title: Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences of Nf1 deficiency in T-cell development and function.
abstract: Ras plays an essential role in lymphocyte development and function. However, in vivo consequence(s) of regulation of Ras activity by guanosine triphosphatase (GTPase)-activating proteins (GAPs) on lymphocyte development and function are not known. In this study we demonstrate that neurofibromin, the protein encoded by the NF1 tumor suppressor gene functions as a GAP for Ras in T cells. Loss of Nf1 in T cells results in enhanced Ras activation, which is associated with thymic and splenic hyperplasia, and an increase in the absolute number of immature and mature T-cell subsets compared with control mice. Interestingly, in spite of a profound T-cell expansion and higher thymidine incorporation in unstimulated Nf1-deficient T cells, T-cell receptor and interleukin-2 receptor-mediated proliferation of thymocytes and mature T cells was substantially reduced compared with control mice. Collectively, these results identify neurofibromin as a GAP for Ras in T cells for maintaining immune homeostasis in vivo.
authors.affiliation: Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, IN 46202, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: McCarthy
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Wenning
authors.forename: Lucy
authors.initials: L
authors.lastname: Fisher
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
mesh_terms: D000818:Animals; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D025542:Neurofibromin 1 / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D025542:Neurofibromin 1; D018631:ras Proteins