Divergent Mechanisms Controlling Hypoxic Sensitivity and Lifespan by the DAF-2InsulinIGF-Receptor Pathway 英文参考文献.docVIP

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Divergent Mechanisms Controlling Hypoxic Sensitivity and Lifespan by the DAF-2InsulinIGF-Receptor Pathway 英文参考文献.doc

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Divergent Mechanisms Controlling Hypoxic Sensitivity and Lifespan by the DAF-2InsulinIGF-Receptor Pathway 英文参考文献

DivergentMechanismsControllingHypoxicSensitivity andLifespanbytheDAF-2/Insulin/IGF-ReceptorPathway MeghannE.Mabon1,3,BarbaraA.Scott1,C.MichaelCrowder1,2,3* 1Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 3The Division of Biology Biomedical Sciences, Program in Developmental Biology,WashingtonUniversitySchoolofMedicine,St.Louis,Missouri,UnitedStatesofAmerica Abstract Organisms and their cells vary greatly in their tolerance of low oxygen environments (hypoxia). A delineation of the determinantsofhypoxiatoleranceisincomplete,despiteintenseinterestforitsimplicationsindiseasessuchasstrokeand myocardialinfarction.Theinsulin/IGF-1receptor(IGFR)signalingpathwaycontrolssurvivalofCaenorhabditiselegansfroma varietyofstressorsincludingaging,hyperthermia,andhypoxia.daf-2encodesaC.elegansIGFRhomologwhoseprimary signalingpathwaymodulatestheactivityoftheFOXOtranscriptionfactorDAF-16.DAF-16regulatesthetranscriptionofa large number of genes, some of which have been shown to control aging. To identify genes that selectively regulate hypoxic sensitivity, we compared the whole-organismal transcriptomes of three daf-2 reduction-of-function alleles, all of whicharehypoxiaresistant,thermotolerant,andlonglived,butdifferintheirrankofseveritiesforthesephenotypes.The transcriptlevelsof172geneswereincreasedinthemosthypoxiaresistantdaf-2allele,e1370,relativetotheotheralleles whereastranscriptsfromonly10genesweredecreasedinabundance.RNAiknockdownof6ofthe10genesproduceda significantincreaseinorganismalsurvivalafterhypoxicexposureaswouldbeexpectedifdownregulationofthesegenes bythee1370mutationwasresponsibleforhypoxiaresistance.However,RNAiknockdownofthesegenesdidnotprolong lifespan. These genes definitively separate the mechanisms of hypoxic sensitivity and lifespan and identify biological strategie