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A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo.

Publication ,  Journal Article
Morishita, R; Gibbons, GH; Horiuchi, M; Ellison, KE; Nakama, M; Zhang, L; Kaneda, Y; Ogihara, T; Dzau, VJ
Published in: Proc Natl Acad Sci U S A
June 20, 1995

The application of DNA technology to regulate the transcription of disease-related genes in vivo has important therapeutic potentials. The transcription factor E2F plays a pivotal role in the coordinated transactivation of cell cycle-regulatory genes such as c-myc, cdc2, and the gene encoding proliferating-cell nuclear antigen (PCNA) that are involved in lesion formation after vascular injury. We hypothesized that double-stranded DNA with high affinity for E2F may be introduced in vivo as a decoy to bind E2F and block the activation of genes mediating cell cycle progression and intimal hyperplasia after vascular injury. Gel mobility-shift assays showed complete competition for E2F binding protein by the E2F decoy. Transfection with E2F decoy inhibited expression of c-myc, cdc2, and the PCNA gene as well as vascular smooth muscle cell proliferation both in vitro and in the in vivo model of rat carotid injury. Furthermore, 2 weeks after in vivo transfection, neointimal formation was significantly prevented by the E2F decoy, and this inhibition continued up to 8 weeks after a single transfection in a dose-dependent manner. Transfer of an E2F decoy can therefore modulate gene expression and inhibit smooth muscle proliferation and vascular lesion formation in vivo.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

June 20, 1995

Volume

92

Issue

13

Start / End Page

5855 / 5859

Location

United States

Related Subject Headings

  • Transfection
  • Transcriptional Activation
  • Transcription Factors
  • Transcription Factor DP1
  • Retinoblastoma-Binding Protein 1
  • Rats
  • Promoter Regions, Genetic
  • Proliferating Cell Nuclear Antigen
  • Polymerase Chain Reaction
  • Oligodeoxyribonucleotides
 

Citation

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Morishita, R., Gibbons, G. H., Horiuchi, M., Ellison, K. E., Nakama, M., Zhang, L., … Dzau, V. J. (1995). A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo. Proc Natl Acad Sci U S A, 92(13), 5855–5859. https://doi.org/10.1073/pnas.92.13.5855
Morishita, R., G. H. Gibbons, M. Horiuchi, K. E. Ellison, M. Nakama, L. Zhang, Y. Kaneda, T. Ogihara, and V. J. Dzau. “A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo.Proc Natl Acad Sci U S A 92, no. 13 (June 20, 1995): 5855–59. https://doi.org/10.1073/pnas.92.13.5855.
Morishita R, Gibbons GH, Horiuchi M, Ellison KE, Nakama M, Zhang L, et al. A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):5855–9.
Morishita, R., et al. “A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo.Proc Natl Acad Sci U S A, vol. 92, no. 13, June 1995, pp. 5855–59. Pubmed, doi:10.1073/pnas.92.13.5855.
Morishita R, Gibbons GH, Horiuchi M, Ellison KE, Nakama M, Zhang L, Kaneda Y, Ogihara T, Dzau VJ. A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):5855–5859.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

June 20, 1995

Volume

92

Issue

13

Start / End Page

5855 / 5859

Location

United States

Related Subject Headings

  • Transfection
  • Transcriptional Activation
  • Transcription Factors
  • Transcription Factor DP1
  • Retinoblastoma-Binding Protein 1
  • Rats
  • Promoter Regions, Genetic
  • Proliferating Cell Nuclear Antigen
  • Polymerase Chain Reaction
  • Oligodeoxyribonucleotides