Hyperactivation of protein kinase B and ERK have discrete effects on survival, proliferation, and cytokine expression in Nf1-deficient myeloid cells

Cancer Cell. 2002 Dec;2(6):507-14. doi: 10.1016/s1535-6108(02)00214-3.


The Nf1 tumor suppressor encodes a GTPase-activating protein for Ras. Previous work has implicated hyperactive Ras in the aberrant growth of Nf1-deficient cells; however, there are limited data on which effectors modulate specific phenotypes. To address this, we generated myeloid cell lines by infecting fetal liver cells with a retrovirus encoding a truncated allele of c-Myb. Granulocyte-macrophage colony stimulating factor (GM-CSF) promoted the survival of wild-type Myb cells in a dose-dependent manner. By contrast, Nf1-deficient myeloid cells deprived of growth factors, were resistant to apoptosis due to hyperactivation of the phosphoinositide-3-OH kinase/protein kinase B cascade. Nf1(-/-) cells also demonstrated growth factor-independent proliferation and upregulation of GM-CSF mRNA production that were dependent upon Raf/MEK/ERK signaling. These data link specific Ras effectors with discrete cellular phenotypes in Nf1-deficient cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Division / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Fetus
  • Genes, myb
  • Genes, ras / drug effects
  • Genes, ras / physiology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Hepatocytes / drug effects
  • Hepatocytes / pathology
  • Hepatocytes / physiology
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Myeloid Cells / physiology
  • Neurofibromin 1 / deficiency*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / analysis
  • Signal Transduction
  • Transfection


  • Enzyme Inhibitors
  • Neurofibromin 1
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases