title: Analysis of Ras-dependent signals that prevent caspase-3 activation and apoptosis induced by cytokine deprivation in hematopoietic cells.
abstract: In hematopoietic cells, Ras has been implicated in signaling pathways that prevent apoptosis triggered by deprivation of cytokines, such as interleukin-3 (IL-3). However, the mechanism whereby Ras suppresses cell death remains incompletely understood. We have investigated the role of Ras in IL-3 signal transduction by using the cytokine-dependent BaF3 cell line. Herein, we show that the activation of the pro-apoptotic protease caspase-3 upon IL-3 removal is suppressed by expression of activated Ras, which eventually prevents cell death. For caspase-3 suppression, the Raf/extracellular signal-regulated kinase (ERK)- or phosphatidylinositol 3-kinase (PI3-K)/Akt-mediated signaling pathway downstream of Ras was required. However, inhibition of both pathways did not block activated Ras-dependent suppression of cell death-associated phenotypes, such as nuclear DNA fragmentation. Thus, a pathway that is independent of both Raf/ERK and PI3-K/Akt pathways may function downstream of Ras, preventing activated caspase-3-initiated apoptotic processes. Conditional activation of c-Raf-1 also suppressed caspase-3 activation and subsequent cell death without affecting Akt activity, providing further evidence for a PI3-K/Akt-independent mechanism.
authors.affiliation: Faculty of Bioscience, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Terada
authors.forename: Y
authors.initials: Y
authors.lastname: Kaziro
authors.forename: T
authors.initials: T
authors.lastname: Satoh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology; D002474:Cell-Free System; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007377:Interleukin-3 / Q000494:pharmacology; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000502:physiology; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D016207:Cytokines; D007377:Interleukin-3; D011994:Recombinant Proteins; D007544:Isopropyl Thiogalactoside; D004958:Estradiol; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D018631:ras Proteins