Disease relevance of Esr1

• Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice [1].
• In this regard, we have shown that estrogen receptor-alpha (Esr1) is crucial for the protective effect of 17 beta-estradiol (E2) in murine experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis [2].
• Consequently, a reduction or loss of REA function may cause overactivation of ER and increase breast cancer risk in humans [3].
• We previously generated and studied knockout mice lacking estrogen receptor alpha and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development [4].
• Finally, females lacking a functional beta isoform of the ER gene showed normal lordosis and courtship behaviors, extending in some cases beyond the day of behavioral estrus [5].
• Activation of ER-alpha is one mechanism by which PRL may contribute to breast cancer and points to other therapeutic strategies for male patients [6].

Psychiatry related information on Esr1

• This is the first demonstration that ER alpha gene expression is involved in the estrogenic control of feeding behavior and weight regulation of female mice [7].
• Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice [7].
• Therefore, the OT, ER-alpha, and ER-beta genes are necessary, to different degrees, for social discrimination and, thus, for the modulation of social behavior (e.g. aggression, affiliation) [8].
• Involvement of estrogen receptor alpha, beta and oxytocin in social discrimination: a detailed behavioral analysis with knockout female mice [8].
• Estrogen increases locomotor activity in mice through estrogen receptor alpha: specificity for the type of activity [9].
• These data indicate that binding of ERs to EREs mediates most if not all of E(2)'s effects on male sexual behavior, whereas ERE-independent ERalpha signaling may mediate E(2)'s inhibitory effects on T production [10].

High impact information on Esr1

• Thus, P58(IPK) is a key mediator of cotranslocational ER protein degradation, and this process likely contributes to ER homeostasis in stressed cells [11].
• Here, we report that P58(IPK)/DNAJC3, a UPR-responsive gene previously implicated in translational control, encodes a cytosolic cochaperone that associates with the ER protein translocation channel Sec61 [11].
• Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor alpha chain gene [12].
• Characterization and colocalization of steroid binding and dimerization activities in the mouse estrogen receptor [13].
• As expected, luciferase activity, monitored with a cooled charged coupled device camera, paralleled circulating estrogen levels in reproductive tissues and in liver, indicating that the peak transcriptional activity of the estrogen receptor occurred at proestrus [14].

Chemical compound and disease context of Esr1

• Aromatase inhibitors are proving to be more effective than tamoxifen for postmenopausal estrogen receptor (ER)-positive breast cancer [15].
• The mitogenic effect of 17beta-estradiol (E2) on the breast is mediated by estrogen receptor alfa (ERalpha), hence ERalpha antagonists are effective in the treatment of breast cancer [16].
• Primary macrophages from ERalpha- and ERbeta-deficient severe combined immunodeficiency mice [ERalpha knockout (KO) and ERssKO, respectively] were used to delineate the effects and potential mechanisms via which steroid receptors modulate macrophage function [17].
• These changes in [Ca(2+)](i) can be inhibited by pertussis toxin, but not by the ER-blockers tamoxifen and raloxifene [18].
• Female B57BL/J6 ER-beta(-/-) transgenic mice [knockout (KO)] and corresponding ovariectomized wild-type (WT) mice were subjected to laparotomy and hemorrhagic shock (35.0+/-5.0 mmHg for 90 min) and treated with E2 (50 microg/25 g) or ER-alpha agonist propyl pyrazole triol (PPT; 50 microg/25 g) following trauma-hemorrhage [19].

Biological context of Esr1

• No significant differences in central nervous system histopathology or MBP(Ac1-11)-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype [1].
• Either this represents a species difference (the neuroanatomy has been conducted in the rat) or compensatory actions of ERalpha or other mechanisms [20].
• Estrogen receptor (ER)-mediated gene expression plays an essential role in mammary gland morphogenesis, function, and carcinogenesis [3].
• The specific role of ERalpha is further confirmed by comparing the effects of ERs on the matrix metalloproteinase 9 promoter activity in transient transfection assays [21].
• Increased cell proliferation and exaggerated response to E(2) in BERKO suggest that ERbeta plays a role in modulation of the effects of ERalpha and in addition (or as a consequence of this) has an antiproliferative function in the immature uterus [22].

