title: Reconstitution of the NF1 GAP-related domain in NF1-deficient human Schwann cells.
abstract: 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.
authors.affiliation: Research Service, Edward Hines Jr. V.A. Hospital, 5th Avenue and Roosevelt Road, Hines, IL 60141, USA.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Thomas
authors.forename: Gail D
authors.initials: GD
authors.lastname: Deadwyler
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Evan B
authors.initials: EB
authors.lastname: Stubbs
authors.forename: David
authors.initials: D
authors.lastname: Muir
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hiatt
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.forename: George H
authors.initials: GH
authors.lastname: De Vries
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D020690:GTPase-Activating Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D025542:Neurofibromin 1 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D020690:GTPase-Activating Proteins; D025542:Neurofibromin 1