Suppression of apoptotic death in hematopoietic cells by signalling through the IL-3/GM-CSF receptors

EMBO J. 1995 Jan 16;14(2):266-75.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Cycle
  • Cell Line
  • Cell Nucleus / metabolism
  • DNA / biosynthesis
  • DNA / drug effects
  • Gene Expression Regulation
  • Genistein
  • Hematopoietic Stem Cells / metabolism*
  • Interleukin-3 / pharmacology
  • Isoflavones / pharmacology
  • Mice
  • Mutation
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogenes
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Receptors, Interleukin-3 / metabolism*
  • Signal Transduction*
  • ras Proteins / genetics

Substances

  • Interleukin-3
  • Isoflavones
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Receptors, Interleukin-3
  • DNA
  • Genistein
  • Protein-Tyrosine Kinases
  • ras Proteins