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dc.contributor.authorNayar, Utthara
dc.contributor.authorLu, Pin
dc.contributor.authorGoldstein, Rebecca L
dc.contributor.authorVider, Jelena
dc.contributor.authorBallon, Gianna
dc.contributor.authorRodina, Anna
dc.contributor.authorTaldone, Tony
dc.contributor.authorErdjument-Bromage, Hediye
dc.contributor.authorChomet, Max
dc.contributor.authorBlasberg, Ronald
dc.contributor.authorMelnick, Ari
dc.contributor.authorCerchietti, Leandro
dc.contributor.authorChiosis, Gabriela
dc.contributor.authorWang, Y Lynn
dc.contributor.authorCesarman, Ethel
dc.date.accessioned2017-05-03T16:06:21Z
dc.date.available2017-05-03T16:06:21Z
dc.date.issued2013
dc.date.modified2014-02-03T04:41:01Z
dc.identifier.issn0006-4971
dc.identifier.doi10.1182/blood-2013-01-479972
dc.identifier.urihttp://hdl.handle.net/10072/56396
dc.description.abstractPU-H71 is a purine-scaffold Hsp90 inhibitor that, in contrast to other Hsp90 inhibitors, displays unique selectivity for binding the fraction of Hsp90 that is preferentially associated with oncogenic client proteins and enriched in tumor cells (teHsp90). This property allows PU-H71 to potently suppress teHsp90 without inducing toxicity in normal cells. We found that lymphoma cells infected by Epstein-Barr virus or Kaposi sarcoma-associated herpes virus (KSHV) are exquisitely sensitive to this compound. Using PU-H71 affinity capture and proteomics, an unbiased approach to reveal oncogenic networks, we identified the teHsp90 interactome in KSHV(+) primary effusion lymphoma cells. Viral and cellular proteins were identified, including many involved in nuclear factor (NF)-?B signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-?B-activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKK?, NF-?B downregulation, apoptosis and autophagy in vitro, and more importantly, tumor responses in mice. Analysis of the interactome revealed apoptosis as a central pathway; therefore, we tested a BCL2 family inhibitor in primary effusion lymphoma cells. We found strong activity and synergy with PU-H71. Our findings demonstrate PU-H71 affinity capture identifies actionable networks that may help design rational combinations of effective therapies.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society of Hematology
dc.publisher.placeUnited States
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom2837
dc.relation.ispartofpageto2847
dc.relation.ispartofissue16
dc.relation.ispartofjournalBlood
dc.relation.ispartofvolume122
dc.rights.retentionY
dc.subject.fieldofresearchCardiovascular medicine and haematology
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchCancer cell biology
dc.subject.fieldofresearchcode3201
dc.subject.fieldofresearchcode3202
dc.subject.fieldofresearchcode321101
dc.titleTargeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.rights.copyrightSelf-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the author[s] for more information.
gro.date.issued2013
gro.hasfulltextNo Full Text
gro.griffith.authorVider, Jelena


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