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Biochemistry and Biophysics

The Farnesyl Protein Transferase Inhibitor BZA-5B Blocks Farnesylation of Nuclear Lamins and p21ras but Does Not Affect Their Function or Localization

Marguerite B. Dalton, Kelley S. Fantle, Heather A. Bechtold, Lucas DeMaio, Robert M. Evans, Alphonse Krystosek and Michael Sinensky
Marguerite B. Dalton
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Kelley S. Fantle
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Heather A. Bechtold
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Lucas DeMaio
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Robert M. Evans
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Alphonse Krystosek
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Michael Sinensky
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DOI:  Published August 1995
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Abstract

BZA-5B is a peptidomimetic inhibitor of protein farnesylation in mammalian cells. We have examined the specificity of this compound toward inhibition of farnesylation of p21ras and the nuclear lamin proteins, prelamin A and lamin B. We have also used the Raney nickel cleavage technique in conjunction with radio-gas liquid chromatography to assess the ability of this compound to block total protein farnesylation. These studies show that BZA-5B blocks farnesylation of the lamin proteins with an IC50 comparable to that seen for p21ras. At a concentration in excess of 25 µm, BZA-5B inhibits all protein farnesylation in CHO-K1 cells below the limits of detection. Furthermore, we found that after a 2-day exposure to high concentrations of BZA-5B, CHO-K1 cell lines exhibit no loss in sensitivity to inhibition of prenylation by this compound. Yet, despite the potent and general inhibition of protein farnesylation, BZA-5B does not interfere with a variety of cellular functions expected to be farnesylation dependent, including cell growth and viability, assembly of the nuclear lamina, membrane association of p21ras, and p21ras-dependent differentiation of PC-12 cells in response to treatment with nerve growth factor.

The maintenance of farnesylation-dependent events in the presence of BZA-5B stands in marked contrast to the inhibition of the oncogenic ras-mediated transformed phenotype that has been observed with this compound and other farnesyl protein transferase inhibitors. This specificity for inhibition of ras transformation by BZA-5B is quite encouraging to its eventual development as an antimalignancy pharmaceutical.

Footnotes

  • ↵1 This work was supported by Grant BE29 (to M. S.) from the American Cancer Society and Grant HD 07197 (to M. B. D.) from the Cancer League of Colorado and the NIH. L. D. was supported by the Brooks Trust of the Colorado Division of the American Cancer Society and by Cancer Education Grant CA 49981 from the National Cancer Institute.

  • ↵2 To whom requests for reprints should be addressed, at Eleanor Roosevelt Institute, 1899 Gaylord Street, Denver, CO 80206.

  • Received March 20, 1995.
  • Accepted May 30, 1995.
  • ©1995 American Association for Cancer Research.
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August 1995
Volume 55, Issue 15
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The Farnesyl Protein Transferase Inhibitor BZA-5B Blocks Farnesylation of Nuclear Lamins and p21ras but Does Not Affect Their Function or Localization
Marguerite B. Dalton, Kelley S. Fantle, Heather A. Bechtold, Lucas DeMaio, Robert M. Evans, Alphonse Krystosek and Michael Sinensky
Cancer Res August 1 1995 (55) (15) 3295-3304;

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The Farnesyl Protein Transferase Inhibitor BZA-5B Blocks Farnesylation of Nuclear Lamins and p21ras but Does Not Affect Their Function or Localization
Marguerite B. Dalton, Kelley S. Fantle, Heather A. Bechtold, Lucas DeMaio, Robert M. Evans, Alphonse Krystosek and Michael Sinensky
Cancer Res August 1 1995 (55) (15) 3295-3304;
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