Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications

Abstract

We previously reported that antiestrogen-liganded estrogen receptor b (ERb) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:-quinone oxidoreductase). Our studies also indicate that upregulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites. We now report on the upregulation of glutathione S-transferases Pi (GST-Pi) and gamma-glutamylcysteine synthetase heavy subunit (GCSh) expression by antiestrogens. Studies indicate the regulation of GST-Pi and GCSh transcriptional activity by ER. While ER regulation is mediated by an electrophile response element (EpRE), we identified mechanistic differences in the involvement of other transcription factors. Regardless of these differences, ERb-mediated regulation of GST-Pi and GCSh point towards an important role for ERb in cellular protection against oxidative stress. A protective role is supported by our observation of inhibition of estrogeninduced DNA damage upon upregulation of GST-Pi and GCSh expression.

Roles of Oxidative Stress and Redox Regulation in Atherosclerosis

“…Estrogens, such as 17beta-estradiol (E2), play an important role in development, growth, and differentiation, and appear to have protective effects on oxidative stress mediated by ER 31) . Inhibitory effects of E2 on atherosclerosis are mediated by COX-2-derived prostacyclin 32) and E2 induces the production of antioxidative enzymes, such as superoxide dismutase 33) , and GST 34) . The effects of E2 are mediated mostly through ER , which functions as a ligandinduced transcription factor and belongs to the nuclear receptor superfamily.…”

Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis

“…Therefore, even relatively modest inductions of phase 2 enzymatic activity can be sufficient to protect against carcinogenesis. Moreover, the ER regulates the expression of other antioxidative enzymes, such as GST-Pi and g-glutamylcysteine synthetase heavy subunit (Montano et al, 2004) in addition to QR, suggesting that ER may play a broad role in protection against antioxidative stress. Finally, breast cancer develops over decades, raising the possibility that chronic, low-level phase 2 enzyme induction might be sufficient to prevent the disease.…”

Regulation of the Glutathione S-Transferase P1 Expression in Melanoma Cells

“…Possible implication of ER into regulation of GSTP1 expression was demonstrated for the first time in 1988 by Moscow et al who described the negative correlation between ER content and GSTP1 expression in breast cancer cells (Moscow et al, 1988). Later Montano et al demonstrated that ER acts as a positive regulator of GSTP1 expression in the same cells (Montano et al, 2004). Here we found that ER indirectly interacts with two distinct sites of GSTP1 promoter -positive regulatory element ARE and a negative regulatory element CRE and in both cases different transcription factors mediate the effect of ER .…”

“…The diversity includes transcription factor AP-1 in breast cancer cells VCREMS (Moffat et al, 1994) and in leukemia cells K562 (Duvoix et al, 2004a); transcription factor NF-E2 in K562 cells (Borde-Chiche et al, 2001); RAR in HeLa cells (Xia et al, 1996) and ER in complex with Jun/Fos or with Nuclear Factor E2 related factor (Nrf2) in mammary carcinoma cells MDA-MB-231 (Montano et al, 2004). It is interesting that transcription factors Jun and Fos in the latter complex cannot activate GSTP1 transcription themselves but they recruit ER and the whole complex substantially activates transcription and mediates up-regulation of GSTP1 expression by estradiol and antiestrogen tamoxifen (Montano et al, 2004). It is also noteworthy that in Me45 cells ER indirectly interacts not only with antioxidant response element ARE, but also with cAMP response element CRE in complex with transcription factor Fos.…”

“…Binding of Sp1 to the proximal G/C-box (Moffat et al, 1996a) and a transcription factor from AP-1 (Morrow et al, 1990) or NF-E2 family (Nishinaka et al, 2007) to ARE located in this minimal promoter are required to initiate the transcription. ARE is also responsible for gene induction by retinoic acid (Xia et al, 1996), estrogens (Montano et al, 2004), phorbol esters (Duvoix et al, 2004b), curcumin (Nishinaka et al, 2007) and doxorubicin (Duvoix et al, 2004a). The region spanning from -1212 to -90, which contains NF-κB-like element at -98 to -90 (Moffat et al, 1996b), NF-κB binding site at -323 to -314 , cAMP response element (CRE) at -512 to -505 (Lo & li-Osman, 2002) and GATA-1 binding site at -1212 to -1207 (Morceau et al, 2000) is not essential for initiation of GSTP1 transcription but mediates gene's responsibility to different stimuli.…”