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.
Article|
January 01 1995
Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene.
C L Sawyers,
C L Sawyers
Department of Medicine, Hematology-Oncology, University of California at Los Angeles 90024.
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J McLaughlin,
J McLaughlin
Department of Medicine, Hematology-Oncology, University of California at Los Angeles 90024.
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O N Witte
O N Witte
Department of Medicine, Hematology-Oncology, University of California at Los Angeles 90024.
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C L Sawyers
Department of Medicine, Hematology-Oncology, University of California at Los Angeles 90024.
J McLaughlin
Department of Medicine, Hematology-Oncology, University of California at Los Angeles 90024.
O N Witte
Department of Medicine, Hematology-Oncology, University of California at Los Angeles 90024.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1995) 181 (1): 307–313.
Citation
C L Sawyers, J McLaughlin, O N Witte; Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene.. J Exp Med 1 January 1995; 181 (1): 307–313. doi: https://doi.org/10.1084/jem.181.1.307
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