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• W2003991752 endingPage "2010" @default.
• W2003991752 startingPage "2000" @default.
• W2003991752 abstract "The antiestrogen ICI 164,384 (ICI) binds the estrogen receptor (ER) with approximately 20% the affinity of estradiol, but without the partial agonistic effects caused by tamoxifen. Investigations into the mechanism of ICI action have used ER molecules expressed in vitro to examine the binding of ER to ICI and the capacity of ICI-ER complexes to dimerize and bind to the estrogen response element (ERE). Our objectives were to study the biological effects, cellular distribution, and ERE-binding capacity of native uterine ICI-ER complexes after ip injection of 1 mg/kg ICI into 10-day castrate adult female mice. Synthesis of DNA and progesterone receptor were measured as end points of agonistic activity. ICI failed to stimulate either DNA or progesterone receptor synthesis above control levels, and pretreatment with ICI for 0.5 h reduced the stimulatory effect of estradiol by 75%. Measurement of uterine nuclear ER and cytosolic levels by exchange binding assay indicated a reduction in total ER levels within 0.5 h after ICI treatment, which remained below 20% for 24 h. Cycloheximide treatment did not block the ICI effect. Western blot analysis, immunohistochemistry, and steroid autoradiography confirmed the loss of ER protein. The ICI effect on ER was also demonstrable in vitro in the mouse TM4 estrogen-responsive cell line. ICI dramatically reduced ER levels to 5% of the control value by 4 h. Northern analysis indicated that ICI did not affect ER message levels, suggesting that the observed reduction in ER did not occur at the level of transcription. Gel shift assays indicated a low, but detectable, amount of ICI-ER binding to the vitellogenin A2 (VitA2) ERE. These results suggest that, although the ICI-ER complex binds weakly to DNA, ICI may cause its antagonistic effect by producing a rapid disappearance of the ER from the target tissue, resulting in an insufficient amount of ER to bind the native ligand and elicit agonist responses." @default.
• W2003991752 created "2016-06-24" @default.
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• W2003991752 date "1991-10-01" @default.
• W2003991752 modified "2023-10-16" @default.
• W2003991752 title "The Mechanism of ICI 164,384 Antiestrogenieity Involves Rapid Loss of Estrogen Receptor in Uterine Tissue" @default.
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• W2003991752 doi "https://doi.org/10.1210/endo-129-4-2000" @default.
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