The GAP-related domain of neurofibromin attenuates proliferation and downregulates N- and K-Ras activation in Nf1 -negative AML cells

• Published in: Leukemia research Vol. 31; no. 8; pp. 1107 - 1113
• Main Authors: Morgan, Kelly J, Rowley, Matthew A, Wiesner, Stephen M, Hasz, Diane E, Van Ness, Brian, Largaespada, David A
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2007
• Subjects: Animals; Blotting, Western; Cell Proliferation; Down-Regulation; GAP-related domain; GTPase-Activating Proteins - physiology; Guanosine Triphosphate - metabolism; Hematology, Oncology and Palliative Medicine; Humans; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Mice, SCID; Myeloid leukemia; Neurofibromin; Neurofibromin 1 - physiology; Protein Structure, Tertiary; Proto-Oncogene Proteins p21(ras) - metabolism; Ras; Tumor Cells, Cultured; GAP-related domain; Neurofibromin; Myeloid leukemia; Ras
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2006.11.022

Abstract 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.