Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for gamma-glutamylcysteine synthetase.

Sekhar KR, Soltaninassab SR, Borrelli MJ, Xu ZQ, Meredith MJ, Domann FE, Freeman ML
Biochem Biophys Res Commun. 2000 270 (1): 311-7

PMID: 10733945 · DOI:10.1006/bbrc.2000.2419

The majority of short- and long-lived cellular proteins are degraded by the activities of the 26S proteasome, a large multi-catalytic protease. Its unique function places it as a central regulatory activity for many important physiological processes. Lactacystin is a very specific 26S proteasome inhibitor and represents an excellent tool for demonstrating that a pathway exhibits proteasome-dependent biochemical regulation. Exposure of HepG2 cells to lactacystin resulted in robust elevation of GLCLC mRNA levels, followed by an increase in GSH concentrations. GLCLC is the gene that encodes the catalytic subunit for gamma-glutamylcysteine synthetase, the rate-limiting enzyme for the synthesis of glutathione (GSH). Inhibition of non-proteasome, protease activities did not induce GLCLC. Gel mobility shift assays and expression of CAT activity from heterologous reporter vectors identified Nrf2 mediation of the GLCLC antioxidant response element, ARE4, as the mechanism by which lactacystin induced GLCLC. These studies have identified 26S proteasome activity as a central regulatory pathway for glutathione synthesis.

Copyright 2000 Academic Press.

MeSH Terms (15)

Acetylcysteine Azetidines Cells, Cultured DNA-Binding Proteins Enzyme Induction Glutamate-Cysteine Ligase Glutathione Liver Neoplasm Proteins NF-E2-Related Factor 2 Peptide Hydrolases Proteasome Endopeptidase Complex Protein Structure, Quaternary Response Elements Trans-Activators

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