Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene

J Exp Med. 1995 Jan 1;181(1):307-13. doi: 10.1084/jem.181.1.307.

Abstract

To determine the functional importance of Ras in transformation by Abl oncogenes, we used a genetic approach to measure the effect of impaired Ras activity on the ability of Bcr-Abl or v-Abl to transform cells. Expression of the catalytic domain of the GTPase activating protein for Ras (Gap C terminus) impaired soft agar colony formation by fibroblasts expressing v-Abl or Bcr-Abl by 70-80%. To test Ras function in a model that more closely resembles clinical diseases involving Bcr-Abl, double gene retroviruses expressing Bcr-Abl paired with the Gap C terminus or dominant negative Ras were introduced into naive mouse bone marrow cells. Transformation by Bcr-Abl was completely blocked in both situations. Coexpression of normal c-H-Ras accelerated the transforming activity of Bcr-Abl. These findings show that Ras activation is essential for the leukemogenic activity of Abl oncogenes in two distinct model systems. The results genetically define a connection between the Bcr-Abl cytoplasmic tyrosine kinase and Ras and add to the accumulating evidence that deregulation of Ras is a central event in the genesis of a number of molecularly distinct forms of human myeloid leukemia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Cells
  • Cells, Cultured
  • Fibroblasts
  • Fusion Proteins, bcr-abl*
  • GTPase-Activating Proteins
  • Genes, Dominant
  • Genes, abl*
  • Hematopoietic Stem Cells / cytology*
  • In Vitro Techniques
  • Mice
  • Mice, Inbred BALB C
  • Oncogenes*
  • Proteins / metabolism
  • Proto-Oncogene Proteins p21(ras) / physiology*
  • Rats
  • Signal Transduction
  • ras GTPase-Activating Proteins

Substances

  • GTPase-Activating Proteins
  • Proteins
  • ras GTPase-Activating Proteins
  • Fusion Proteins, bcr-abl
  • Proto-Oncogene Proteins p21(ras)