title: Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function.
abstract: The central nervous dysfunctions of lethargy, fever and anorexia are manifestations of sepsis that seem to be mediated by increased cytokine production. Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling. The stabilization of RGS7 by TNF-alpha requires activation of the stress-activated protein kinase p38 and the presence of candidate mitogen-activated protein kinase phosphorylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-alpha, a response that is nearly abrogated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: T
authors.initials: T
authors.lastname: Benzing
authors.forename: R
authors.initials: R
authors.lastname: Brandes
authors.forename: L
authors.initials: L
authors.lastname: Sellin
authors.forename: B
authors.initials: B
authors.lastname: Schermer
authors.forename: S
authors.initials: S
authors.lastname: Lecker
authors.forename: G
authors.initials: G
authors.lastname: Walz
authors.forename: E
authors.initials: E
authors.lastname: Kim
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011493:Protein Kinase C / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D015703:Antigens, CD; D029742:Caenorhabditis elegans Proteins; C105577:EGL-10 protein, C elegans; D007976:Leupeptins; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D011506:Proteins; D020710:RGS Proteins; C492039:RGS7 protein, human; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C492038:Rgs7 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D019204:GTP-Binding Proteins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde