Hyperactivation of protein kinase B and ERK have discrete effects on survival, proliferation, and cytokine expression in Nf1-deficient myeloid cells.
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.
Donovan
Shane
S
Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
See
Wendy
W
Bonifas
Jeannette
J
Stokoe
David
D
Shannon
Kevin M
KM
D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D020570:Genes, myb; D011905:Genes, ras / Q000187:drug effects / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D022423:Myeloid Cells / Q000502:physiology; D025542:Neurofibromin 1 / Q000172:deficiency*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D014162:Transfection
D004791:Enzyme Inhibitors; D025542:Neurofibromin 1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases