Distinct requirements for Ras oncogenesis in human versus mouse cells

  1. Nesrin M. Hamad1,4,
  2. Joel H. Elconin1,4,5,
  3. Antoine E. Karnoub3,
  4. Wenli Bai1,
  5. Jeremy N. Rich2,
  6. Robert T. Abraham1,6,
  7. Channing J. Der3, and
  8. Christopher M. Counter1,7
  1. 1Departments of Pharmacology and Cancer Biology and Radiation Oncology and 2Department of Medicine, Division of Neurology, Duke University Medical Center, Durham North Carolina 27710, USA; 3Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA

Abstract

The spectrum of tumors associated with oncogenic Ras in humans often differs from those in mice either treated with carcinogens or engineered to sporadically express oncogenic Ras, suggesting that the mechanism of Ras transformation may be different in humans. Ras stimulates primarily three main classes of effector proteins, Rafs, PI3-kinase, and RalGEFs, with Raf generally being the most potent at transforming murine cells. Using oncogenic Ras mutants that activate single effectors as well as constitutively active effectors, we find that the RalGEF, and not the Raf or PI3-kinase pathway, is sufficient for Ras transformation in human cells. Thus, oncogenic Ras may transform murine and human cells by distinct mechanisms, and the RalGEF pathway—previously deemed to play a secondary role in Ras transformation—could represent a new target for anti-cancer therapy.

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Footnotes

  • 4 These authors contributed equally to this work.

  • Present addresses: 5New Mexico Oncology Consultants, Albuquerque, New Mexico 87102, USA; 6The Burnham Institute, La Jolla, California 92037, USA.

  • 7 Corresponding author.

  • E-MAIL count004{at}mc.duke.edu; FAX (919) 684-8958.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.993902.

    • Received March 21, 2002.
    • Accepted June 17, 2002.
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