AMP-Activated Protein Kinase-Regulated Activation of the PGC-1α Promoter in Skeletal Muscle Cells 英文参考文献.docVIP

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AMP-Activated Protein Kinase-Regulated Activation of the PGC-1α Promoter in Skeletal Muscle Cells 英文参考文献.doc

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AMP-Activated Protein Kinase-Regulated Activation of the PGC-1α Promoter in Skeletal Muscle Cells 英文参考文献

AMP-ActivatedProteinKinase-RegulatedActivationof thePGC-1aPromoterinSkeletalMuscleCells IsabellaIrrcher3,VladimirLjubicic1,2,AngieF.Kirwan3,DavidA.Hood1,2,3* 1School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada, 2Muscle Health Research Centre, York University, Toronto, Ontario, Canada, 3DepartmentofBiology,YorkUniversity,Toronto,Ontario,Canada Abstract The mechanisms by which PGC-1a gene expression is controlled in skeletal muscle remains largely undefined. Thus, we soughttoinvestigatethetranscriptionalregulationofPGC-1ausingAICAR,anactivatorofAMPK,thatisknowntoincrease PGC-1aexpression.A2.2kbfragmentofthehumanPGC-1apromoterwasclonedandsequenceanalysisrevealedthatthis TATA-lesssequencehousesputativeconsensussitesincludingaGC-box,aCRE,severalIRSs,aSRE,bindingsitesforGATA, MEF2, p53, NF-kB, and EBox binding proteins. AMPK activation for 24hours increased PGC-1a promoter activity with concomitant increases in mRNA expression. The effect of AICAR on transcriptional activation was mediated by an overlapping GATA/EBox binding site at 2495 within the PGC-1a promoter based on gel shift analyses that revealed increasesinGATA/EBoxDNAbinding.MutationoftheEBoxwithintheGATA/EBoxbindingsiteinthepromoterreduced basalpromoteractivityandcompletelyabolishedtheAICAReffect.SupershiftanalysesidentifiedUSF-1asaDNAbinding transcription factor potentially involved in regulating PGC-1a promoter activity, which was confirmed in vivo by ChIP. Overexpression of either GATA-4 or USF-1 alone increased the p851 PGC-1a promoter activity by 1.7- and 2.0-fold respectively,whileco-expressionofGATA-4andUSF-1ledtoanadditiveincreaseinPGC-1apromoteractivity.TheUSF-1- mediatedincreaseinPGC-1apromoteractivationledtosimilarincreasesatthemRNAlevel.OurdataidentifyanovelAMPK- mediatedregulatorypathwaythatregulatesPGC-1ageneexpression.Thiscouldrepresentapotentialtherapeutictargetto controlPGC-1aexpressioninskeletalmuscle. Citation: Irrcher I, Ljubicic V, Kirwan AF, Hood DA (200