Estrogen receptor α revised: Expression, structure, function, and stability

Habara, Makoto; Shimada, Midori

doi:10.1002/bies.202200148

Cited by 8 publications

(10 citation statements)

References 165 publications

(151 reference statements)

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“…In this chapter, we briefly discuss ERα PTMs whose physiological functions have been evaluated in vivo primarily using genetic mouse models ( Table 2 ). For a more comprehensive description of ERα PTMs, the readers are referred to other excellent reviews [ 56 , 57 , 58 ].…”

Section: Erα Isoform Variation and Functionsmentioning

confidence: 99%

“…Plasma membrane-bound ERα is palmitoylated at the cysteine 447 residue (C447) [ 71 , 72 ]. The C447 is known to be the sole palmitoylation site in ERα [ 57 , 87 ], and C447 palmitoylation is essential for ERα plasma membrane localization, in part through the interaction with caveolin-1 [ 88 ]. A point mutation of C447 to the non-palmitoylable form is sufficient to inhibit its interaction with caveolin-1 and ERα membrane-initiated rapid signaling [ 71 ].…”

Section: Erα Isoform Variation and Functionsmentioning

confidence: 99%

“…The majority of transcription factors possess intrinsically disordered protein (IDP) domains, which are more likely to undergo PTMs and alternative splicing than structured domains [ 105 ]. ERα is also intrinsically disordered, especially in the N-terminal domain [ 106 , 107 ], and many of the ERα PTMs and splicing sites appear to be located at IDP domains [ 56 , 57 ]. The coordination of alternative splicing and PTMs in IDP domains is proposed to provide cells and organisms with flexibility in protein functionality in a context-dependent manner.…”

Section: Perspectivesmentioning

confidence: 99%

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Estrogen Receptor Alpha Splice Variants, Post-Translational Modifications, and Their Physiological Functions

Saito

Cui

2023

Cells

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The importance of estrogenic signaling for a broad spectrum of biological processes, including reproduction, cancer development, energy metabolism, memory and learning, and so on, has been well documented. Among reported estrogen receptors, estrogen receptor alpha (ERα) has been known to be a major mediator of cellular estrogenic signaling. Accumulating evidence has shown that the regulations of ERα gene transcription, splicing, and expression across the tissues are highly complex. The ERα promoter region is composed of multiple leader exons and 5′-untranslated region (5′-UTR) exons. Differential splicing results in multiple ERα proteins with different molecular weights and functional domains. Furthermore, various post-translational modifications (PTMs) further impact ERα cellular localization, ligand affinity, and therefore functionality. These splicing isoforms and PTMs are differentially expressed in a tissue-specific manner, mediate certain aspects of ERα signaling, and may work even antagonistically against the full-length ERα. The fundamental understanding of the ERα splicing isoforms in normal physiology is limited and association studies of the splicing isoforms and the PTMs are scarce. This review aims to summarize the functional diversity of these ERα variants and the PTMs in normal physiological processes, particularly as studied in transgenic mouse models.

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Section: Erα Isoform Variation and Functionsmentioning

confidence: 99%

Section: Erα Isoform Variation and Functionsmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

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Estrogen Receptor Alpha Splice Variants, Post-Translational Modifications, and Their Physiological Functions

Saito

Cui

2023

Cells

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“…Oestrogens, a known risk factor for breast cancer, affect multiple signalling pathways associated with cell proliferation, survival and apoptosis and, therefore, they play a key role in the carcinogenesis of mammary tissue [ 2 ]. Oestrogens interact with two subtypes of oestrogen receptors (ERs): ERα and ERβ [ 3 , 4 ]. In addition, most breast cancers in women express ERs and are sensitive to treatment.…”

Section: Introductionmentioning

confidence: 99%

Comparative EPR Studies on the Influence of Genistein on Free Radicals in Non-Irradiated and UV-Irradiated MCF7, T47D and MDA-MB-231 Breast Cancer Cells

