Repression of cancer protective genes by 17β-estradiol: Ligand-dependent interaction between human Nrf2 and estrogen receptor α

Ansell, Pete; Lo, S.-C.B.; Newton, L. G.; Espinosa-Nicholas, C.; Zhang, D.D.; Liu, J.-H.; Hannink, Mark; Lubahn, Dennis B.

doi:10.1016/j.mce.2005.08.002

Cited by 73 publications

(47 citation statements)

References 31 publications

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“…It is not clear how the activation of PXR and CAR can be suppressed during exposure to the high concentrations of steroid hormones that are required for establishing and maintaining pregnancy. However, it may not be surprising to observe the downregulation of Nrf2 activity by pregnancy because Lubahn's group has elucidated that estrogen receptor alpha and estrogen-related receptor beta possess potent inhibitory effects on Nrf2 activity by interacting with Nrf2 (Ansell et al, 2004;Ansell et al, 2005;Zhou et al, 2007). The current results reveal the importance of Nrf2 in pregnancy-associated biological events, including cell proliferation, cell size adjustment, and the activation of several critical signaling molecules.…”

Section: Discussionmentioning

confidence: 64%

Nrf2 Participates in Regulating Maternal Hepatic Adaptations to Pregnancy

Zou

Bao

et al. 2013

Journal of Cell Science

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SummaryPregnancy induces widespread adaptive responses in maternal organ systems including the liver. The maternal liver exhibits significant growth by increasing the number and size of hepatocytes, by largely unknown mechanisms. Nrf2 mediates cellular defense against oxidative stress and inflammation and also regulates liver regeneration. To determine whether Nrf2 is involved in the regulation of maternal hepatic adaptations to pregnancy, we assessed the proliferation and size of maternal hepatocytes and the associated molecular events in wild-type and Nrf2-null mice at various stages of gestation. We found that wild-type maternal hepatocytes underwent proliferation and size reduction during the first half, and size increase without overt replication during the second half, of pregnancy. Although pregnancy decreased Nrf2 activity in the maternal liver, Nrf2 deficiency caused a delay in maternal hepatocyte proliferation, concomitant with dysregulation of the activation of Cyclin D1, E1, and, more significantly, A2. Remarkably, as a result of Nrf2 absence, the maternal hepatocytes were largely prevented from reducing their sizes during the first half of pregnancy, which was associated with an increase in mTOR activation. During the second half of pregnancy, maternal hepatocytes of both genotypes showed continuous volume increase accompanied by persistent activation of mTOR. However, the lack of Nrf2 resulted in dysregulation of the activation of the mTOR upstream regulator AKT1 and the mTOR target p70SK6 and thus disruption of the AKT1/mTOR/p70S6K pathway, which is known to control cell size. This suggests an mTOR-dependent and AKT1-and p70S6K-independent compensatory mechanism when Nrf2 is deficient. In summary, our study demonstrates that Nrf2 is required for normal maternal hepatic adjustments to pregnancy by ensuring proper regulation of the number and size of maternal hepatocytes.

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Section: Discussionmentioning

confidence: 64%

Nrf2 Participates in Regulating Maternal Hepatic Adaptations to Pregnancy

Zou

Bao

et al. 2013

Journal of Cell Science

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“…Taken together, we hypothesize that RXRa plays a key role in linking xenobiotic metabolism with the NRF2-ARE cytoprotective signaling pathway. Furthermore, several nuclear receptors besides RXRa repress NRF2 (11,46,47). It is interesting to speculate that antagonism of NRF2 by RXRa occurs because at some level the CNC-bZIP protein and nuclear receptors are functionally incompatible, and that it might be advantageous to attenuate NRF2 activity.…”

