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Originally published In Press as doi:10.1074/mcp.M400054-MCP200 on June 4, 2004.
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Molecular & Cellular Proteomics 3:834-840, 2004.
© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

High-throughput Functional Genomics Identifies Genes That Ameliorate Toxicity Due to Oxidative Stress in Neuronal HT-22 Cells

GFPT2 Protects Cells Against Peroxide*

Jürgen Zitzler{ddagger}, Dieter Link{ddagger}, Rolf Schäfer{ddagger}, Wolfgang Liebetrau{ddagger}, Michael Kazinski{ddagger}, Angelika Bonin-Debs{ddagger}, Christian Behl§, Peter Buckel{ddagger} and Ulrich Brinkmann{ddagger},¶

From the {ddagger} Xantos Biomedicine AG, Max-Lebsche Platz 31, D-81377 Munich, Germany; and § Institute for Physiological Chemistry and Pathobiochemistry, Johannes-Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany

We describe a novel genetic screen that is performed by transfecting every individual clone of an expression clone collection into a separate population of cells in a high-throughput mode. We combined high-throughput functional genomics with experimental validation to discover human genes that ameliorate cytotoxic responses of neuronal HT-22 cells upon exposure to oxidative stress. A collection of 5,000 human cDNAs in mammalian expression vectors were individually transfected into HT-22 cells, which were then exposed to H2O2. Five genes were found that are known to be involved in pathways of detoxification of peroxide (catalase, glutathione peroxidase-1, peroxiredoxin-1, peroxiredoxin-5, and nuclear factor erythroid-derived 2-like 2). The presence of those genes in our "hit list" validates our screening platform. In addition, a set of candidate genes was found that has not been previously described as involved in detoxification of peroxide. One of these genes, which was consistently found to reduce H2O2 -induced toxicity in HT-22, was GFPT2. This gene is expressed at significant levels in the central nervous system (CNS) and encodes glutamine-fructose-6-phosphate transaminase (GFPT) 2, a rate-limiting enzyme in hexosamine biosynthesis. GFPT has recently also been shown to ameliorate the toxicity of methylmercury in Saccharomyces cerevisiae. Methylmercury causes neuronal cell death in part by protein modification as well as enhancing the production of reactive oxygen species (ROS). The protective effect of GFPT2 against H2O2 toxicity in neuronal HT-22 cells may be similar to its protection against methylmercury in yeast. Thus, GFPT appears to be conserved among yeast and men as a critical target of methylmercury and ROS-induced cytotoxicity.

To whom correspondence should be addressed: Xantos Biomedicine AG, Max-Lebsche-Platz 31, 81377 Munich, Germany. Tel.: 0049-0-89-89959415; Fax: 0049-0-89 89959420; E-mail: u.brinkmann{at}xantos.de


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