geldanamycin

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Geldanamycin, A Potent and Specific Inhibitor of Hsp90, Inhibits Gene Expression and Replication of Human Cytomegalovirus

Journal Title, Volume, Page: 
Antivir Chem Chemother. (2):135-46
Year of Publication: 
2005
Authors: 
Walid Basha
Division of Virology, Department of Laboratory Science, School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan
Current Affiliation: 
Faculty of Medicine & Health Sciences, Department of Biomedical Sciences, An-Najah National University, Nablus, Palestine
Ryoko Kitagawa
Division of Virology, Department of Laboratory Science, School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan
Miho Uhara
Division of Virology, Department of Laboratory Science, School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan
Hiromi Imazu
Division of Virology, Department of Laboratory Science, School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan
Kouhei Uechi
Division of Virology, Department of Laboratory Science, School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan
Junji Tanaka
Division of Virology, Department of Laboratory Science, School of Health Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan
Preferred Abstract (Original): 

The effect of geldanamycin (GA), a specific inhibitor of heat shock protein 90 (Hsp90), on gene expression and replication of human cytomegalovirus (HCMV) was studied in human embryonic lung (HEL) fibroblasts. Kinetic analysis indicated that GA delayed synthesis of major immediate early (MIE), early and late viral proteins,and blocked a second tier of the synthesis of these proteins that occurred in untreated cells after 48 h post-infection (pi). Moreover, when HCMV-infected HEL cells were maintained with medium containing 40 nM GA for 6 days, with medium changes at 2-day intervals, the virus yield was reduced to an undetectable level. On a molecular level, the cellular kinase Akt and the transcription factor NFκB were activated in HCMV-infected cells within 30 min pi. NFκB was shown to be essential for MIE gene expression. However, in GA-treated cells, activation of both Akt and NFκB was greatly inhibited.Because LY294002, an inhibitor of cellular phosphatidylinositol 3-kinase (PI3-K), also prohibited HCMV-mediated activation of Akt and NFκB and synthesis of the MIE proteins, PI3-K signalling was necessary for expressing the MIE genes. These results suggest that the inhibitory effect of GA on HCMV replication is primarily caused by the disruption of the PI3-K signalling pathway, leading to the activation of NFκB, which plays a crucial role in expression of the critical MIE genes.Keywords: human cytomegalovirus, heat shock protein 90, geldanamycin, gene expression, virus replication

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