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Research ArticleArticle

Selective Inhibition of A-Raf and C-Raf mRNA Expression by Antisense Oligodeoxynucleotides in Rat Vascular Smooth Muscle Cells: Role of A-Raf and C-Raf in Serum-Induced Proliferation

Catherine L. Cioffi, Michelle Garay, Joseph F. Johnston, Kathy McGraw, Russell T. Boggs, David Hreniuk and Brett P. Monia
Molecular Pharmacology March 1997, 51 (3) 383-389;
Catherine L. Cioffi
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Michelle Garay
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Joseph F. Johnston
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Kathy McGraw
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Russell T. Boggs
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David Hreniuk
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Brett P. Monia
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Abstract

Raf kinases, cytoplasmic serine/threonine protein kinases, have been proposed as important participants in mitogen-induced signal transduction. However, the precise role that Raf kinase isozymes play in cellular responses such as proliferation has not been resolved. The present study investigates the ability of antisense phosphorothioate oligodeoxynucleotides (ODNs), targeted against rat C-Raf and A-Raf kinases, to reduce gene expression and proliferation of cultured rat A10 smooth muscle cells (SMCs). Exposure of A10 cells to ISIS 11061, an active C-Raf antisense ODN, resulted in a potent, dose-dependent inhibition (IC50 = 55 nm) of C-Raf mRNA and protein expression. This inhibition was completely dependent on ODN sequence because the incorporation of increasing numbers of mismatches (up to six) into the sequence resulted in sequential loss of potency. Similarly, a dose-dependent reduction (IC50 = 125 nm) in A-Raf gene expression was observed after treatment of cells with the active A-Raf ODN, ISIS 9069, whereas two scrambled controls were without effect. These results demonstrate that ISIS 11061 and ISIS 9069 reduced gene expression in a sequence-specific and isozyme-specific manner. Moreover, administration of ISIS 11061 and ISIS 9069 to rat SMCs resulted in a significant and potent diminution of seruminduced proliferation with corresponding IC50values of 216 and 273 nm, respectively. Taken together, these results indicate that A-Raf and C-Raf kinases play an important role in regulating vascular SMC proliferation and that antisense-mediated inhibition of Raf kinase activity may serve as a therapeutic modality in the treatment of vascular proliferative disorders.

Footnotes

  • Send reprint requests to: Catherine L. Cioffi, Ph.D., Research Department, CIBA-GEIGY Corporation, 556 Morris Avenue, Summit, NJ 07901. E-mail:cathy.cioffi{at}ussu.mhs.ciba.com

  • ↵1 C. Cioffi, unpublished observations.

  • Abbreviations:
    MEK
    mitogen-activated protein kinase/extracellular signal-regulated kinase kinase
    MAP
    mitogen-activated protein
    FBS
    fetal bovine serum
    SMC
    smooth muscle cell
    DOTMA/DOPE
    N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride/dioleoylphosphatidylethanolamine
    DMEM
    Dulbecco’s modified Eagle’s medium
    MTS
    3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
    G3PDH
    glyceraldehyde-3-phosphate dehydrogenase
    ODN
    oligodeoxynucleotide
    • Received July 29, 1996.
    • Accepted December 3, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology
Vol. 51, Issue 3
1 Mar 1997
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Research ArticleArticle

Selective Inhibition of A-Raf and C-Raf mRNA Expression by Antisense Oligodeoxynucleotides in Rat Vascular Smooth Muscle Cells: Role of A-Raf and C-Raf in Serum-Induced Proliferation

Catherine L. Cioffi, Michelle Garay, Joseph F. Johnston, Kathy McGraw, Russell T. Boggs, David Hreniuk and Brett P. Monia
Molecular Pharmacology March 1, 1997, 51 (3) 383-389;

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Research ArticleArticle

Selective Inhibition of A-Raf and C-Raf mRNA Expression by Antisense Oligodeoxynucleotides in Rat Vascular Smooth Muscle Cells: Role of A-Raf and C-Raf in Serum-Induced Proliferation

Catherine L. Cioffi, Michelle Garay, Joseph F. Johnston, Kathy McGraw, Russell T. Boggs, David Hreniuk and Brett P. Monia
Molecular Pharmacology March 1, 1997, 51 (3) 383-389;
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