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DNA Binding by Estrogen Receptor- Is Essential for the Transcriptional Response to Estrogen in the Liver and the Uterus

Bayer Schering Pharma AG (D.L.A.-D., J.S., S.T., C.O., T.M.W.), Global Drug Discovery (GDD)-Therapeutic Research Group Women’s Healthcare, Müllerstrasse 178, D-13353 Berlin, Germany; Bayer Schering Pharma AG (G.L., H.S., A.S.), GDD-Target Discovery Müllerstrasse 178, 13353 Berlin, Germany; German Cancer Research Center (B.D.S., G.S., T.M.W.), Molecular Biology of the Cell I, D-69120 Heidelberg, Germany; and Imperial College London (M.G.P.), Institute for Reproductive and Developmental Biology

Address all correspondence and requests for reprints to: Dr. Tim M. Wintermantel, Therapeutic Research Group Women’s Healthcare, Bayer Schering Pharma, Müllerstrasse 178, 13353 Berlin, Germany. E-mail: tim.wintermantel{at}bayerhealthcare.com.

The majority of the biological effects of estrogens in the reproductive tract are mediated by estrogen receptor (ER), which regulates transcription by several mechanisms. Because the tissue-specific effects of some ER ligands may be caused by tissue-specific transcriptional mechanisms of ER, we aimed to identify the contribution of DNA recognition to these mechanisms in two clinically important target organs, namely uterus and liver. We used a genetic mouse model that dissects DNA binding-dependent vs. independent transcriptional regulation elicited by ER. The EAAE mutant harbors amino acid exchanges at four positions of the DNA-binding domain (DBD) of ER. This construct was knocked in the ER gene locus to produce ER_(EAAE/EAAE) mice devoid of a functional ER DBD. The phenotype of the ER_(EAAE/EAAE) mice resembles the general loss-of-function phenotype of ER knockout mutant mice with hypoplastic uteri, hemorrhagic ovaries, and impaired mammary gland development. In agreement with this phenotype, the expression pattern of the ER_(EAAE/EAAE) mutant mice in liver obtained by genome-wide gene expression profiling supports the observation of a near-complete loss of estrogen-dependent gene regulation in comparison with the wild type. Further gene expression analyses to validate the results of the microarray data were performed by quantitative RT-PCR. The analyses indicate that both gene activation and repression by estrogen-bound ER rely on an intact DBD in vivo.

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Nuclear Receptors:   ER-α

Ligands:   17α-ethinylestradiol  |  17β-estradiol