Mdm2 Induces Mono-Ubiquitination of FOXO4 英文参考文献.docVIP

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Mdm2 Induces Mono-Ubiquitination of FOXO4 英文参考文献.doc

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Mdm2 Induces Mono-Ubiquitination of FOXO4 英文参考文献

Mdm2InducesMono-UbiquitinationofFOXO4 ArjanB.Brenkman1¤a,¤b,PeterL.J.deKeizer1,NielsJ.F.vandenBroek1¤a,¤b,A.G.Jochemsen2, BoudewijnM.Th.Burgering1,3 * 1DepartmentofPhysiologicalChemistryandCentreforBiomedicalGenetics,UniversityMedicalCentreUtrecht,Utrecht,TheNetherlands,2DepartmentofMolecularCell Biology, Leiden University Medical Center, Leiden, The Netherlands, 3Department of Physiological Chemistry and Centre for Biomedical Genetics Universiteitsweg, Utrecht,TheNetherlands Abstract Background: The Forkhead box O (FOXO) class of transcription factors are involved in the regulation of several cellular responsesincludingcellcycleprogressionandapoptosis.Furthermore,inmodelorganismsFOXOsactastumorsuppressors and affect aging. Previously, we noted that FOXOs and p53 are remarkably similar within their spectrum of regulatory proteins[1].Forexample,thede-ubiquitinatingenzymeUSP7removesubiquitinfrombothFOXOandp53.However,Skp2 hasbeenidentifiedasE3ligaseforFOXO1,whereasMdm2istheprimeE3ligaseforp53. Principal Findings/Methodology: Here we provide evidence that Mdm2 acts as an E3 ligase for FOXO as well. In vitro incubationofMdm2andFOXOresultsinATP-dependent(multi)mono-ubiquitinationofFOXOsimilartop53.Furthermore, in vivo co-expression of Mdm2 and FOXO induces FOXO mono-ubiquitination and consistent with this result, siRNA- mediateddepletionofMdm2inhibitsmono-ubiquitinationofFOXOinducedbyhydrogenperoxide.RegulationofFOXO ubiquitinationbyMdm2islikelytobedirectsinceMdm2andFOXOco-immunoprecipitate.Inaddition,Mdm2-mediated ubiquitinationregulatesFOXOtranscriptionalactivity. Conclusions/Significance: ThesedataidentifyMdm2asanovelE3ligaseforFOXOsandextendtheanalogousmodeof regulationbetweenFOXOandp53. Citation:BrenkmanAB,deKeizerPLJ,vandenBroekNJF,JochemsenAG,BurgeringBMTh(2008)Mdm2InducesMono-UbiquitinationofFOXO4.PLoSONE3(7): e2819.doi:10.1371/journal.pone.0002819 Editor:MarkR.Cookson,NationalInstitutesofHealth,UnitedStatesofAmerica ReceivedFebruary1,2008;AcceptedJuly7,2008;Pu