Reversal of human cytomegalovirus major immediate-early enhancer/promoter silencing in quiescently infected cells via the cyclic AMP signaling pathway

Michael J Keller; Allen W Wu; Janet I Andrews; Patrick W McGonagill; Eric E Tibesar; Jeffery L Meier

doi:10.1128/JVI.01524-06

Back

Reversal of human cytomegalovirus major immediate-early enhancer/promoter silencing in quiescently infected cells via the cyclic AMP signaling pathway

Journal article

Open access

Peer reviewed

Reversal of human cytomegalovirus major immediate-early enhancer/promoter silencing in quiescently infected cells via the cyclic AMP signaling pathway

Michael J Keller, Allen W Wu, Janet I Andrews, Patrick W McGonagill, Eric E Tibesar and Jeffery L Meier

Journal of virology, Vol.81(12), pp.6669-6681

06/2007

DOI: 10.1128/JVI.01524-06

PMCID: PMC1900132

PMID: 17301150

Files and links (1)

url

https://doi.org/10.1128/JVI.01524-06View

Published (Version of record) Open Access

Abstract

The human cytomegalovirus (HCMV) major immediate-early (MIE) enhancer contains five functional cyclic AMP (cAMP) response elements (CRE). Because the CRE in their native context do not contribute appreciably to MIE enhancer/promoter activity in lytically infected human fibroblasts and NTera2 (NT2)-derived neurons, we postulated that they might have a role in MIE enhancer/promoter reactivation in quiescently infected cells. Here, we show that stimulation of the cAMP signaling pathway by treatment with forskolin (FSK), an adenylyl cyclase activator, greatly alleviates MIE enhancer/promoter silencing in quiescently infected NT2 neuronal precursors. The effect is immediate, independent of de novo protein synthesis, associated with the phosphorylation of ATF-1 serine 63 and CREB serine 133, dependent on protein kinase A (PKA) and the enhancer's CRE, and linked to viral-lytic-cycle advancement. Coupling of FSK treatment with the inhibition of either histone deacetylases or protein synthesis synergistically activates MIE gene expression in a manner suggesting that MIE enhancer/promoter silencing is optimally relieved by an interplay of multiple regulatory mechanisms. In contrast, MIE enhancer/promoter silence is not overcome by stimulation of the gamma interferon (IFN-gamma) signaling pathway, despite the enhancer having two IFN-gamma-activated-site-like elements. We conclude that stimulation of the cAMP/PKA signaling pathway drives CRE-dependent MIE enhancer/promoter activation in quiescently infected cells, thus exposing a potential mode of regulation in HCMV reactivation.

Cell Line

Cytomegalovirus - genetics

Promoter Regions, Genetic

Phosphorylation

Signal Transduction

Humans

Gene Silencing

Interferon-gamma - metabolism

Serine - chemistry

RNA, Viral - genetics

Enhancer Elements, Genetic

Models, Genetic

Genes, Immediate-Early

DNA, Viral - genetics

Cyclic AMP - metabolism

Details

Title: Subtitle: Reversal of human cytomegalovirus major immediate-early enhancer/promoter silencing in quiescently infected cells via the cyclic AMP signaling pathway
Creators: Michael J Keller - Department of Internal Medicine, University of Iowa Carver College of Medicine, and Veterans Affairs Medical Center, Iowa City, Iowa 52242, USA
Allen W Wu
Janet I Andrews
Patrick W McGonagill
Eric E Tibesar
Jeffery L Meier
Resource Type: Journal article
Publication Details: Journal of virology, Vol.81(12), pp.6669-6681
DOI: 10.1128/JVI.01524-06
PMID: 17301150
PMCID: PMC1900132
NLM abbreviation: J Virol
ISSN: 0022-538X
eISSN: 1098-5514
Publisher: United States
Grant note: T32 AI007485 / NIAID NIH HHS
Language: English
Date published: 06/2007
Academic Unit: Infectious Diseases; Epidemiology; Surgery; Obstetrics and Gynecology; Internal Medicine
Record Identifier: 9984051770902771

Metrics

11 Record Views

55 Times Cited - Web of Science