Mutual Regulation of Bcl-2 Proteins Independent of the BH3 Domain as Shown by the BH3-Lacking Protein Bcl-xAK 英文参考文献.docVIP

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Mutual Regulation of Bcl-2 Proteins Independent of the BH3 Domain as Shown by the BH3-Lacking Protein Bcl-xAK 英文参考文献.doc

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Mutual Regulation of Bcl-2 Proteins Independent of the BH3 Domain as Shown by the BH3-Lacking Protein Bcl-xAK 英文参考文献

MutualRegulationofBcl-2ProteinsIndependentofthe BH3DomainasShownbytheBH3-LackingProtein Bcl-xAK MichaelPlo¨tz1,AmirM.Hossini1,BernhardGillissen2,PeterT.Daniel2,EggertStockfleth1, Ju¨rgenEberle1* 1DepartmentofDermatologyandAllergy,SkinCancerCenter,UniversityMedicalCenterCharite′, Berlin,Germany,2DepartmentofHematology,OncologyandTumor Immunology,UniversityMedicalCenterCharite′, Berlin,Germany Abstract TheBH3domainofBcl-2proteinswasregardedasindispensableforapoptosisinductionandformutualregulationoffamily members.WerecentlydescribedBcl-xAK,aproapoptoticspliceproductofthebcl-xgene,whichlacksBH3butenclosesBH2, BH4 and a transmembrane domain. It remained however unclear, how Bcl-xAK may trigger apoptosis. For efficient overexpression,Bcl-xAKwassubclonedinanadenoviralvectorunderTet-OFFcontrol.Theconstructresultedinsignificant apoptosis induction in melanoma and nonmelanoma cell lines with up to 50% apoptotic cells as well as decreased cell proliferation and survival. Disruption of mitochondrial membrane potential, and cytochrome c release clearly indicated activation of the mitochondrial apoptosis pathways. Both Bax and Bak were activated as shown by clustering and conformationanalysis.MitochondrialtranslocationofBcl-xAKappearedasanessentialandinitialstep.Bcl-xAKwascritically dependent on either Bax or Bak, and apoptosis was abrogated in Bax/Bak double knockout conditions as well by overexpression of Bcl-2 or Bcl-xL. A direct interaction with Bcl-2, Bax, Bad, Noxa or Puma was however not seen by immunoprecipitation.ThusbesidesBH3-mediatedinteractions,thereexistsanadditionalwayformutualregulationofBcl-2 proteins,whichisindependentoftheBH3.Thispathwayappearstoplayasupplementaryrolealsoforotherproapoptotic familymembers,anditsunravelingmayhelptoovercometherapyresistanceincancer. Citation:Plo¨tzM,HossiniAM,GillissenB,DanielPT,StockflethE,etal.(2012)MutualRegulationofBcl-2ProteinsIndependentoftheBH3DomainasShownby theBH3-LackingProteinBcl-xAK.PLoSONE7(4):e34549.doi: