Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB-binding protein.

Authors: Shen, Guoxiang; Hebbar, Vidya; Nair, Sujit; Xu, Changjiang; Li, Wenge; Lin, Wen; Keum, Young-Sam; Han, Jiahuai; Gallo, Michael A; Kong, A-N Tony

Published In J Biol Chem, (2004 May 28)

Abstract: Transcription factor NF-E2-related factor 2 (Nrf2) regulates the induction of Phase II detoxifying enzymes as well as anti-oxidative enzymes. In this study, we investigated the transactivation potential of different Nrf2 transactivation domain regions by using the Gal4-Nrf2 chimeras and Gal4-Luc reporter co-transfection assay system in HepG2 cells. The results indicated that chimera Gal4-Nrf2-(1-370), which contains the full transactivation domain showed very potent transactivation activity. The high transactivation activity of Gal4-Nrf2-(113-251) and the diminished transactivation activities of chimera Gal4-Nrf2-(1-126) and Gal4-Nrf2-(230-370) suggested that the Nrf2 N-terminal 113-251 amino acids region is critical in maintaining its transactivation activity. Overexpression of upstream MAPKs such as Raf, MEKK1, TAK1-DeltaN, and ASK1 up-regulated the transactivation activities of Gal4-Nrf2-(1-370) and Gal4-Nrf2-(113-251) in a dose-dependent manner. Further investigation on the effects of the three MAPK pathways on Nrf2 transactivation domain activity demonstrated that both ERK and JNK signaling pathways stimulated the Gal4-Nrf2-(1-370) transactivation activity while the p38 pathway played a negative role. Site-directed mutagenesis studies on potential MAPK phosphorylation sites of Gal4-Nrf2-(113-251) showed no significant effect on its basal transactivation activity or the fold of induction by Raf. Interestingly, the nuclear transcription coactivator CREB-binding protein (CBP), which can bind to Nrf2 transactivation domain and can be activated by ERK cascade, showed synergistic stimulation with Raf on the transactivation activities of both the chimera Gal4-Nrf2-(1-370) and the full-length Nrf2. Taken together, this study clearly demonstrated that different segments of Nrf2 transactivation domain have different transactivation potential and different MAPKs have differential effects on Nrf2 transcriptional activity. It also suggested that the up-regulation of Nrf2 transactivation domain activity by upstream MAPKs such as Raf may not be mediated by direct phosphorylation of the Nrf2 transactivation domain, but rather by regulation of the transcriptional activity of coactivator CBP.

PubMed ID: 15020583 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

Back
to Top