Homeodomain Interacting Protein Kinase 2 A Target for Alzheimers Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival 英文参考文献.docVIP

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Homeodomain Interacting Protein Kinase 2 A Target for Alzheimers Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival 英文参考文献.doc

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Homeodomain Interacting Protein Kinase 2 A Target for Alzheimers Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival 英文参考文献

HomeodomainInteractingProteinKinase2:ATargetfor Alzheimer’sBetaAmyloidLeadingtoMisfoldedp53and InappropriateCellSurvival CristinaLanni1*.,LaviniaNardinocchi2,3.,RosaPuca2,3,SerenaStanga1,DanielaUberti4 ,Maurizio Memo4,StefanoGovoni1,GabriellaD’Orazi2,3,MarcoRacchi1 1DepartmentofExperimentalandAppliedPharmacology,CentreofExcellenceinAppliedBiology,UniversityofPavia,Pavia,Italy,2MolecularOncogenesisLaboratory, DepartmentofExperimentalOncology,NationalCancerInstituteReginaElena,Rome,Italy,3DepartmentofOncologyandNeurosciences,University‘‘G.d’Annunzio’’, Chieti,Italy,4DepartmentofBiomedicalSciencesandBiotechnologies,UniversityofBrescia,Brescia,Italy Abstract Background: Homeodomain interacting protein kinase 2 (HIPK2) is an evolutionary conserved serine/threonine kinase whoseactivityisfundamentalinmaintainingwild-typep53function,therebycontrollingthedestinyofcellswhenexposed to DNA damaging agents. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer’sDisease(AD)thatledtoanimpairedanddysfunctionalresponsetostressors. Methodology/PrincipalFindings:Hereweexaminedthemolecularmechanismsunderlyingtheimpairmentofp53activity in two cellular models, HEK-293 cells overexpressing the amyloid precursor protein and fibroblasts from AD patients, starting from recent findings showing that p53 conformation may be regulated by HIPK2. We demonstrated that beta- amyloid 1–40 induces HIPK2 degradation and alters HIPK2 binding activity to DNA, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus. Expression of HIPK2 was analysed by western blot experiments, whereas HIPK2 DNA binding was examined by chromatin immunoprecipitation analysis. In particular, we evaluatedtherecruitmentofHIPK2ontosometargetpromoters,includinghypoxiainduciblefactor-1aandmetallothionein 2A. Conclusions/Significance: Theseresultssupport theexistenceof anovel amyloid-based pathogenetic mechanisminAD potentiallyleadingtothesurvivalofi