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K- and N-Ras Are Geranylgeranylated in Cells Treated with Farnesyl Protein Transferase Inhibitors

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K- and N-Ras Are Geranylgeranylated in Cells Treated with Farnesyl Protein Transferase Inhibitors*

  1. David B. Whyte,
  2. Paul Kirschmeier,
  3. Tish N. Hockenberry,
  4. Irma Nunez-Oliva,
  5. Linda James,
  6. Joseph J. Catino,
  7. W. Robert Bishop and
  8. Jin-Keon Pai
  1. From the Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033

Abstract

The association of mutant forms of Ras protein with a variety of human cancers has stimulated intense interest in therapies based on inhibiting oncogenic Ras signaling. Attachment of Ras proteins to the plasma membrane is required for effective Ras signaling and is initiated by the enzyme farnesyl protein transferase. We found that in the presence of potent farnesyl protein transferase inhibitors, Ras proteins in the human colon carcinoma cell line DLD-1 were alternatively prenylated by geranylgeranyl transferase-1. When H-Ras, N-Ras, K-Ras4A, and K-Ras4B were expressed individually in COS cells, H-Ras prenylation and membrane association were found to be uniquely sensitive to farnesyl transferase inhibitors; N- and K-Ras proteins incorporated the geranylgeranyl isoprene group and remained associated with the membrane fraction. The alternative prenylation of N- and K-Ras has significant implications for our understanding of the mechanism of action of farnesyl protein transferase inhibitors as anti-cancer chemotherapeutics.

Footnotes

  • * The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • ‡ To whom correspondence should be addressed: Schering Plough Research Institute, Bldg. K15–4/4600, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. Tel.: 908-298-7346; Fax: 908-298-7115; E-mail:david.whyte{at}spcorp.com.

  • Received November 7, 1996.
  • Revision received March 14, 1997.
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  1. doi: 10.1074/jbc.272.22.14459 May 30, 1997 The Journal of Biological Chemistry 272, 14459-14464.
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