Estrogen Receptor α L543A,L544A Mutation Changes Antagonists to Agonists, Correlating with the Ligand Binding Domain Dimerization Associated with DNA Binding Activity

Arao, Yukitomo; Hamilton, Katherine; Coons, Laurel A.; Korach, Kenneth S.

doi:10.1074/jbc.m113.463455

Cited by 27 publications

(54 citation statements)

References 29 publications

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“…It was recently demonstrated in vitro that the ICI-dependent estrogen response element (ERE)-mediated transcriptional activity of the AF-2-mutated ERα is associated with the LBD dimerization activity (28). Furthermore, prevention of dimerization impaired the ICI-dependent activation and ERE binding of the AF-2-mutated ERα.…”

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

“…A portion of the AF-2 domain resides in H12, and it was proposed that the dislocation of H12 causes ICI-dependent LBD homodimerization involving the F-domain of ERα, which facilitates dimerization. Involvement of the F-domain in the antagonist-dependent LBD dimerization occurred not only with the AF-2-mutated ERα but also with WT ERα (28). A portion of the antagonistic effect of ICI on WT ERα results from the stimulation of ERα proteolysis (28)(29)(30), and it was recently reported that ICI induces SUMOylation of human ERα protein and that the mutations of H12 reduced SUMOylation in the presence of ICI (31).…”

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

“…Involvement of the F-domain in the antagonist-dependent LBD dimerization occurred not only with the AF-2-mutated ERα but also with WT ERα (28). A portion of the antagonistic effect of ICI on WT ERα results from the stimulation of ERα proteolysis (28)(29)(30), and it was recently reported that ICI induces SUMOylation of human ERα protein and that the mutations of H12 reduced SUMOylation in the presence of ICI (31). These results suggest that the prevention of ICI-dependent proteolysis maintains the dimer formation of AF-2-mutated ERα and that this increases ERE binding and transcription activation.…”

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

“…These results suggest that the prevention of ICI-dependent proteolysis maintains the dimer formation of AF-2-mutated ERα and that this increases ERE binding and transcription activation. Human breast cancer mutations in H12 result in a disruption of the nonpolar surface of H12, provoking antagonist reversal activity, and such mutations might be the mechanism for the development of antagonist resistance in breast cancer treatment (18,19,28,32).…”

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

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The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Movérare‐Skrtic

Börjesson

Farman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Estrogen exerts important effects in the skeleton, which are primarily mediated via estrogen receptor (ER)α, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. Previous studies demonstrate that ERα ligands might act as agonists, partial agonists, or antagonists. We demonstrate that the ERα antagonist ICI 182,780 (ICI) acts in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. Importantly, ICI exerted a pronounced inverse agonistic activity in the growth plate of mice lacking ERαAF-2. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.

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Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

See 2 more Smart Citations

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Movérare‐Skrtic

Börjesson

Farman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In the AF2ERKI mice, estradiol (E2) does not induce any estrogen responsive functions even though AF-2-mutated ER␣ protein is expressed in the tissues and resulted in an identical phenotype to ER␣ null mutant mice (␣ERKO), supporting a major role of AF-2 in E2-mediated responses in some tissues. One of the interesting characteristics of the AF2ER mutant receptor is an antagonist reversal activity, where antagonists such as 4-hydroxytamoxifen (4OHT) and fulvestrant/ ICI182780 (ICI) activate the AF2ER mutant receptor through the activation of AF-1 in a similar manner to SERM-mediated ER␣ activation (14,16). The antagonist reversal through AF-1 was tissue-selective as it was observed in certain tissues of AF2ERKI mice but not all tissues (14,15), suggesting that the AF-1 activity is different in the various tissues.…”

mentioning

confidence: 99%

Transactivation Function-2 of Estrogen Receptor α Contains Transactivation Function-1-regulating Element

Arao

Coons

Zuercher

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism of ligand mediated ER␣ N-terminal transactivation function (AF-1) regulation is unclear. Results: Disruption of ER␣ C-terminal transactivation function (AF-2) resulted in reversal of antagonists to AF-1-dependent agonists. Conclusions: ER␣ AF-2 contains AF-1 repression activity. Significance: This function may explain partial agonist/antagonist activity of selected estrogen receptor modulators.

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Bisphenol A (BPA) binding on full‐length architectures of estrogen receptor

Liu

Ying

et al. 2018

J of Cellular Biochemistry

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Previous research has shown that the major toxicity mechanism for many environment chemicals is binding with estrogen receptor (ER) and blocking endogenous estrogen access, including bisphenol A (BPA). However, the molecular level understanding the global consequence of BPA binding on the full-length architectures of ER is largely unknown, which is a necessary stage to evaluate estrogen-like toxicity of BPA. In the present work, the consequence of BPA on full-length architectures of ER was firstly modeled based on molecular dynamics, focusing on the cross communication between multi-domains including ligand binding domain (LBD) and DNA binding domain (DBD). The study proved consequence of BPA upon full-length ER structure was dependent on long-range communications between multiple protein domains. The allosteric effects occurring in LBD units could alter dimerization formation through a crucial change in residue-residue connections, which resulted in relaxation of DBD. It indicated BPA could present consequence on the full-size receptor, not only on the separate domains, but also on the cross communication among LBD, DBD, and DNA molecules. It might provide detailed insight into the knowledge about the structural characteristics of ER and its role in gene regulation, which eventually helped us evaluate the estrogen-like toxicity upon BPA binding with full-length ER.

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Estrogen Receptor α L543A,L544A Mutation Changes Antagonists to Agonists, Correlating with the Ligand Binding Domain Dimerization Associated with DNA Binding Activity

Cited by 27 publications

References 29 publications

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Transactivation Function-2 of Estrogen Receptor α Contains Transactivation Function-1-regulating Element

Bisphenol A (BPA) binding on full‐length architectures of estrogen receptor

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