Dissecting the Signaling Events That Impact Classical Nuclear Import and Target Nuclear Transport Factors 英文参考文献.docVIP

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Dissecting the Signaling Events That Impact Classical Nuclear Import and Target Nuclear Transport Factors 英文参考文献.doc

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Dissecting the Signaling Events That Impact Classical Nuclear Import and Target Nuclear Transport Factors 英文参考文献

DissectingtheSignalingEventsThatImpactClassical NuclearImportandTargetNuclearTransportFactors MohamedKodiha,DanTran,AndreeaMorogan,CynthiaQian,UrsulaStochaj* DepartmentofPhysiology,McGillUniversity,Montreal,Canada Abstract Background:SignalingthroughMEKRERK1/2andPI3kinasesisimplicatedinmanyaspectsofcellphysiology,including thesurvivalofoxidantexposure.Oxidantsplayaroleinnumerousphysiologicalandpathophysiologicalprocesses,manyof which rely on transport in and out of the nucleus. However, how oxidative stress impacts nuclear trafficking is not well defined. Methodology/PrincipalFindings:Tobetterunderstandtheeffectofstressonnucleocytoplasmictrafficking,weexposed cells to the oxidant diethyl maleate. This treatment activated MEKRERK1/2 as well as PI3 kinaseRAkt cascades and triggeredtheinhibitionofclassicalnuclearimport.Todefinethemolecularmechanismsthatregulatenucleartransport,we examinedwhetherMEKandPI3kinasesignalingaffectedthelocalizationofkeytransportfactors.Usingrecentlydeveloped tools for image acquisition and analysis, the subcellular distributions of importin-a, CAS, and nucleoporins Nup153 and Nup88werequantifiedindifferentcellularcompartments.Thesestudiesidentifiedspecificprofilesforthelocalizationof transport factors in the nucleus and cytoplasm, and at the nuclear envelope. Our results demonstrate that MEK and PI3 kinase signaling as well as oxidative stress control nuclear trafficking and the localization of transport components. Furthermore, stress not only induced changes in transport factor distribution, but also upregulated post-translational modification of transport factors. Our results are consistent with the idea that the phosphorylation of importin-a , CAS, Nup153,andNup88,andtheO-GlcNAcmodificationofNup153increasewhencellsareexposedtooxidant. Conclusions/Significance: Our studies defined the complex regulation of classical nuclear import and identified key transportfactorsthataretargetedbystress,MEK,andPI3kinasesignaling. Citation: Kodiha M, Tr