title: Impaired generation of reactive oxygen species in leprechaunism through downregulation of Nox4.
abstract: Leprechaunism features a clinical constellation characterized by extreme insulin resistance, growth retardation, and several distinct developmental abnormalities. One puzzling observation about leprechaunism is that mutations in the insulin receptor gene frequently associated with this syndrome cannot account for the aberrant responses of cultured cells to other growth factors. Here we report that the generation of reactive oxygen species (ROS) is impaired in cells from leprechaunism patients, thus shedding new light on this issue. Stimulation of patients' skin fibroblast cells with platelet-derived growth factor (PDGF) resulted in a lower-level tyrosine phosphorylation of cytosolic proteins compared with that seen in normal cells. In addition, consistent with the hypothesis that ROS mediate the level of tyrosine phosphorylation of cytosolic proteins through inactivation of protein tyrosine phosphatases (PTPases), patient fibroblast cells showed a significantly higher phosphatase activity than normal cells. We further showed that the lower-level tyrosine phosphorylation in response to growth factors results from the downregulation of an NADPH oxidase, Nox4, which in turn results in the reduction of ROS generation. Ectopic expression of Nox4 in the patient fibroblast cells consistently restored PDGF-induced ROS production and regulation of PTPase activities. Taken together, these data provide insight into the mechanisms through which growth retardation is associated with leprechaunism syndrome.
authors.affiliation: Division of Molecular Life Sciences, Center for Cell Signaling Research, Ewha Womans University, Seoul, Korea.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Park
authors.forename: Dong Kyu
authors.initials: DK
authors.lastname: Jin
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Shin
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Jang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Longo
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Park
authors.forename: Duk Soo
authors.initials: DS
authors.lastname: Bae
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014443:Tyrosine
chemical_list: D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; D014443:Tyrosine; D004815:Epidermal Growth Factor; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human