Nrf2, not the estrogen receptor, mediates catechol estrogen-induced activation of the antioxidant responsive element.
The antioxidant responsive element (ARE) plays an important role in the gene expression of phase II detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), and NF-E2-related factor2 (Nrf2) is the transcription factor for the ARE-driven genes. Interestingly, estrogen receptor (ER) was reported to increase NQO1 gene expression through the ARE. In this study, we investigated the role of ER and Nrf2 in ARE activation using IMR-32 cells and mouse primary astrocytes. Among tested estrogen-related compounds, only catechol estrogens (i.e. 4-hydroxyestradiol) activated the ARE. Since 4-hydroxyestradiol-induced ARE activation was not inhibited by either 17beta-estradiol or tamoxifen, and overexpression of ER-alpha decreased 4-hydroxyestradiol-induced ARE activation, ARE activation by catechol estrogen was independent of ER. Nrf2, however, was very important in the 4-hydroxyestradiol-induced ARE activation. 4-Hydroxyestradiol did not activate the ARE in Nrf2 knockout (-/-) primary astrocytes, but did activate the ARE when Nrf2 was transfected into Nrf2-/- astrocytes. In addition, dominant negative Nrf2 completely blocked 4-hydroxyestradiol-induced ARE activation in Nrf2+/+ astrocytes, and only 4-hydroxyestradiol induced Nrf2 nuclear translocation in IMR-32 cells. A selective phosphatidylinositol 3-kinase (PI3-kinase) inhibitor (LY294002) blocked 4-hydroxyestradiol-induced Nrf2 nuclear translocation and NQO1 activity induction in IMR-32 cells. Taken together, these observations suggest that 4-hydroxyestradiol activates the ARE by a PI3-kinase-Nrf2 dependent mechanism, not involving ER.
Lee
Jong-Min
JM
School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA.
Anderson
Peter C
PC
Padgitt
Janette K
JK
Hanson
Janean M
JM
Waters
Christopher M
CM
Johnson
Jeffrey A
JA
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology*; D047628:Estrogen Receptor alpha; D002393:Estrogens, Catechol / Q000502:physiology; D006801:Humans; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000502:physiology; D020218:Response Elements; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D002393:Estrogens, Catechol; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D011960:Receptors, Estrogen; D015534:Trans-Activators; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D019869:Phosphatidylinositol 3-Kinases