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

Arao, Yukitomo; Coons, Laurel A.; Zuercher, William J.; Korach, Kenneth S.

doi:10.1074/jbc.m115.638650

Cited by 17 publications

(23 citation statements)

References 28 publications

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“…Our results suggested that the N-terminal transactivation function (AF-1) is the primary element for the 4OHT-dependent transcriptional activity of full-length ER␣, following the previous reports (13,14), and that the F domain plays a role in this regulation. We have previously reported that the SERMmediated partial agonist activity of ER␣ is correlated with the efficacy of LBD (EF domain) dimerization cooperating with ERE binding (15).…”

Section: Species Difference Of Er␣ F Domain Functionalitysupporting

confidence: 85%

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The F domain of estrogen receptor α is involved in species-specific, tamoxifen-mediated transactivation

Arao

Korach

2018

Journal of Biological Chemistry

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Estrogen receptor α (ERα) is a major transducer of estrogen-mediated physiological signals. ERα is a member of the nuclear receptor superfamily, which encompasses ligand-dependent transcription factors. The C terminus of nuclear receptors, termed the F domain, is the least homologous region among the members of this family. The ERα F domain possesses 45 amino acids; however, its function remains unclear. We noticed that the homology of the F domains between mouse and human ERαs is remarkably lower (75.6% similarity) than that between the entire proteins (94.7% similarity). To assess the functionality of the ERα F domains, here we generated chimeric ERα expression constructs with mouse-human-exchanged F domains. Using cell-based assays, we analyzed the transcriptional coactivator interaction and ligand-binding domain dimerization activities of these mouse-human F domain-swapped ERαs. We found that the transcriptional activity of the mouse WT ERα is more potent than that of the human WT ERα in the human hepatoma cell line HepG2. 4-Hydroxytamoxifen (4OHT)-mediated transcriptional activity of mouse-human F domain-swapped ERαs was the inverse of the WT ERα activities but not estradiol-mediated transcriptional activities. Further experiments with constructs containing deletion or point mutations of a predicted β-strand region within the F domain suggested that this region governs the species-specific 4OHT-mediated transcriptional activity of ERα. We conclude that the ERα F domain has a species-specific function in 4OHT-mediated receptor transactivation and that mouse-human F domain-swapped ERα mutants enable key insights into ERα F domain structure and function.

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Section: Species Difference Of Er␣ F Domain Functionalitysupporting

confidence: 85%

“…the AF-2 truncated ER␣ mutants (mER␣339 and hER␣340) ( Fig. 2, A and B), which exhibit only a constitutive AF-1mediated transcriptional activity (13,14). There was no difference between mER␣339 and hER␣340 in ERE-luc reporter activation function (Fig.…”

Section: Species Difference Of Er␣ F Domain Functionalitymentioning

confidence: 96%

The F domain of estrogen receptor α is involved in species-specific, tamoxifen-mediated transactivation

Arao

Korach

2018

Journal of Biological Chemistry

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“…It remains unclear whether ERα can also recruit other cofactors in the presence of tamoxifen via its AF1 region, such as the p68 RNA helicase and the RNA molecule SRA (Lanz et al . 1999, Janknecht 2010), and how cofactor recruitment via AF1 is enabled by the specific conformation of AF2 in tamoxifen-liganded ERα (Arao et al . 2015).…”

Section: Impact Of Ae-induced Erα Conformation On Cofactor Recruitmenmentioning

confidence: 99%

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Traboulsi

Ezzy

Gleason

et al. 2017

Journal of Molecular Endocrinology

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About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.

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“…ERα-dependent transcription is mediated through direct binding to specific DNA sequences termed the estrogen responsive element (ERE) [ 16 ]. In addition, ERα may activate ligand dependent transcription through indirect DNA binding with other DNA binding factors such as AP-1, which is referred to as tethered transcription regulation [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice

et al. 2017

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BACKGROUNDTreatment with estrogen in early menopausal women protects against development of hepatic steatosis and NAFLD but estrogen has undesirable side effects which negate its beneficial effects in pre- and post-menopausal women. Targeted therapies require better understanding of the target sites and mechanisms by which estrogen signaling exerts its protective effects in women. ERα is thought to be the primary mediator for estrogen signaling to protect against hepatic steatosis. ERα has several mechanisms for signal transduction: 1) inducing gene transcription by direct binding to specific DNA sequences 2) inducing tethered transcription with other DNA binding factors 3) stimulating nongenomic action through membrane associated ERα. However, it is still unclear which mechanisms mediate ERα dependent protection against hepatic steatosis.METHODSTo understand the mechanisms of estrogen signaling for protection against hepatic steatosis in females, we analyzed the global ERα knockout mouse (αERKO), ERα DNA binding domain mutant mouse (KIKO), and liver-specific ERα knockout mouse (LERKO) fed high fat diets (HFD). The KIKO mouse disrupts the direct DNA binding transcription activity but retains tethered transcription regulation and nongenomic action. Hepatic steatosis was evaluated by scoring the macrovesicular and microvesicular steatosis as well as serum ALT levels. We analyzed serum testosterone to assess its correlation with hepatic steatosis.RESULTSLiver fat accumulation was far greater in HFD-fed αERKO and KIKO females than in HFD-fed WT controls. Conversely, HFD-fed LERKO females did not accumulate excess liver fat. HFD-fed αERKO and KIKO females showed higher microvesicular steatosis and ALT levels than WT controls which correlated with increased serum testosterone levels.CONCLUSIONSERα mediated direct transcription in non-hepatic tissues is essential for estrogen mediated protection against hepatic steatosis in HFD-fed females. The balance between non-hepatic estrogen signaling and hepatic or non-hepatic testosterone action may control hepatic steatosis.

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

Cited by 17 publications

References 28 publications

The F domain of estrogen receptor α is involved in species-specific, tamoxifen-mediated transactivation

The F domain of estrogen receptor α is involved in species-specific, tamoxifen-mediated transactivation

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice

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