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Molecular Pharmacology

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Research ArticleArticle

Inhibition of c-myc Expression in Cells by Targeting an RNA-Protein Interaction Using Antisense Oligonucleotides

Christopher M. Coulis, Chunja Lee, Violet Nardone and Rebecca D. Prokipcak
Molecular Pharmacology March 2000, 57 (3) 485-494; DOI: https://doi.org/10.1124/mol.57.3.485
Christopher M. Coulis
Department of Pharmacology, University of Toronto, Toronto, Canada
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Chunja Lee
Department of Pharmacology, University of Toronto, Toronto, Canada
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Violet Nardone
Department of Pharmacology, University of Toronto, Toronto, Canada
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Rebecca D. Prokipcak
Department of Pharmacology, University of Toronto, Toronto, Canada
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Abstract

Antisense oligodeoxynucleotides (ODNs) are designed to bind to and inhibit a target mRNA. We used a novel approach for the design of ODNs to the c-myc mRNA using protein binding sites as targets for ODN action. Our strategy was to identify ODNs that could interfere with the coding region determinant-binding protein (CRD-BP), a protein that binds to the CRD region of the c-myc mRNA. Using an in vitro gel shift assay, we show that ODN molecules can occlude the CRD-BP from the mRNA. The best ODN, CRD-ODN4, was able to inhibit RNA binding of the CRD-BP by 75%. This effect was sequence-specific and concentration dependent. K562 cells treated with a 2′-O-methyl derivative of CRD-ODN4 showed a concentration-dependent decrease in both c-myc mRNA and protein levels, with a maximal 65% inhibition of protein expression at 200 nM CRD-ODN4. In contrast, a 2′-O-methyl ODN derivative targeting the translation initiation codon (antimyc-aug) reduced c-myc protein but actually increased mRNA levels, an effect resulting at least partly from stabilization of the c-myc mRNA. CRD-ODN4 treatment did not alter the c-myc mRNA half-life. CRD-ODN4 was more effective in inhibiting K562 cell growth than antimyc-aug, reducing cell number by ≈70% after 48 h of exposure to 750 nM. The correlation between ODN effects on RNA-protein interactions in vitro and those observed in cells supports the hypothesis that CRD-ODN4 inhibits the interaction between the CRD-BP and the c-myc mRNA and that disrupting this RNA-protein interaction reduces c-mycexpression in cells.

Footnotes

    • Received June 17, 1999.
    • Accepted November 15, 1999.
  • Send reprint requests to: Dr. Becky Prokipcak, Department of Pharmacology, Medical Sciences Bldg., University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail:Becky.Prokipcak{at}utoronto.ca

  • This work was supported by a grant from the Leukemia Research Fund of Canada and through support from the Connaught Funds of the University of Toronto.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (3)
Molecular Pharmacology
Vol. 57, Issue 3
1 Mar 2000
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Research ArticleArticle

Inhibition of c-myc Expression in Cells by Targeting an RNA-Protein Interaction Using Antisense Oligonucleotides

Christopher M. Coulis, Chunja Lee, Violet Nardone and Rebecca D. Prokipcak
Molecular Pharmacology March 1, 2000, 57 (3) 485-494; DOI: https://doi.org/10.1124/mol.57.3.485

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Research ArticleArticle

Inhibition of c-myc Expression in Cells by Targeting an RNA-Protein Interaction Using Antisense Oligonucleotides

Christopher M. Coulis, Chunja Lee, Violet Nardone and Rebecca D. Prokipcak
Molecular Pharmacology March 1, 2000, 57 (3) 485-494; DOI: https://doi.org/10.1124/mol.57.3.485
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