Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications.
We previously reported that antiestrogen-liganded estrogen receptor beta (ERbeta) 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, ER beta-mediated regulation of GST-Pi and GCSh point towards an important role for ER beta in cellular protection against oxidative stress. A protective role is supported by our observation of inhibition of estrogen-induced DNA damage upon upregulation of GST-Pi and GCSh expression.
Montano
Monica M
MM
Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44102, USA. mxm126@po.cwru.edu
Deng
Huayun
H
Liu
Min
M
Sun
Xiaoyan
X
Singal
Rakesh
R
D000975:Antioxidants / Q000494:pharmacology*; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004798:Enzymes / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology; D047629:Estrogen Receptor beta; D015971:Gene Expression Regulation, Enzymologic; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic; D015854:Up-Regulation
D000975:Antioxidants; D004798:Enzymes; D020847:Estrogen Receptor Modulators; D047629:Estrogen Receptor beta; D007527:Isoenzymes; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase