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Functional upregulation of system xc- by fibroblast growth factor-2

Xiaoqian Liu¹, Jon Resch, Travis Rush

¹Dept. of Biomedical Sciences, Marquette University, 561 N. 15th Street, Rm 426, Milwaukee, WI 53233, USA. xiaoqian.1.liu@marquette.edu

Neuropharmacology

|October 5, 2011

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'.

Insights

Fibroblast growth factor-2 (FGF-2) upregulates the cystine/glutamate antiporter (system xc-) in astrocytes, potentially influencing neurological disease pathways. This mechanism involves increased xCT mRNA and protein synthesis, mediated by FGFR1 and PI3-kinase/ERK signaling.

Area of Science:

Neuroscience
Cellular Biology
Neurochemistry

Background:

The cystine/glutamate antiporter (system xc-) is crucial for maintaining cellular glutathione levels in the central nervous system (CNS).
Glutathione depletion is implicated in various neurological diseases, suggesting system xc- dysfunction may play a role.
Growth factor signaling disruptions are also linked to neurological disorders, hinting at a potential regulatory connection with system xc-.

Purpose of the Study:

To investigate whether specific growth factors regulate system xc- activity in CNS cultures.
To determine the cellular localization and molecular mechanisms underlying FGF-2's effect on system xc-.

Main Methods:

Assessed 14C-cystine uptake in mixed neuronal and glial cortical cultures treated with various growth factors (FGF-2, IGF-1, NRG, NT-4, BDNF).
Utilized astrocyte-enriched, neuronal, and microglial cultures to pinpoint cell-type specificity.
Employed system xc- inhibitors, protein synthesis inhibitors, quantitative PCR for xCT mRNA, kinetic analysis, receptor blocking (FGFR1), and signaling pathway inhibitors (PI3-kinase, MEK/ERK).

Main Results:

Fibroblast growth factor-2 (FGF-2) significantly increased cystine uptake specifically in astrocytes, mediated by system xc-.
FGF-2's effect required at least 12 hours of treatment, protein synthesis, FGFR1 signaling, and partially involved PI3-kinase and MEK/ERK pathways.
Quantitative PCR revealed FGF-2 upregulated xCT mRNA, the functional subunit of system xc-, with increased Vmax for cystine transport.

Conclusions:

FGF-2 upregulates the cystine/glutamate antiporter (system xc-) in astrocytes, likely through transcriptional and translational mechanisms involving FGFR1.
This FGF-2-mediated upregulation of system xc- may contribute to the neuroprotective or physiological roles of FGF-2 in the CNS.
Understanding this pathway offers potential therapeutic insights for neurological conditions associated with glutathione depletion and growth factor dysregulation.

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