Document Detail


Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism.
MedLine Citation:
PMID:  20133771     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
EBV causes infectious mononucleosis and is associated with certain malignancies. EBV nuclear antigen 1 (EBNA1) mediates EBV genome replication, partition, and transcription, and is essential for persistence of the viral genome in host cells. Here we demonstrate that Hsp90 inhibitors decrease EBNA1 expression and translation, and that this effect requires the Gly-Ala repeat domain of EBNA1. Hsp90 inhibitors induce the death of established, EBV-transformed lymphoblastoid cell lines at doses nontoxic to normal cells, and this effect is substantially reversed when lymphoblastoid cell lines are stably infected with a retrovirus expressing a functional EBNA1 mutant lacking the Gly-Ala repeats. Hsp90 inhibitors prevent EBV transformation of primary B cells, and strongly inhibit the growth of EBV-induced lymphoproliferative disease in SCID mice. These results suggest that Hsp90 inhibitors may be particularly effective for treating EBV-induced diseases requiring the continued presence of the viral genome.
Authors:
Xiaoping Sun; Elizabeth A Barlow; Shidong Ma; Stacy R Hagemeier; Sarah J Duellman; Richard R Burgess; Judy Tellam; Rajiv Khanna; Shannon C Kenney
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-01-26
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-17     Completed Date:  2010-05-10     Revised Date:  2010-09-28    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3146-51     Citation Subset:  IM    
Affiliation:
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects
Benzoquinones / pharmacology*,  therapeutic use
Cell Line, Tumor
DNA Primers / genetics
Dipeptides / genetics
Epstein-Barr Virus Nuclear Antigens / metabolism*
Gene Expression Regulation, Viral / drug effects
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Herpesvirus 4, Human*
Humans
Immunoblotting
Immunoprecipitation
Lactams, Macrocyclic / pharmacology*,  therapeutic use
Lymphoproliferative Disorders / drug therapy*,  virology
Mice
Mice, SCID
Reverse Transcriptase Polymerase Chain Reaction
Virus Replication / drug effects
Grant Support
ID/Acronym/Agency:
P01 CA022443/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/17-(allylamino)-17-demethoxygeldanamycin; 0/17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; 0/Benzoquinones; 0/DNA Primers; 0/Dipeptides; 0/Epstein-Barr Virus Nuclear Antigens; 0/HSP90 Heat-Shock Proteins; 0/Lactams, Macrocyclic; 926-77-2/N-glycylalanine
Comments/Corrections

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