Journal
CELL
Volume 101, Issue 7, Pages 753-762Publisher
CELL PRESS
DOI: 10.1016/S0092-8674(00)80887-9
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Funding
- NCI NIH HHS [CA55908, CA80058] Funding Source: Medline
- NIGMS NIH HHS [GM55059] Funding Source: Medline
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Mdm2 is an E3 ubiquitin ligase for the p53 tumor suppressor protein. We demonstrate that Mdm2 is conjugated with SUMO-1 (sumoylated) at Lys-446, which is located within the RING finger domain and plays a critical role in Mdm2 self-ubiquitination. Whereas mutant Mdm2(K446R) is stabilized, it elicits increased degradation of p53 and concomitant inhibition of p53-mediated apoptosis. In vitro sumoylation of Mdm2 abrogates its self-ubiquitination and increases its ubiquitin ligase activity toward p53. Radiation caused a dose- and time-dependent decrease in the degree of Mdm2 SUMO-1 modification, which is inversely correlated with the levels of p53. Our results suggest that the maintenance of the intrinsic activity of a RING finger E3 ubiquitin ligase is sumoylation dependent and that reduced Mdma sumoylation in response to DNA damage contributes to p53 stability.
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