Anatomical context of Esr1

• The results showed that E2-responsive, Esr1+/+ disease-inducing encephalitogenic T cells were neither necessary nor sufficient for E2-mediated protection from EAE [2].
• We also confirm the presence of two ERalpha mRNA splice variants in uterus and aorta from ERalpha-Neo KO mice [23].
• Estrogens induce mammary epithelial cell proliferation during puberty via epithelial estrogen receptor alpha (ERalpha) by a paracrine mechanism [24].
• Because ERalpha is expressed in the stroma, but not in the epithelium, of the adult ventral prostate, the concept of indirect estrogen effects through stromal signaling has been proposed [25].
• Finally, we report that genetic ablation of ERalpha is associated with a spontaneous reactive phenotype of microglia in specific brain regions of adult ERalpha-null mice [21].

Associations of Esr1 with chemical compounds

• Because the ligand binding domains of ERalpha and ERbeta are significantly different from each other, selective ligands can be (and have been) developed to target the estrogenic pathway that is malfunctioning, without interfering with the other estrogen-regulated pathways [26].
• Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor [27].
• To directly compare the effect of ER activation on bone in vivo with the effect of AR activation, 9-month-old orchidectomized wild-type and ER-inactivated mice were treated with the nonaromatizable androgen 5alpha-dihydrotestosterone, 17beta-estradiol, or vehicle [28].
• However, upon E(2) + progesterone treatment, ERalpha and ERbeta were not coexpressed in any cells [29].
• Although ERalpha was abundant in intact mice, after ovariectomy, ERalpha could not be detected in the luminal epithelium of either WT or ERbeta(-/-) mice [29].

Physical interactions of Esr1

• Mouse estrogen receptor beta forms estrogen response element-binding heterodimers with estrogen receptor alpha [30].
• The S522A mutant was also 60% less effective than wt ERalpha in binding caveolin 1, which facilitates ER transport to the PM [31].
• A fusion gene consisting of wild-type p53 linked to a modified ligand binding domain of the murine estrogen receptor has been constructed and should be a useful tool for studying controlled activation of wild-type p53 function in a variety of experimental cell systems [32].
• The use of tfm/y mice permitted study of the estrogen-receptor complex in the absence of androgen receptor [33].
• These results indicate that the Ah receptor regulates the effects of TCDD on the binding of estrogen to the hepatic estrogen receptor, but suggest that the decrease in the binding capacity of the hepatic GC receptor does not appear to be mediated directly by the Ah locus [34].

Co-localisations of Esr1

• In the female rat, oestrogen receptor (ER) beta is colocalized with both oxytocin- and vasopressin-producing neurones in the paraventricular nucleus of the hypothalamus (PVN) [35].

Regulatory relationships of Esr1

• ERalpha gene expression was up-regulated on d 14.5 pc in Rlx+/+ mice, with mRNA levels remaining high throughout late gestation [36].
• These findings support the notion that ER-beta activation may exert an attenuating action on male aggression induced by estrogen through ER-alpha-mediated brain mechanisms, whereas its effect on male sexual behaviour is relatively small [37].
• PR was found to be co-expressed with ERalpha in cell nuclei of urothelium, lamina propria fibroblasts and smooth muscle cells in the female urethra [38].
• Intact, but not dimer mutant, ERalpha also supported E2-induced epidermal growth factor receptor transactivation and cell survival [39].
• Administration of estrogen, progesterone, and prolactin altered the percentage of LRECs expressing ER-alpha [40].

Other interactions of Esr1

• In contrast, estradiol prevented ovariectomy-induced bone loss in ERbeta(-/-) mice, as in WT males and females, indicating that ERalpha is the major mediator of estradiol effects in bone [41].
• A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice [41].
• An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice [42].
• We propose that these findings are related to changes in ER corepressor levels, regulated by EGF [43].
• Finally, we also found that another growth factor, insulin-like growth factor-1, which provokes ER-dependent transcription in vitro, activates mating behavior in a similar E-independent manner [44].

Analytical, diagnostic and therapeutic context of Esr1

• One of them encodes a chimeric ERalpha protein (ERalpha55), partially deleted in the A/B domain, that was detected in both uterus and aorta by Western blot analysis [23].
• The initial gene targeting of ERalpha, consisting in the introduction of a Neo cassette in exon 1 [alphaERKO, hereafter called ERalpha-Neo KO (knockout)], was reported in 1993 [23].
• They also underline the key role of ERalpha in brain macrophage reactivity and hint toward the usefulness of ERalpha-specific drugs in hormone replacement therapy of inflammatory diseases [21].
• Estrogen Receptor {beta} Inhibits Angiogenesis and Growth of T47D Breast Cancer Xenografts [45].
• Finally, we show a physical interaction between endogenous ER alpha and signal transducer and activator of transcription 5 in differentiated HC11 cells [43].

References