Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene.
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.
Sawyers
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CL
Department of Medicine, Hematology-Oncology, University of California at Los Angeles 90024.
McLaughlin
J
J
Witte
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ON
D000818:Animals; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D005347:Fibroblasts; D016044:Fusion Proteins, bcr-abl; D020690:GTPase-Activating Proteins; D005799:Genes, Dominant; D016313:Genes, abl; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D009857:Oncogenes; D011506:Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins
D020690:GTPase-Activating Proteins; D011506:Proteins; D020703:ras GTPase-Activating Proteins; D016044:Fusion Proteins, bcr-abl; D016283:Proto-Oncogene Proteins p21(ras)