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, Arthur B. Raitano, Hong Gang Wang, John C. Reed, Charles L. Sawyers

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1179-1186
Number of pages8
JournalMolecular and cellular biology
Volume20
Issue number4
DOIs
StatePublished - Feb 2000

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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