The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression

Sekine, Hiroshi; Okazaki, Kazuyuki; Ota, Nao; Shima, Hiroki; Katoh, Yohei; Suzuki, Norio; Igarashi, Kazuhiko; Ito, Mitsuhiro; Motohashi, Hozumi; Yamamoto, Masayuki

doi:10.1128/mcb.00785-15

Cited by 76 publications

(74 citation statements)

References 37 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…pGEX4T-1 mNRF2 mutant vectors expressing GST and GST-NRF2 mutants were used for recombinant protein production (22). For a reporter assay and protein expression in HEK293T cells, pRBGP2 (3ϫ ARE-LUC), pRBGP4 (3ϫ mut ARE-LUC), p3xFLAG-NRF2, pcDNA3-FLAG-hGR␣, and pRL-LUC (internal control) were used (39,40).…”

Section: Plasmidsmentioning

confidence: 99%

Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2

Alam

Okazaki

Nguyen

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

NRF2 (nuclear factor erythroid 2-related factor 2) is a key transcriptional activator that mediates the inducible expression of antioxidant genes. NRF2 is normally ubiquitinated by KEAP1 (Kelch-like ECH-associated protein 1) and subsequently degraded by proteasomes. Inactivation of KEAP1 by oxidative stress or electrophilic chemicals allows NRF2 to activate transcription through binding to antioxidant response elements (AREs) and recruiting histone acetyltransferase CBP (CREB-binding protein). Whereas KEAP1-dependent regulation is a major determinant of NRF2 activity, NRF2-mediated transcriptional activation varies from context to context, suggesting that other intracellular signaling cascades may impact NRF2 function. To identify a signaling pathway that modifies NRF2 activity, we immunoprecipitated endogenous NRF2 and its interacting proteins from mouse liver and identified glucocorticoid receptor (GR) as a novel NRF2-binding partner. We found that glucocorticoids, dexamethasone and betamethasone, antagonize diethyl maleate-induced activation of NRF2 target genes in a GR-dependent manner. Dexamethasone treatment enhanced GR recruitment to AREs without affecting chromatin binding of NRF2, resulting in the inhibition of CBP recruitment and histone acetylation at AREs. This repressive effect was canceled by the addition of histone deacetylase inhibitors. Thus, GR signaling decreases NRF2 transcriptional activation through reducing the NRF2-dependent histone acetylation. Consistent with these observations, GR signaling blocked NRF2-mediated cytoprotection from oxidative stress. This study suggests that an impaired antioxidant response by NRF2 and a resulting decrease in cellular antioxidant capacity account for the side effects of glucocorticoids, providing a novel viewpoint for the pathogenesis of hypercorticosteroidism.

show abstract

Section: Plasmidsmentioning

confidence: 99%

Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2

Alam

Okazaki

Nguyen

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Very recently, it has been reported that Nrf2 directly interacts with the subunit MED16 of the Mediator complex. Given that the association Nrf2-MED16 does not affect Nrf2 binding to the ARE, and that MED16 can recruit and/or activate RNA Polymerase II, the interaction Nrf2-MED16 is crucial for connecting stress signals to the transcriptional apparatus [72].…”

Section: Positive Regulatorsmentioning

confidence: 99%

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

Paladino

Conte

Caggiano

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.

show abstract

“…The tail has also been reported to be dispensable for Mediator occupancy at TFIID-dominated genes (39), though this has recently been questioned (34). One possible mechanism for recruitment of Mediator to sn/snoRNAs is via the interaction of activators, including Tbf1, with other subunits of Mediator, such as the tail/middle module connector Med16, which interacts with activators such as Gcn4 in yeast (49), DIF in Drosophila (53), and NRF2 in mouse and human (54). Indeed, a recent proteomic analysis of Mediator interactions reported a modest interaction between Mediator and Tbf1 (55).…”

Section: Discussionmentioning

confidence: 99%

Mediator Is Essential for Small Nuclear and Nucleolar RNA Transcription in Yeast

Tourigny

Saleh

Schumacher

et al. 2018

Molecular and Cellular Biology

View full text Add to dashboard Cite

Eukaryotic RNA polymerase II (RNAPII) transcribes mRNA genes and non-protein-coding RNA (ncRNA) genes, including those encoding small nuclear and nucleolar RNAs (sn/snoRNAs). In metazoans, RNAPII transcription of sn/snoRNAs is facilitated by a number of specialized complexes, but no such complexes have been discovered in yeast. It has been proposed that yeast sn/snoRNA and mRNA expression relies on a set of common factors, but the extent to which regulators of mRNA genes function at yeast sn/snoRNA genes is unclear. Here, we investigated a potential role for the Mediator complex, essential for mRNA gene transcription, in sn/ snoRNA gene transcription. We found that Mediator maps to sn/snoRNA gene regulatory regions and that rapid depletion of the essential structural subunit Med14 strongly reduces RNAPII and TFIIB occupancy as well as nascent transcription of sn/ snoRNA genes. Deletion of Med3 and Med15, subunits of the activator-interacting Mediator tail module, does not affect Mediator recruitment to or RNAPII and TFIIB occupancy of sn/snoRNA genes. Our analyses suggest that Mediator promotes PIC formation and transcription at sn/snoRNA genes, expanding the role of this critical regulator beyond its known functions in mRNA gene transcription and demonstrating further mechanistic similarity between the transcription of mRNA and sn/snoRNA genes. E ukaryotic RNA polymerase II (RNAPII), responsible for the transcription of mRNA genes, also transcribes several classes of non-protein-coding RNA (ncRNA) genes. Two prominent classes of RNAPII-transcribed eukaryotic ncRNA genes are small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs). snRNAs are involved in pre-mRNA splicing (1), while snoRNAs primarily function in rRNA maturation via guiding methylation and pseudouridylation of specific rRNA bases (2).Most sn/snoRNA transcription in eukaryotes is carried out by RNAPII, with a few notable RNAPIII-transcribed exceptions, including the U6 snRNA gene (3). While transcription of both mRNA and the majority of sn/snoRNA genes is carried out by RNAPII, notable differences between their regulation have been described, particularly in metazoans. In addition to the documented dependence of a few sn/snoRNAs on several general transcription factors (GTFs) that are components of the preinitiation complex and generally essential for RNAPII transcription (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH) (4-6), metazoan sn/snoRNA gene transcription relies on a number of specialized factors. One such factor is the small nuclear RNA activating complex (SNAPc), which contains the TATA-binding protein (TBP) as well as five specific subunits and is essential for

show abstract

The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression

Cited by 76 publications

References 37 publications

Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2

Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

Mediator Is Essential for Small Nuclear and Nucleolar RNA Transcription in Yeast

Contact Info

Product

Resources

About