Suppression of apoptotic death in hematopoietic cells by signalling through the IL-3/GM-CSF receptors.
Interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) exert their biological functions through acting on a specific receptor which consists of a ligand-specific alpha subunit and the shared common beta subunit. Inhibition by genistein of a subset of IL-3/GM-CSF-mediated signals, including c-myc induction, resulted in the abrogation of DNA synthesis, however, IL-3 still protected cells from apoptotic cell death. Conversely, a C-terminal truncated form of the GM-CSF receptor, which is missing a critical cytoplasmic region required for activation of the Ras/Raf-1/MAP kinase pathway, induced DNA synthesis, but failed to prevent cell death in response to GM-CSF. Consequently, cells died by apoptosis in the presence of GM-CSF, despite displaying a transient mitogenic response. However, expression of activated Ras protein complemented defective signalling through the mutant receptor and supported long-term proliferation in concert with GM-CSF. These results indicate that IL-3 and GM-CSF prevent apoptosis of hematopoietic cells by activating a signalling pathway distinct from the induction of DNA synthesis and that long-term cell proliferation requires the activation of both pathways.
Department of Cell Biology, DNAX Research Institute of Molecular and Cellular Biology.
T
T
Kinoshita
T
T
Yokota
K
K
Arai
A
A
Miyajima
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D005786:Gene Expression Regulation; D019833:Genistein; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007377:Interleukin-3 / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics
D007377:Interleukin-3; D007529:Isoflavones; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016185:Receptors, Interleukin-3; D004247:DNA; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D018631:ras Proteins