic Domain Inhibits E3 Ligase Activity

ABSTRACT

Missense p53 mutants often accumulate in tumors and drive progression through gain of function. MDM2 efficiently degrades wild-type p53 but fails to degrade mutant p53 in tumor cells. Previous studies revealed that mutant p53 inhibits MDM2 autoubiquitination, suggesting that the interaction inhibits MDM2 E3 activity. Recent work showed that MDM2 E3 activity is stimulated by intramolecular interaction between the RING and acidic domains. Here, we show that in the mutant p53-MDM2 complex, the mutant p53 core domain binds to the MDM2 acidic domain with significantly higher avidity than wild-type p53. The mutant p53-MDM2 complex is deficient in catalyzing ubiquitin release from the activated E2 conjugating enzyme. An MDM2 construct with extra copies of the acidic domain is resistant to inhibition by mutant p53 and efficiently promotes mutant p53 ubiquitination and degradation. The results suggest that mutant p53 interferes with the intramolecular autoactivation mechanism of MDM2, contributing to reduced ubiquitination and increased accumulation in tumor cells.

KEYWORDS:

• E3 ligase
• MDM2
• mutant p53
• RING domain
• acidic domain
• conformation
• ubiquitination

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ACKNOWLEDGMENTS

This work was supported in part by grants from the National Institutes of Health (grants number CA141244 and CA186917) and by NCI Cancer Center support grant number P30-CA076292.

We declare no conflict of interest.

Experimental work was done by L.Y., T.S., Q.C., and L.C. Experimental design was done by L.Y., T.S, Q.C., L.C., and J.C. The manuscript was written by L.Y. and J.C. The study was conceived by J.C.