Human Cytomegalovirus and Map Kinase Pathways

Toreplicateinthehostcell,virusescommandeercellularsignalingpathways.Cytomegalovirus(CMV)isaDNAviruswiththatiswidespreadinthepopulationbutusuallycausesdiseaseonlyinimmunocompromisedindividualsandisalsoaviralcauseofbirthdefects.OneoftheactionsofCMVinthehostcellistostimulateMAPkinasepathways.Bothp38andERKkinasesareactivatedbyCMVinfectionthroughactivationmapkinasekinasesandinhibitionofphosphatases.OneresultofMapkinaseactivationbyCMVisactivationoftranscriptionofviralgenes,increasingtheproductionofviralgeneproducts.Bothp38andERKkinasescontributetotheactivationofviralgenesbycellulartranscriptionfactorsactingthroughtheviralUL4promoteratupstreamandbasaltranscriptionelements.Anothertargetofprolongedp38activationduringinfectionisRb,contributingtoviralreplication.ActivationofMKK1andMKK2leadstoErk1andErk2activation,andphosphorylationofdownstreamtargets.TheMEKK1kinaseregulatestheimmediateearlypromoterindirectlythroughdownstreamkinasesignalingandperhapsmoredirectlythroughactivationofNF-kB.MapkinasepathwaysactivatedbyCMVconvergeonincreasedtranscriptionofviralgenesandincreasedreplicationoftheviralgenome.BetterunderstandingofthemechanismsinvolvedintheinteractionofCMVwithcellularsignalingmachinerywillprovideimprovedwaystotreatCMV-mediateddisease.

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REFERENCES:Chen,J.,Stinski,M.F.(2002)RoleofregulatoryelementsandtheMAPK/ERKorp38MAPKpathwaysforactivationofhumancytomegalovirusgeneexpression.J.Virol.76(10),4873-85.Johnson,R.A.,Huong,S.M.,Huang,E.S.(2000)Activationofthemitogen-activatedproteinkinasep38byhumancytomegalovirusinfectionthroughtwodistinctpathways:anovelmechanismforactivationofp38.J.Virol.74(3),1158-67.Johnson,R.A.,Ma,X.L.,Yurochko,A.D.,Huang,E.S.(2001)TheroleofMKK1/2kinaseactivityinhumancytomegalovirusinfection.J.Gen.Virol.82(Pt3),493-7.Johnson,R.A.,Wang,X.,Ma,X.L.,Huong,S.M.,Huang,E.S.(2001)Humancytomegalovirusup-regulatesthephosphatidylinositol3-kinase(PI3-K)pathway:inhibitionofPI3-Kactivityinhibitsviralreplicationandvirus-inducedsignaling.J.Virol.75(13),6022-32.SanchezV,SpectorDH.Virology.CMVmakesatimelyexit.Science.2002Aug2;297(5582):778-9.Noabstractavailable.Sun,B.,Harrowe,G.,Reinhard,C.,Yoshihara,C.,Chu,K.,Zhuo,S.(2001)Modulationofhumancytomegalovirusimmediate-earlygeneenhancerbymitogen-activatedproteinkinasekinasekinase-1.J.Cell.Biochem.83(4),563-73.