MDM2-C Functions as an E3 Ubiquitin Ligase
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Jun Yeob Kim,1 Rusia Lee,1,2 Gu Xiao,1 Dominique Forbes,1 Jill Bargonetti1– 3 1The Department of Biological Sciences, Hunter College, City University of New York, New York, NY, USA; 2Biology PhD Program, The Graduate Center of Biology, City University of New York, New York, NY, USA; 3Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10021, USACorrespondence: Jill Bargonetti The Department of Biological SciencesHunter College, Belfer Building, 413 East 69 th Street, New York, NY 10021, USATel +1 212-896-0465Email bargonetti@genectr.hunter.cuny.eduBackground: Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that is over-expressed in many cancers and regulates target proteins through ubiquitination. Full-length MDM2 (MDM2-FL) is best known for targeting wild-type p53 for degradation by the proteasome, but the functions of the many splice variants of MDM2 are under-explored. The three well-studied alternative MDM2 isoforms are MDM2-A/ALT2, MDM2-B/ALT1, and MDM2-C/ALT3. MDM2-A and MDM2-B are capable of down-regulating MDM2-FL activity and have transforming activity in cancers with mutant p53. The MDM2 isoform MDM2-C is over-expressed in breast cancer and correlates with decreased survival in the context of mutant p53 expression. Therefore, MDM2-C requires further study to determine if it has biochemical activities similar to MDM2-FL. Hypothesis: We hypothesized that like MDM2-FL, the MDM2-C isoform (lacking exons 5– 9 and containing a full C-terminal RING finger sequence) would maintain E3 ubiquitin ligase activity.Materials and Methods: In order to explore the biochemical function of MDM2-C, we used an in vitro ubiquitination assay and a glutaraldehyde cross-linking assay.Results: Here we report, for the first time, that MDM2-C has E3 auto-ubiquitin ligase activity, which can promote ubiquitination of wild-type p53 and mutant p53 R273H, and also can form a protein–protein interaction with p53 proteins.Conclusion: This information strongly positions MDM2-C as a protein with biochemical activities that may explain the varied outcomes observed in patients with high-level expression of MDM2-C in the presence of wild-type p53 versus mutant p53.Keywords: MDM2 splice variants, mutant p53, wild-type p53, breast cancer
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