Evolutionary Conserved Regulation of HIF-1β by NF-κB 英文参考文献.docVIP

EvolutionaryConservedRegulationofHIF-1bbyNF-kB PatrickvanUden1,NiallS.Kenneth1,RyanWebster2,H.ArnoMu¨ller2,SharonMudie1,SoniaRocha1* 1Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom, 2Division of Cell and DevelopmentalBiology,CollegeofLifeSciences,UniversityofDundee,Dundee,UnitedKingdom Abstract HypoxiaInducibleFactor-1(HIF-1)isessentialformammaliandevelopmentandistheprincipaltranscriptionfactoractivated bylowoxygentensions.HIF-asubunitquantitiesandtheirassociatedactivityareregulatedinapost-translationalmanner, through the concerted action of a class of enzymes called Prolyl Hydroxylases (PHDs) and Factor Inhibiting HIF (FIH) respectively.However,alternativemodesofHIF-aregulationsuchastranslationortranscriptionareunder-investigated,and their importance has not been firmly established. Here, we demonstrate that NF-kB regulates the HIF pathway in a significantandevolutionaryconservedmanner.WedemonstratethatNF-kBdirectlyregulatesHIF-1bmRNAandprotein.In addition,wefoundthatNF-kB–mediatedchangesinHIF-1bresultinmodulationofHIF-2aprotein.HIF-1boverexpression canrescueHIF-2aproteinlevelsfollowingNF-kBdepletion.Significantly,NF-kBregulatesHIF-1b(tango)andHIF-a(sima) levels and activity (Hph/fatiga, ImpL3/ldha) in Drosophila, both in normoxia and hypoxia, indicating an evolutionary conservedmodeofregulation.TheseresultsrevealanovelmechanismofHIFregulation,withimpactinthedevelopmentof noveltherapeuticstrategiesforHIF–relatedpathologiesincludingageing,ischemia,andcancer. Citation:vanUdenP,KennethNS,WebsterR,Mu¨llerHA,MudieS,etal.(2011)EvolutionaryConservedRegulationofHIF-1bbyNF-kB.PLoSGenet7(1):e1001285. doi:10.1371/journal.pgen.1001285 Editor:VishvaM.Dixit,Genentech,UnitedStatesofAmerica ReceivedAugust5,2010;AcceptedDecember22,2010;PublishedJanuary27,2011 Copyright: ? 2011 van Uden et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, whic