Downregulation of Bim, a Proapoptotic Relative of Bcl-2, Is a Pivotal Step in Cytokine-Initiated Survival Signaling in Murine Hematopoietic Progenitors
| Autor: | Takeshi Inukai, Ryoko Kuribara, Toshiya Inaba, H Hosoi, Atsushi Miyajima, Tetsuharu Shinjyo, Keiya Ozawa, Peter J. Houghton, A T Look, Taisei Kinoshita |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Cell Survival
Proto-Oncogene Proteins c-akt medicine.medical_treatment Down-Regulation Apoptosis Protein Serine-Threonine Kinases Cell Line Mice Phosphatidylinositol 3-Kinases Downregulation and upregulation Proto-Oncogene Proteins medicine Animals Humans Phosphorylation Protein kinase A Cell Growth and Development Molecular Biology Protein kinase B STAT5 Bcl-2-Like Protein 11 biology TOR Serine-Threonine Kinases Membrane Proteins Cell Biology Hematopoietic Stem Cells Cell biology Phosphotransferases (Alcohol Group Acceptor) Cytokine Proto-Oncogene Proteins c-bcl-2 ras Proteins biology.protein Cancer research Interleukin-3 Mitogen-Activated Protein Kinases Signal transduction Apoptosis Regulatory Proteins Carrier Proteins Protein Kinases Signal Transduction |
| Zdroj: | Molecular and Cellular Biology. 21:854-864 |
| ISSN: | 1098-5549 |
| Popis: | Two distinct signaling pathways regulate the survival of interleukin-3 (IL-3)-dependent hematopoietic progenitors. One originates from the membrane-proximal portion of the cytoplasmic domain of the IL-3 receptor (betac chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating factor and is involved in the regulation of Bcl-x(L) through activation of STAT5. The other pathway emanates from the distal region of the betac chain and overlaps with downstream signals from constitutively active Ras proteins. Although the latter pathway is indispensable for cell survival, its downstream targets remain largely undefined. Here we show that the expression of Bim, a member of the BH3-only subfamily of cell death activators, is downregulated by IL-3 signaling through either of two major Ras pathways: Raf/mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/mammalian target of rapamycin. Akt/phosphokinase B does not appear to play a significant role in this regulatory cascade. Bim downregulation has important implications for cell survival, since enforced expression of this death activator at levels equivalent to those induced by cytokine withdrawal led to apoptosis even in the presence of IL-3. We conclude that Bim is a pivotal molecule in cytokine regulation of hematopoietic cell survival. |
| Databáze: | OpenAIRE |
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