title: SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53.
abstract: 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 Mdm2 sumoylation in response to DNA damage contributes to p53 stability.
authors.affiliation: Derald H Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: T
authors.initials: T
authors.lastname: Buschmann
authors.forename: S Y
authors.initials: SY
authors.lastname: Fuchs
authors.forename: C G
authors.initials: CG
authors.lastname: Lee
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Pan
authors.forename: Z
authors.initials: Z
authors.lastname: Ronai
mesh_terms: D002461:Cell Line, Transformed; D004249:DNA Damage; D006801:Humans; D009687:Nuclear Proteins; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D025842:SUMO-1 Protein; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025842:SUMO-1 Protein; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2