RRC ID 18673
Author Zang L, Nishikawa M, Machida K, Ando M, Takahashi Y, Watanabe Y, Takakura Y.
Title Inhibition of nuclear delivery of plasmid DNA and transcription by interferon γ: hurdles to be overcome for sustained gene therapy.
Journal Gene Ther
Abstract Sustained expression of murine interferon (IFN)-γ (Muγ) was found to be effective in preventing tumor metastasis and atopic dermatitis in mouse models. However, our preliminary experiments suggested that the time-dependent decrease in the Muγ expression was not compensated for by repeated injections of Muγ-expressing plasmid. To identify the mechanism underlying this observation, a reporter plasmid was hydrodynamically injected into mice and the levels of the plasmid, mRNA and reporter protein were measured in mice receiving a pre- or co-administration of Muγ-expressing plasmid. Co-injection of Muγ-expressing plasmid had no significant effects on transgene expression from the reporter plasmid. In contrast, pre-injection of Muγ-expressing plasmid greatly inhibited the expression of the reporter protein. Moreover, pre-injection of Muγ-expressing plasmid also reduced the amount of the reporter plasmid in the nuclear fraction of mouse liver to < 10%, and that of reporter mRNA to < 1%. The degree of reduction in the expression of reporter protein was comparable with the reduction in mRNA. These results indicate that the difficulty in regaining the expression level of IFN-γ is due to the impaired delivery of plasmid to the nucleus and to the suppression of transcription from the plasmid.
Volume 18(9)
Pages 891-7
Published 2011-9-1
DOI 10.1038/gt.2011.35
PII gt201135
PMID 21451577
MeSH Animals Cell Nucleus / genetics* Cells, Cultured Gene Expression Gene Transfer Techniques* Hydrodynamics Injections, Intramuscular Interferon-gamma / blood Interferon-gamma / genetics* Male Mice Mice, Inbred ICR Plasmids RNA, Messenger / metabolism Transgenes
IF 4.128
Times Cited 2
Human and Animal Cells C2C12(RCB0987)