Section: Discussionmentioning

confidence: 99%

RXRα Inhibits the NRF2-ARE Signaling Pathway through a Direct Interaction with the Neh7 Domain of NRF2

et al. 2013

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The transcription factor NRF2 (NFE2L2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that limit the action of cytotoxic therapies in cancer. NRF2 acts by binding antioxidant response elements (ARE) in its target genes, but there is relatively limited knowledge about how it is negatively controlled. Here, we report that retinoic X receptor alpha (RXRa) is a hitherto unrecognized repressor of NRF2. RNAi-mediated knockdown of RXRa increased basal ARE-driven gene expression and induction of ARE-driven genes by the NRF2 activator tert-butylhydroquinone (tBHQ). Conversely, overexpression of RXRa decreased ARE-driven gene expression. Biochemical investigations showed that RXRa interacts physically with NRF2 in cancer cells and in murine small intestine and liver tissues. Furthermore, RXRa bound to ARE sequences in the promoters of NRF2-regulated genes. RXRa loading onto AREs was concomitant with the presence of NRF2, supporting the hypothesis that a direct interaction between the two proteins on gene promoters accounts for the antagonism of ARE-driven gene expression. Mutation analyses revealed that interaction between the two transcription factors involves the DNA-binding domain of RXRa and a region comprising amino acids 209-316 in human NRF2 that had not been defined functionally, but that we now designate as the NRF2-ECH homology (Neh) 7 domain. In non-small cell lung cancer cells where NRF2 levels are elevated, RXRa expression downregulated NRF2 and sensitized cells to the cytotoxic effects of therapeutic drugs. In summary, our findings show that RXRa diminishes cytoprotection by NRF2 by binding directly to the newly defined Neh7 domain in NRF2. Cancer Res; 73(10);

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“…The Nrf2 expression vector and the 4X antioxidant response element luciferase reporter have been previously described [22].…”

Section: Plasmidsmentioning

confidence: 99%

“…This transcription factor gives robust transcriptional activation so any alteration in its activity will readily be detected [22,28]. As shown in Figure 4, Dlk1 was unable to significantly repress transcription mediated by Nrf2, indicating that the ability of Dlk1 to repress Pit-1-induced transcription is specific.…”

Section: Dlk1 Regulates Pit-1-mediated Transcriptional Activationmentioning

confidence: 99%

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Ansell

Zhou

Schjeide

et al. 2007

Molecular and Cellular Endocrinology

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Delta-like protein 1 (Dlk1) is a transmembrane protein characterized by epidermal growth factor (EGF)-like repeats. Dlk1, which is also known as preadipocyte factor 1 (pref-1) because of its ability to inhibit preadipocyte differentiation, regulates the differentiation of several other cell types through unknown mechanisms. To elucidate Dlk1 functions, identification of Dlk1-regulated target genes is critical. The observation that Dlk1 is expressed in many endocrine tissues suggests that Dlk1 may have endocrine-related functions. Because Dlk1 is expressed in GH producing cells, we hypothesize that one function of Dlk1 is to regulate GH expression. We found that GH mRNA, protein, and secretion were significantly decreased in GH3 pituitary cell clones that stably express Dlk1. In contrast, Dlk1 expression was unable to alter prolactin expression. Co-transfection of GH3 cells with a GH promoter-regulated reporter gene showed that Dlk1 repressed GH promoter activity. Deletion and mutation analysis of the GH promoter indicated that Pit-1 binding sites in the GH promoter are required for Dlk1-mediated repression. Furthermore, Dlk1 expression represses Pit-1-mediated transcription when both proteins are co-expressed in MCF-7 cells. Deletion analysis of Dlk1 revealed that the ability of Dlk1 to regulate GH promoter activity is independent of both its EGF-like repeats and its ability to modulate MAP kinase activity. The observation that Dlk1 regulates GH expression identifies the first endocrine function of Dlk1, establishes GH as a Dlk1-regulated target gene, and provides a model system to facilitate studies of Dlk1-mediated signaling.

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Repression of cancer protective genes by 17β-estradiol: Ligand-dependent interaction between human Nrf2 and estrogen receptor α

Cited by 73 publications

References 31 publications

Nrf2 Participates in Regulating Maternal Hepatic Adaptations to Pregnancy

Nrf2 Participates in Regulating Maternal Hepatic Adaptations to Pregnancy

RXRα Inhibits the NRF2-ARE Signaling Pathway through a Direct Interaction with the Neh7 Domain of NRF2

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

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