Reconstitution of the NF1 GAP-related domain in NF1-deficient human Schwann cells

• Published in: Biochemical and biophysical research communications 2006-09, Vol.348 (3), p.971-980
• Main Authors: Thomas, Stacey L., Deadwyler, Gail D., Tang, Jun, Stubbs, Evan B., Muir, David, Hiatt, Kelly K., Clapp, D. Wade, De Vries, George H.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Angiogenesis; Base Sequence; Cell Line; CELL PROLIFERATION; Cells, Cultured; GTPase-Activating Proteins - biosynthesis; GTPase-Activating Proteins - deficiency; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Humans; IN VITRO; Molecular Sequence Data; MORPHOLOGY; MPNST; NEOPLASMS; Neurofibroma; Neurofibromatosis; Neurofibromin 1 - biosynthesis; Neurofibromin 1 - deficiency; Neurofibromin 1 - genetics; Neurofibromin 1 - metabolism; NF1; NF1-GRD; PHENOTYPE; Proliferation; Protein Structure, Tertiary - genetics; PROTEINS; Ras; Retroviridae - genetics; Schwann cell; Schwann Cells - metabolism; STIMULI; Transduction, Genetic
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2006.07.159

Schwann cells derived from peripheral nerve sheath tumors from individuals with Neurofibromatosis Type 1 (NF1) are deficient for the protein neurofibromin, which contains a GAP-related domain (NF1-GRD). Neurofibromin-deficient Schwann cells have increased Ras activation, increased proliferation in response to certain growth stimuli, increased angiogenic potential, and altered cell morphology. This study examined whether expression of functional NF1-GRD can reverse the transformed phenotype of neurofibromin-deficient Schwann cells from both benign and malignant peripheral nerve sheath tumors. We reconstituted the NF1-GRD using retroviral transduction and examined the effects on cell morphology, growth potential, and angiogenic potential. NF1-GRD reconstitution resulted in morphologic changes, a 16–33% reduction in Ras activation, and a 53% decrease in proliferation in neurofibromin-deficient Schwann cells. However, NF1-GRD reconstitution was not sufficient to decrease the in vitro angiogenic potential of the cells. This study demonstrates that reconstitution of the NF1-GRD can at least partially reverse the transformation of human NF1 tumor-derived Schwann cells.