Jurzak,

Ramos,

Pilawa

et al. 2024

Biomedicines

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The antioxidant activity and the association of genistein with carcinogenesis are widely documented. Few studies directly measure the number of free radicals generated in cells, either during the action of factors stimulating their formation, e.g., ultraviolet (UV), or after exposure to antioxidants. The most suitable method for analysing free radicals is electron paramagnetic resonance (EPR) spectroscopy. The EPR method detects a paramagnetic centre with a single electron. Antioxidants neutralize free radicals, therefore, EPR analysis of antioxidant efficacy is as valuable and important as studying the paramagnetic centres of radicals. The aim of the study was to determine the influence of genistein on free radicals basal level and after UV exposure in breast cancer cell lines MCF7, T47D and MDA-MB-231 cell lines. The impact of genistein on cell viability was investigated at concentrations of 0.37 μM, 3.7 μM, 37 μM and 370 μM. Genistein at a concentration of 370 μM revealed a cytotoxic effect on the cells of all three tested breast cancer lines. Genistein at a concentration of 0.37 μM showed no significant effect on the cell viability of all tested breast cancer lines. Therefore, cell proliferation and antioxidant properties were examined using genistein at a concentration of 0.37 μM and 37 μM. X-band (9.3 GHz) EPR spectra of three different types of breast cancer cells (ER-positive, PR-positive and HER-2 negative: MCF7 and T47D and triple-negative MDA-MB-231) were compared. UV irradiation was used as a factor to generate free radicals in cells. The effect of free radical interactions with the antioxidant genistein was tested for non-UV-irradiated (corresponding to the basal level of free radicals in cells) and UV-irradiated cells. The levels of free radicals in the non-irradiated cells studied increased in the following order in breast cancer cells: T47D < MDA-MB-231 < MCF7 and UV-irradiated breast cancer cells: MDA-MB-231 < MCF7 < T47D. UV-irradiation altered free radical levels in all control and genistein-cultured cells tested. UV irradiation caused a slight decrease in the amount of free radicals in MCF7 cells. A strong decrease in the amount of free radicals was observed in UV-irradiated MDA-MB-231 breast cancer cells. The amount of free radicals in T47D cancer cells increased after UV irradiation. Genistein decreased the amount of free radicals in non-irradiated and UV-irradiated MCF7 cells, and only a weak effect of genistein concentrations was reported. Genistein greatly decreased the amount of free radicals in UV-irradiated T47D cancer cells cultured with genistein at a concentration of 3.7 μM. The effect of genistein was negligible in the other samples. Genistein at a concentration of 3.7 μM decreased the amount of free radicals in non-irradiated MDA-MB-231 cancer cells, but genistein at a concentration of 37 μM did not change the amount of free radicals in these cells. An increase in the amount of free radicals in UV-irradiated MDA-MB-231 cancer cells was observed with increasing genistein concentration. The antioxidant efficacy of genistein as a potential plant-derived agent supporting the treatment of various cancers may be determined by differences in signalling pathways that are characteristic of breast cancer cell line subtypes and differences in activation of oxidative stress response pathways.

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“…The human ERα is composed of four distinct domains: (1) a A/B domain (residues 1 to 180), also called AF1 for ligand-independent transactivation function 1; (2) a C domain (residues 181 to 262), for the DNA-binding domain; (3) a D domain (residues 263 to 302), which corresponds to the hinge region; (4) an E/F domain (residues 303 to 595), which is defined as the ligand-dependent activation function AF2. The fragment defined by amino acids 295 to 311 (sequence: P 295 LMIKRSKKNSLALSLT 311 , Figure 1a) is issued from the hinge (residues 295 to 302) and AF2 (residues 303 to 311) regions and is strongly targeted by post-translational modifications such as methylation [4], acetylation and phosphorylation [5], ubiquitination [6] and SUMOylation [7]. The K 299 RSKK 303 motif, which corresponds to the third nuclear localization signal (NLS) of ERα, is targeted by proteolytic enzymes [8,9].…”

Section: Introductionmentioning

confidence: 99%

Promising Perspectives of the Antiproliferative GPER Inverse Agonist ERα17p in Breast Cancer

Kampa

Lappano

Grande

et al. 2023

Cells

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The estrogen receptor α (ERα) corresponds to a large platform in charge of the recruitment of a panel of molecules, including steroids and related heterocyclic derivatives, oligonucleotides, peptides and proteins. Its 295–311 region is particularly targeted by post-translational modifications, suggesting that it could be crucial for the control of transcription. In addition to anionic phospholipids, the ERα 295–311 fragment interacts with Ca2+-calmodulin, the heat shock protein 70 (Hsp70), ERα and possibly importins. More recently, we have demonstrated that it is prone to interacting with the G-protein-coupled estrogen receptor (GPER). In light of these observations, the pharmacological profile of the corresponding peptide, namely ERα17p, has been explored in breast cancer cells. Remarkably, it exerts apoptosis through GPER and induces a significant decrease (more than 50%) of the size of triple-negative breast tumor xenografts in mice. Herein, we highlight not only the promising therapeutic perspectives in the use of the first peptidic GPER modulator ERα17p, but also the opportunity to modulate GPER for clinical purposes.

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Estrogen receptor α revised: Expression, structure, function, and stability

Cited by 8 publications

References 165 publications

Estrogen Receptor Alpha Splice Variants, Post-Translational Modifications, and Their Physiological Functions

Estrogen Receptor Alpha Splice Variants, Post-Translational Modifications, and Their Physiological Functions

Comparative EPR Studies on the Influence of Genistein on Free Radicals in Non-Irradiated and UV-Irradiated MCF7, T47D and MDA-MB-231 Breast Cancer Cells

Promising Perspectives of the Antiproliferative GPER Inverse Agonist ERα17p in Breast Cancer

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