Generation and Characterization of Mice Carrying a Conditional Allele of the Wwox Tumor Suppressor Gene 英文参考文献.docVIP

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Generation and Characterization of Mice Carrying a Conditional Allele of the Wwox Tumor Suppressor Gene 英文参考文献.doc

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Generation and Characterization of Mice Carrying a Conditional Allele of the Wwox Tumor Suppressor Gene 英文参考文献

GenerationandCharacterizationofMiceCarryinga ConditionalAlleleoftheWwoxTumorSuppressorGene JohnH.Ludes-Meyers1,HyunsukKil1,JanParker-Thornburg2,DonnaF.Kusewitt1,MarkT.Bedford1 ,C. MarceloAldaz1* 1Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, United States of America, 2DepartmentofBiochemistryandMolecularBiology,UniversityofTexasM.D.AndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica Abstract WWOX,thegenethatspansthesecondmostcommonhumanchromosomalfragilesite,FRA16D,isinactivatedinmultiple humancancersandbehavesasasuppressoroftumorgrowth.SinceweareinterestedinunderstandingWWOXfunctionin bothnormalandcancertissueswegeneratedmiceharboringaconditionalWwoxallelebyflankingExon1oftheWwox gene with LoxP sites. Wwox knockout (KO) mice were developed by breeding with transgenic mice carrying the Cre- recombinasegeneunderthecontroloftheadenovirusEIIApromoter.WefoundthatWwoxKOmicesufferedfromsevere metabolicdefect(s)resultingingrowthretardationandallmicediedby3wkofage.AllWwoxKOmicedisplayedsignificant hypocapniasuggestingastateofmetabolicacidosis.ThisfindingandtheknownhighexpressionofWwoxinkidneytubules suggestaroleforWwoxinacid/basebalance.Importantly,WwoxKOmicedisplayedhistopathologicalandhematological signsofimpairedhematopoeisis,leukopenia,andsplenicatrophy.Impairedhematopoeisiscanalsobeacontributingfactor tometabolicacidosisanddeath.HypoglycemiaandhypocalcemiawasalsoobservedaffectingtheKOmice.Inaddition, bonemetabolicdefectswereevidentinWwoxKOmice.Bonesweresmallerandthinnerhavingreducedbonevolumeasa consequenceofadefectinmineralization.NoevidenceofspontaneousneoplasiawasobservedinWwoxKOmice.Wehave generatedanewmousemodeltoinactivatetheWwoxtumorsuppressorgeneconditionally.Thiswillgreatlyfacilitatethe functionalanalysisofWwoxinadultmiceandwillallowinvestigatingneoplastictransformationinspecifictargettissues. Citation:Ludes-MeyersJH,KilH,Parker-ThornburgJ,KusewittDF,BedfordMT,etal.(2009)G