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The survival function of the Bcr-Abl oncogene is mediated by Bad-dependent and -independent pathways: roles for phosphatidylinositol 3-kinase and Raf.
Neshat, M S; Raitano, A B; Wang, H G; Reed, J C; Sawyers, C L.
Afiliação
  • Neshat MS; Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, 90095-1678, USA.
Mol Cell Biol ; 20(4): 1179-86, 2000 Feb.
Article em En | MEDLINE | ID: mdl-10648603
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Transporte / Genes abl / Fosfatidilinositol 3-Quinases / Proteínas Proto-Oncogênicas c-raf Limite: Humans Idioma: En Revista: Mol Cell Biol Ano de publicação: 2000 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Transporte / Genes abl / Fosfatidilinositol 3-Quinases / Proteínas Proto-Oncogênicas c-raf Limite: Humans Idioma: En Revista: Mol Cell Biol Ano de publicação: 2000 Tipo de documento: Article País de afiliação: Estados Unidos