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

Geldanamycin, a Potent and Specific Inhibitor of Hsp90, Inhibits Gene Expression and Replication... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Chemistry and Chemotherapy SAGE

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

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Publisher
SAGE
Copyright
Copyright © 2019 by SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses
ISSN
2040-2066
eISSN
2040-2066
DOI
10.1177/095632020501600206
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

Antiviral Chemistry and ChemotherapySAGE

Published: Jun 23, 2016

Keywords: human cytomegalovirus,heat shock protein 90,geldanamycin,gene expression,virus replication

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