Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0062564
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dc.titleIn Vitro Selection of Mutant HDM2 Resistant to Nutlin Inhibition
dc.contributor.authorWei, S.J.
dc.contributor.authorJoseph, T.
dc.contributor.authorSim, A.Y.L.
dc.contributor.authorYurlova, L.
dc.contributor.authorZolghadr, K.
dc.contributor.authorLane, D.
dc.contributor.authorVerma, C.
dc.contributor.authorGhadessy, F.
dc.date.accessioned2014-10-27T08:31:20Z
dc.date.available2014-10-27T08:31:20Z
dc.date.issued2013-04-30
dc.identifier.citationWei, S.J., Joseph, T., Sim, A.Y.L., Yurlova, L., Zolghadr, K., Lane, D., Verma, C., Ghadessy, F. (2013-04-30). In Vitro Selection of Mutant HDM2 Resistant to Nutlin Inhibition. PLoS ONE 8 (4) : -. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0062564
dc.identifier.issn19326203
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/100903
dc.description.abstractHDM2 binds to the p53 tumour suppressor and targets it for proteosomal degradation. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2 and abrogates its repressive function. Using a novel in vitro selection methodology, we simulated the emergence of resistance by evolving HDM2 mutants capable of binding p53 in the presence of Nutlin concentrations that inhibit the wild-type HDM2-p53 interaction. The in vitro phenotypes were recapitulated in ex vivo assays measuring both p53 transactivation function and the direct p53-HDM2 interaction in the presence of Nutlin. Mutations conferring drug resistance were not confined to the N-terminal p53/Nutlin-binding domain, and were additionally seen in the acidic, zinc finger and RING domains. Mechanistic insights gleaned from this broad spectrum of mutations will aid in future drug design and further our understanding of the complex p53-HDM2 interaction. © 2013 Wei et al.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1371/journal.pone.0062564
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentBIOLOGICAL SCIENCES
dc.description.doi10.1371/journal.pone.0062564
dc.description.sourcetitlePLoS ONE
dc.description.volume8
dc.description.issue4
dc.description.page-
dc.identifier.isiut000319077300076
dc.published.statePublished
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