Article

Valproic acid enhances gene expression from viral gene transfer vectors

Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Ave., Box 672 (Room 3-9609), Rochester, NY 14642, USA.
Journal of Virological Methods (Impact Factor: 1.88). 05/2005; 125(1):23-33. DOI: 10.1016/j.jviromet.2004.11.023
Source: PubMed

ABSTRACT Viral vectors represent an efficient delivery method for in vitro and in vivo gene transfer, and their utility may be further enhanced through the use of pharmacologic agents that increase gene expression. Here, we demonstrate that valproic acid (VPA), a drug which is widely used for the treatment of epilepsy and mood disorders, enhances and prolongs expression of exogenous genes in cells transduced with various gene transfer agents, including adenovirus, adeno-associated virus and herpesvirus vectors. This effect occurs in a wide range of cell types, including both primary cells and cell lines, and appears to be associated with VPA's ability to function as a histone deacetylase inhibitor (HDACi). VPA treatment also enhanced adenovirally-vectored expression of a luciferase reporter gene in mice, as demonstrated by in vivo imaging. VPA was also less cytotoxic than a commonly used HDAC inhibitor, TSA, suggesting its use as a safer alternative. Taken together, these results suggest that VPA treatment may represent a useful approach to various gene transfer approaches in which enhanced transgene expression is desirable.

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    • "Fan and colleagues reported that treatment with VPA resulted in increased expression of exogenous genes in cells transduced with various viral-based gene transfer vectors, including adenovirus, adeno-associated virus and herpesvirus vectors 28. Recently, the effect of VPA on adenovirus vector-mediated transduction was reported. "
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    • "We examined MIE gene-expression levels after increasing MIEP activity by using transcriptional activators known to upregulate MIEP activity (Choi et al., 2005; Fan et al., 2005; Hummel and Abecassis, 2002). These transcriptional activators, Valproic "
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    ABSTRACT: Many signaling circuits face a fundamental tradeoff between accelerating their response speed while maintaining final levels below a cytotoxic threshold. Here, we describe a transcriptional circuitry that dynamically converts signaling inputs into faster rates without amplifying final equilibrium levels. Using time-lapse microscopy, we find that transcriptional activators accelerate human cytomegalovirus (CMV) gene expression in single cells without amplifying steady-state expression levels, and this acceleration generates a significant replication advantage. We map the accelerator to a highly self-cooperative transcriptional negative-feedback loop (Hill coefficient ∼7) generated by homomultimerization of the virus's essential transactivator protein IE2 at nuclear PML bodies. Eliminating the IE2-accelerator circuit reduces transcriptional strength through mislocalization of incoming viral genomes away from PML bodies and carries a heavy fitness cost. In general, accelerators may provide a mechanism for signal-transduction circuits to respond quickly to external signals without increasing steady-state levels of potentially cytotoxic molecules.
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    • "It inhibits class I HDACs and also shows anti-tumour activity in a variety of human cancer cell lines including estrogen-sensitive and estrogen- insensitive breast cancer cell lines [40,41]. It is less toxic compared to TSA [42] and is in phase II and III clinical trials for many human cancers [43]. MS-275 and VPA are selected for this study for their functional similarity and low toxicity. "
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