Inhibition of the 26S Proteasome Induces Expression of GLCLC, the Catalytic Subunit for γ-Glutamylcysteine Synthetase

Sekhar, Konjeti R.; Soltaninassab, Syrus R.; Borrelli, Michael J.; Xu, Zhi-Qi; Meredith, Michael; Domann, Frederick E.; Freeman, Michael L.

doi:10.1006/bbrc.2000.2419

Cited by 46 publications

(35 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ARE-dependent ␥-gcs gene expression is regulated, in part, by the "cap'n'collar" family of basic leucine zipper transcription factor Nrf2 (41,42). Previous studies have demonstrated that Nrf2 is degraded by proteasomes, and proteasome inhibition induces the accumulation of Nrf2 and ARE activation, resulting in ␥-gcs catalytic gene expression (43)(44)(45). Corresponding to these reports, we showed that Nrf2 translocated to the nucleus and that ␥-GCS mRNA expression was significantly increased after exposure to lactacystin (Fig.…”

Section: Discussionsupporting

confidence: 81%

Proteasome Inhibition Induces Glutathione Synthesis and Protects Cells from Oxidative Stress

Yamamoto

Sawada

Izumi

et al. 2007

Journal of Biological Chemistry

131

View full text Add to dashboard Cite

The cause of selective dopaminergic neuronal degeneration in Parkinson disease has still not been resolved, but it has been hypothesized that oxidative stress and the ubiquitin-proteasome system are important in the pathogenesis. In this report, we investigated the effect of proteasome inhibition on oxidative stress-induced cytotoxicity in PC12 cells, an in vitro model of Parkinson disease. Treatment with proteasome inhibitors provided significant protection against toxicity by 6-hydroxydopamine and H 2 O 2 in a concentration-dependent manner. The measurement of intracellular reactive oxygen species using 2,7-dichlorofluorescein diacetate demonstrated that lactacystin, a proteasome inhibitor, significantly reduced 6-hydroxydopamine-and H 2 O 2 -induced reactive oxygen species production. Proteasome inhibitors elevated the amount of glutathione and phosphorylated p38 mitogenactivated protein kinase (MAPK) prior to glutathione elevation. The treatment with lactacystin induced the nuclear translocation of NF-E2-related factor 2 (Nrf2) and increased the level of mRNA for ␥-glutamylcysteine synthetase, a rate-limiting enzyme in glutathione synthesis. Furthermore, SB203580, an inhibitor of p38 MAPK, abolished glutathione elevation and cytoprotection by lactacystin. These data suggest that proteasome inhibition afforded cytoprotection against oxidative stress by the elevation of glutathione content, and its elevation was mediated by p38 MAPK phosphorylation.

show abstract

Section: Discussionsupporting

confidence: 81%

Proteasome Inhibition Induces Glutathione Synthesis and Protects Cells from Oxidative Stress

Yamamoto

Sawada

Izumi

et al. 2007

Journal of Biological Chemistry

131

View full text Add to dashboard Cite

show abstract

“…Inhibition of the proteasomal degradation of Nrf2 blocks the cycle, leading to the accumulation of the Keap1-Nrf2 complex in the closed conformation. Inducers function to inhibit the ubiquitination of Nrf2, but crucially, in the absence of new translation, Nrf2 is not stabilized in the induced state, and Nrf2-target genes are not upregulated (24,25), suggesting it is the de novo translated Nrf2 which translocates to the nucleus, whereas the existing population of Nrf2 remains bound to Keap1.…”

Section: Discussionmentioning

confidence: 99%

Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex

Baird

Llères

Swift

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

319

312

View full text Add to dashboard Cite

Significance We have developed a quantitative Förster resonance energy transfer-based methodology using multiphoton fluorescence lifetime imaging microscopy to investigate in single live cells the interaction between the substrate adaptor protein Kelch-like ECH associated protein 1 (Keap1) and transcription factor NF-E2 p45-related factor 2 (Nrf2), the master regulator of the mammalian cell response to oxidants and electrophiles. The application of this methodology revealed that the system is much more dynamic than previously anticipated, whereby Keap1 utilizes a unique cyclic mechanism to target Nrf2 for ubiquitination and proteasomal degradation, which also leads to Keap1 regeneration. The nature of this mechanism allows rapid transcriptional responses to environmental changes and is capable of accommodating multiple modes of regulation.

show abstract

“…Nrf2 is a substrate for the ubiquitin-proteasome system. Treatment of cells with a proteasome inhibitor prevents rapid degradation of this protein, leading to enhanced expression of the downstream gene encoding ␥-glutamylcysteine ligase (37). Recently, Itoh et al (21) proposed that Nrf2 protein turnover is regulated by Keap1-mediated subcellular compartmentalization of this transcription factor.…”

Section: Discussionmentioning

confidence: 99%

Antioxidants Enhance Mammalian Proteasome Expression through the Keap1-Nrf2 Signaling Pathway

Kwak

Wakabayashi

Greenlaw

et al. 2003

Molecular and Cellular Biology

459

350

View full text Add to dashboard Cite

Proteasomes degrade damaged proteins formed during oxidative stress, thereby promoting cell survival. Neurodegenerative and other age-related disorders are associated with reduced proteasome activity. We show herein that expression of most subunits of 20S and 19S proteasomes, which collectively assemble the 26S proteasome, was enhanced up to threefold in livers of mice following treatment with dithiolethiones, which act as indirect antioxidants. Subunit protein levels and proteasome activity were coordinately increased. No induction was seen in mice where the transcription factor Nrf2 was disrupted. Promoter activity of the PSMB5 subunit of the 20S proteasome increased with either Nrf2 overexpression or treatment with antioxidants in mouse embryonic fibroblasts. Tandem antioxidant response elements in the proximal promoter of PSMB5 that controlled these responses were identified. We propose that induction of the 26S proteasome through the Nrf2 pathway represents an important indirect action of these antioxidants that can contribute to their protective effects against chronic diseases.

show abstract

Inhibition of the 26S Proteasome Induces Expression of GLCLC, the Catalytic Subunit for γ-Glutamylcysteine Synthetase

Cited by 46 publications

References 34 publications

Proteasome Inhibition Induces Glutathione Synthesis and Protects Cells from Oxidative Stress

Proteasome Inhibition Induces Glutathione Synthesis and Protects Cells from Oxidative Stress

Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex

Antioxidants Enhance Mammalian Proteasome Expression through the Keap1-Nrf2 Signaling Pathway

Contact Info

Product

Resources

About