Ectodermal-Neural Cortex 1 Down-Regulates Nrf2 at the Translational Level 英文参考文献.docVIP

Ectodermal-NeuralCortex1Down-RegulatesNrf2atthe TranslationalLevel Xiao-JunWang,DonnaD.Zhang* DepartmentofPharmacologyandToxicology,UniversityofArizona,Arizona,UnitedStatesofAmerica Abstract The transcription factor Nrf2 is the master regulator of a cellular defense mechanism against environmental insults. The Nrf2-mediated antioxidant response is accomplished by the transcription of a battery of genes that encode phase II detoxifying enzymes, xenobiotic transporters, and antioxidants. Coordinated expression of these genes is critical in protectingcellsfromtoxicandcarcinogenicinsultsandinmaintainingcellularredoxhomeostasis.ActivationoftheNrf2 pathwayisprimarilycontrolledbyKelch-likeECH-associatedprotein1(Keap1),whichisamolecularswitchthatturnsonor off the Nrf2 signaling pathway according to intracellular redox conditions. Here we report our finding of a novel Nrf2 suppressor ectodermal-neural cortex 1 (ENC1), which is a BTB-Kelch protein and belongs to the same family as Keap1. Transient expression of ENC1 reduced steady-state levels of Nrf2 and its downstream gene expression. Although ENC1 interacted with Keap1 indirectly, the ENC1-mediated down-regulation of Nrf2 was independent of Keap1. The negative effectofENC1onNrf2wasnotduetoachangeinthestabilityofNrf2becauseneitherproteasomalnorlysosomalinhibitors hadanyeffects.OverexpressionofENC1didnotresultinachangeinthelevelofNrf2mRNA,rather,itcausedadecreasein therateofNrf2proteinsynthesis.TheseresultsdemonstratethatENC1functionsasanegativeregulatorofNrf2through suppressingNrf2proteintranslation,whichaddsanotherlevelofcomplexityincontrollingtheNrf2signalingpathway. Citation: Wang X-J, Zhang DD (2009) Ectodermal-Neural Cortex 1 Down-Regulates Nrf2 at the Translational Level. PLoS ONE 4(5): e5492. doi:10.1371/ journal.pone.0005492 Editor:RoryEdwardMorty,UniversityofGiessenLungCenter,Germany ReceivedMarch2,2009;AcceptedApril16,2009;PublishedMay8,2009 Copyright: ? 2009 Wang et al. This is an open-access article distribute