title: Functional upregulation of system xc- by fibroblast growth factor-2.
abstract: The cystine/glutamate antiporter (system xc-) is a Na(+)-independent amino acid transport system. Disruption of this system may lead to multiple effects in the CNS including decreased cellular glutathione. Since multiple neurological diseases involve glutathione depletion, and disruption of growth factor signaling has also been implicated in these diseases, it is possible that some growth factors effects are mediated by regulation of system xc-. We tested the growth factors fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1 (IGF-1), neuregulin-1 (NRG), neurotrophin-4 (NT-4), and brain derived neurotrophic factor (BDNF) on system xc- mediated 14C-cystine uptake in mixed neuronal and glial cortical cultures. Only FGF-2 significantly increased cystine uptake. The effect was observed in astrocyte-enriched cultures, but not in cultures of neurons or microglia. The increase was blocked by the system xc- inhibitor (s)-4-carboxyphenylglycine, required at least 12 h FGF-2 treatment, and was prevented by the protein synthesis inhibitor cycloheximide. Kinetic analysis indicated FGF-2 treatment increased the V(max) for cystine uptake while the K(m) remained the same. Quantitative PCR showed an increase in mRNA for xCT, the functional subunit of system xc-, beginning at 3 h of FGF-2 treatment, with a dramatic increase after 12 h. Blocking FGFR1 with PD 166866 blocked the FGF-2 effect. Treatment with a PI3-kinase inhibitor (LY-294002) or a MEK/ERK inhibitor (U0126) for 1 h prior to and during the FGF-2 treatment, each partially blocked the increased cystine uptake. The upregulation of system xc- by FGF-2 may be responsible for some of the known physiological actions of FGF-2. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
authors.affiliation: Dept. of Biomedical Sciences, Marquette University, 561 N. 15th Street, Rm 426, Milwaukee, WI 53233, USA. xiaoqian.1.liu@marquette.edu
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Liu
authors.forename: Jon
authors.initials: J
authors.lastname: Resch
authors.forename: Travis
authors.initials: T
authors.lastname: Rush
authors.forename: Doug
authors.initials: D
authors.lastname: Lobner
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D003513:Cycloheximide / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology; D020890:Neuregulin-1 / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D027182:Amino Acid Transport System y+; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020890:Neuregulin-1; C492255:Slc7a11 protein, mouse; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D003513:Cycloheximide; D003545:Cysteine; C073922:neurotrophin 4