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dc.contributor.authorStindt, MH
dc.contributor.authorMuller, PAJ
dc.contributor.authorLudwig, RL
dc.contributor.authorKehrloesser, Sebastian
dc.contributor.authorDötsch, V
dc.contributor.authorVousden, KH
dc.date.accessioned2018-11-14T00:30:23Z
dc.date.available2018-11-14T00:30:23Z
dc.date.issued2015-08-13
dc.identifier.issn0950-9232
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285017
dc.description.abstractMany cancers express mutant p53 proteins that have lost wild-type tumor suppressor activity and, in many cases, have acquired oncogenic functions that can contribute to tumor progression. These activities of mutant p53 reflect interactions with several other proteins, including the p53 family members p63 and p73. Mutations in p53 that affect protein conformation (such as R175H) show strong binding to p63 and p73, whereas p53 mutants that only mildly affect the conformation (such as R273H) bind less well. A previously described aggregation domain of mutant p53 is not required for p63 or p73 binding; indeed, mutations within this region lead to the acquisition of a mutant p53 phenotype-including a conformational shift, p63/p73 binding and the ability to promote invasion. The activity of wild-type p53 is regulated by an interaction with MDM2 and we have investigated the potential role of MDM2 in the mutant p53/p63/p73 interactions. Both mutant p53 and p73 bind MDM2 well, whereas p63 binds much more weakly. We found that MDM2 can inhibit p63 binding to p53R175H but enhances the weaker p53R273H/p73 interaction. These effects on the interactions are reflected in an ability of MDM2 to relieve the inhibition of p63 by p53R175H, but enhance the inhibition of p73 activity by p53R175H and R273H. We propose a model in which MDM2 competes with p63 for binding to p53R175H to restore p63 activity, but forms a trimeric complex with p73 and p53R273H to more strongly inhibit p73 function.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/4.0/
dc.subjectCell Line
dc.subjectCell Line, Tumor
dc.subjectHCT116 Cells
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectDNA-Binding Proteins
dc.subjectMembrane Proteins
dc.subjectTumor Suppressor Proteins
dc.subjectNuclear Proteins
dc.subjectProtein Binding
dc.subjectMutation
dc.subjectTumor Suppressor Protein p53
dc.subjectProto-Oncogene Proteins c-mdm2
dc.subjectProtein Interaction Domains and Motifs
dc.subjectHEK293 Cells
dc.subjectTumor Protein p73
dc.titleFunctional interplay between MDM2, p63/p73 and mutant p53.
dc.typeArticle
prism.endingPage4310
prism.issueIdentifier33
prism.publicationDate2015
prism.publicationNameOncogene
prism.startingPage4300
prism.volume34
dc.identifier.doi10.17863/CAM.32387
dcterms.dateAccepted2014-09-14
rioxxterms.versionofrecord10.1038/onc.2014.359
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2015-08
dc.contributor.orcidKehrloesser, Sebastian [0000-0002-6791-2421]
dc.identifier.eissn1476-5594
rioxxterms.typeJournal Article/Review
cam.issuedOnline2014-11-24


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