Role of T198 Modification in the Regulation of p27Kip1 Protein Stability and Function 英文参考文献.docVIP

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Role of T198 Modification in the Regulation of p27Kip1 Protein Stability and Function 英文参考文献.doc

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Role of T198 Modification in the Regulation of p27Kip1 Protein Stability and Function 英文参考文献

RoleofT198ModificationintheRegulationofp27Kip1 ProteinStabilityandFunction MonicaSchiappacassi.,SaraLovisa.,FrancescaLovat,LindaFabris,AlfonsoColombatti,Barbara Belletti,GustavoBaldassarre* DivisionofExperimentalOncology2,CentrodiRiferimentoOncologico,NationalCancerInstitute,Aviano,Italy Abstract Thetumorsuppressorgenep27Kip1playsafundamentalroleinhumancancerprogression.Itsexpressionand/orfunctions arealteredinalmostallthedifferenttumorhistotypeanalyzedsofar.Recently,ithasbeendemonstratedthatthetumor suppressionfunctionofp27residesnotonlyintheabilitytoinhibitCyclins/CDKscomplexesthroughitsN-terminaldomain butalsointhecapacitytomodulatecellmotilitythroughitsC-terminalportion.Particularinteresthasbeenraisedbythe lastamino-acid, (Threonine198)intheregulationofbothproteinstabilityandcellmotility. Here,wedescribethatthe presenceofThreonineinposition198isofprimaryimportancefortheregulationoftheproteinstabilityandforthecontrol ofcellmotility.However,whilethecontrolofcellmotilityisdependentonthephosphorylationofT198,thestabilityofthe proteinisspecificallycontrolledbythesterichindranceofthelastaminoacid.TheeffectsofT198modificationonprotein stabilityarenotlinkedtothecapacityofp27tobindCyclins/CDKscomplexesand/ortheF-boxproteinSkp2.Conversely, ourresultssupportthehypothesisthatconformationalchangesinthedisorderedstructureoftheC-terminalportionofp27 are important in its ability to be degraded via a proteasome-dependent mechanism. On the other hand T198 phosphorylationfavorsp27/stathmininteractioneventuallycontributingtotheregulationofcellmotility,supportingthe hypothesisthatthepresenceofT198isfundamentalfortheregulationofp27functions. Citation: SchiappacassiM, LovisaS,Lovat F,FabrisL, Colombatti A,etal.(2011)RoleofT198Modificationin theRegulation ofp27Kip1 ProteinStabilityand Function.PLoSONE6(3):e17673.doi:10.1371/journal.pone.0017673 Editor:JanineSantos,UniversityofMedicineandDentistryofNewJersey,UnitedStatesofAmerica ReceivedSeptember8,2010;AcceptedFebruary1