title: Activation of proteasome by insulin-like growth factor-I may enhance clearance of oxidized proteins in the brain.
abstract: The insulin-like growth factor type 1 (IGF-I) plays an important role in neuronal physiology. Reduced IGF-I levels are observed during aging and this decrease may be important to age-related changes in the brain. We studied the effects of IGF-I on total protein oxidation in brain tissues and in cell cultures. Our results indicate that in frontal cortex the level of oxidized proteins is significantly reduced in transgenic mice designed to overproduce IGF-I compared with wild-type animals. The frontal cortex of IGF-I-overproducing mice exhibited high chymotrypsin-like activity of the 20S and 26S proteasomes. The proteasome can also be activated in response to IGF-I in cell cultures. Kinetic studies revealed peak activation of the proteasome within 15 min following IGF-I stimulation. The effects of IGF-I on proteasome were not observed in R(-) cells lacking the IGF-I receptor. Experiments using specific kinase inhibitors suggested that activation of proteasome by IGF-I involves phosphatidyl inositol 3-kinase and mammalian target of rapamycin signaling. IGF-I also attenuated the increase in protein carbonyl content induced by proteasome inhibition. Thus, appropriate levels of IGF-I may be important for the elimination of oxidized proteins in the brain in a process mediated by activation of the proteasome.
authors.affiliation: Department of Pathology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Crowe
authors.forename: Christian
authors.initials: C
authors.lastname: Sell
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Thomas
authors.forename: Gregg J
authors.initials: GJ
authors.lastname: Johannes
authors.forename: Claudio
authors.initials: C
authors.lastname: Torres
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D050050:Protein Carbonylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000502:physiology
chemical_list: D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D046988:Proteasome Endopeptidase Complex