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Molecular and Cellular Biology, February 2000, p. 1179-1186, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Survival Function of the Bcr-Abl Oncogene Is Mediated by Bad-Dependent and -Independent Pathways: Roles for Phosphatidylinositol 3-Kinase and Raf

Mehran S. Neshat,1,2 Arthur B. Raitano,1 Hong-Gang Wang,3 John C. Reed,3 and Charles L. Sawyers1,2,*

Departments of Medicine1 and Molecular Biology Institute,2 University of California, Los Angeles, and Program on Apoptosis and Cell Death Research, Burnham Institute, La Jolla,3 California

Received 25 October 1999/Accepted 10 November 1999

The Bcr-Abl tyrosine kinase constitutively activates cytokine signal transduction pathways that stimulate growth and prevent apoptosis in hematopoietic cells. The antiapoptotic action of interleukin-3 (IL-3) has been linked to a signaling pathway which inactivates the proapoptotic protein Bad by phosphorylation through kinases such as Akt and Raf. Here we report also that expression of Bcr-Abl leads to phosphorylation of Bad in hematopoietic cells. Bad phosphorylation induced by Bcr-Abl is kinase dependent, requires phosphatidylinositol 3-kinase (PI3-kinase), and mitochondrial targeting of Raf, and occurs independently of Erk. The ability of Bcr-Abl to confer cytokine-independent survival to hematopoietic cells was compromised by inhibitors of PI3-kinase, as well as by a dominant negative form of Raf targeted to the mitochondria. Furthermore, when the capacity of Bcr-Abl to phosphorylate Bad was completely blocked by dominant negative Raf, a subpopulation of cells remained viable, providing evidence for Bad-independent survival pathways. This alternative survival pathway remained PI3-kinase dependent. Finally, Bcr-Abl, but not IL-3, inhibited the proapoptotic activity of overexpressed Bad. We conclude that the antiapoptotic function of Bcr-Abl is mediated through pathways involving PI3-kinase and Raf and that survival can occur in the absence of Bad phosphorylation.

* Corresponding author. Mailing address: 11-934 Factor Building, UCLA/Hematology-Oncology, 10833 Le Conte Ave., Los Angeles, CA 90095-1678. Phone: (310) 206-5585. Fax: (310) 206-8502. E-mail: csawyers{at}mednet.ucla.edu.

Molecular and Cellular Biology, February 2000, p. 1179-1186, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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