Separation of Anti-Proliferation and Anti-Apoptotic Functions of Retinoblastoma Protein through Targeted Mutations of Its AB Domain 英文参考文献.docVIP

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Separation of Anti-Proliferation and Anti-Apoptotic Functions of Retinoblastoma Protein through Targeted Mutations of Its AB Domain 英文参考文献.doc

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Separation of Anti-Proliferation and Anti-Apoptotic Functions of Retinoblastoma Protein through Targeted Mutations of Its AB Domain 英文参考文献

SeparationofAnti-ProliferationandAnti-Apoptotic FunctionsofRetinoblastomaProteinthroughTargeted MutationsofItsA/BDomain B.NelsonChau,ChrisW.Pan,JeanY.J.Wang* Department of Medicine, Division of Hematology/Oncology, Moores-UCSD Cancer Center, University of California San Diego, La Jolla, California, UnitedStatesofAmerica Background. The human retinoblastoma susceptibility gene encodes a nuclear phosphoprotein RB, which is a negative regulatorofcellproliferation.ThegrowthsuppressionfunctionofRBrequiresanevolutionarilyconservedA/Bdomainthat containstwodistinctpeptide-bindingpockets.AttheA/BinterfaceisabindingsitefortheC-terminaltrans-activationdomain of E2F. Within the B-domain is a binding site for proteins containing the LxCxE peptide motif. Methodology/Principle Findings.BasedonthecrystalstructureoftheA/Bdomain,wehaveconstructedanRB-K530A/N757F(KN)mutanttodisrupt theE2F-andLxCxE-bindingpockets.TheRB-K530A(K)mutantissufficienttoinactivatetheE2F-bindingpocket,whereasthe RB-N757F(N)mutantissufficienttoinactivatetheLxCxE-bindingpocket.Eachsinglemutantinhibitscellproliferation,butthe RB-KNdoublemutantisdefectiveingrowthsuppression.Nevertheless,theRB-KNmutantiscapableofreducingetoposide- induced apoptosis. Conclusion/Significance. Previous studies have established that RB-dependent G1-arrest can confer resistance to DNA damage-induced apoptosis. Results from this study demonstrate that RB can also inhibit apoptosis independentofgrowthsuppression. Citation: Chau BN, Pan CW, Wang JYJ (2006) Separation of Anti-Proliferation and Anti-Apoptotic Functions of Retinoblastoma Protein through TargetedMutationsofItsA/BDomain.PLoSONE1(1):e82.doi:10.1371/journal.pone.0000082 INTRODUCTION tions with E2F [8,10]. One of the LxCxE binding-defective mutants constructed by our lab contains a single substitution mutationofAsn757(RB-N,N757F),whichissufficienttodisrupt theLxCxE-bindingpocket[8].ThisRB-NmutantrepressesE2F- dependent transcription, inhibits DNA synthesis, and reduces colony f