The GAP-related domain of neurofibromin attenuates proliferation and downregulates N- and K-Ras activation in Nf1-negative AML cells.
Inactivation of the NF1 tumor suppressor causes myeloproliferative diseases. NF1 encodes a GTPase activating protein (GAP) for Ras. Myeloid cells with loss of NF1 have high levels of Ras-GTP, functionally equivalent to the effects of RAS oncogenes. We investigated the effects of the NF1 GAP-related domain (GRD) in proliferation, apoptosis and Ras-GTP levels in Nf1-negative acute myeloid leukemia (AML) cells. In AML cells, with cooperating mutations, the expression of the neurofibromin GRD causes significant reductions of N- and K-Ras-GTP levels, which is not incompatible with AML cell survival, but which is strongly selected against due to suppression of proliferation.
Morgan
Kelly J
KJ
University of Minnesota, Department of Genetics, Cell Biology and Development, University of Minnesota Cancer Center, Minneapolis, MN, USA.
Rowley
Matthew A
MA
Wiesner
Stephen M
SM
Hasz
Diane E
DE
Van Ness
Brian
B
Largaespada
David A
DA
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D015536:Down-Regulation; D020690:GTPase-Activating Proteins / Q000502:physiology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D025542:Neurofibromin 1 / Q000502:physiology*; D017434:Protein Structure, Tertiary; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D020690:GTPase-Activating Proteins; D025542:Neurofibromin 1; D006160:Guanosine Triphosphate; D016283:Proto-Oncogene Proteins p21(ras)