Negative Regulators of Insulin Signaling Revealed in a Genome-Wide Functional Screen 英文参考文献.docVIP

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Negative Regulators of Insulin Signaling Revealed in a Genome-Wide Functional Screen 英文参考文献.doc

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Negative Regulators of Insulin Signaling Revealed in a Genome-Wide Functional Screen 英文参考文献

NegativeRegulatorsofInsulinSignalingRevealedina Genome-WideFunctionalScreen Shih-MinA.Huang1.¤a,MichaelK.Hancock1.¤b,JeffreyL.Pitman2,AnthonyP.Orth1,NicholasGekakis2* 1GenomicsInstituteoftheNovartisResearchFoundation,SanDiego,California,UnitedStatesofAmerica, 2TheScrippsResearchInstitute,LaJolla,California,United StatesofAmerica Abstract Background:Type2diabetesdevelopsduetoacombinationofinsulinresistanceandb-cellfailureandcurrenttherapeutics aimatbothoftheseunderlyingcauses.Severalnegativeregulatorsofinsulinsignalingareknownandarethesubjectof drugdiscoveryefforts.Wesoughttoidentifynovelcontributorstoinsulinresistanceandhencepotentiallynoveltargetsfor therapeuticintervention. Methodology:AnarrayedcDNAlibraryencoding18,441humantranscriptswasscreenedforinhibitorsofinsulinsignaling and revealed known inhibitors and numerous potential novel regulators. The novel hits included proteins of various functionalclassessuchaskinases,phosphatases,transcriptionfactors,andGTPaseassociatedproteins.Aseriesofsecondary assaysconfirmedtherelevanceoftheprimaryscreenhitstoinsulinsignalingandprovidedfurtherinsightintotheirmodes ofaction. Conclusion/Significance: AmongthenovelhitswasPALD(KIAA1274,paladin),apreviouslyuncharacterizedproteinthat when overexpressed led to inhibition of insulin’s ability to down regulate a FOXO1A-driven reporter gene, reduced upstreaminsulin-stimulatedAKTphosphorylation,anddecreasedinsulinreceptor(IR)abundance.Conversely,knockdown of PALD gene expression resulted in increased IR abundance, enhanced insulin-stimulated AKT phosphorylation, and an improvementininsulin’sabilitytosuppressFOXO1A-drivenreportergeneactivity.Thepresentdatademonstratethatthe applicationofarrayedgenome-widescreeningtechnologiestoinsulinsignalingisfruitfulandislikelytorevealnoveldrug targetsforinsulinresistanceandthemetabolicsyndrome. Citation: Huang S-MA, Hancock MK, Pitman JL, Orth AP, Gekakis N (2009) Negative Regulators of Insulin Signaling Revealed in a Genome-Wide Functiona