Human C-terminally truncated ERα variants resulting from the use of alternative exons in the ligand-binding domain

Hattori, Yujiro; Ishii, Hirotaka; Munetomo, Arisa; Watanabe, Hiroshi; Morita, Akio; Sakuma, Yasuo; Ozawa, Hitoshi

doi:10.1016/j.mce.2016.01.026

Cited by 14 publications

(25 citation statements)

References 53 publications

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“…Recent study has identified three new exons inside intron 4 region of ESR1 [41]. Variants containing these exons encode C-terminal truncated ESR1 isoforms, which showed constitutive activity in the absence of estrogen (same reference as above).These isoforms are all expressed in the brain (data not shown).…”

Section: Resultsmentioning

confidence: 84%

Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits

et al. 2017

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Genetic variants of ESR1 have been implicated in multiple diseases, including behavioral disorders, but causative variants remain uncertain. We have searched for regulatory variants affecting ESR1 expression in human brain, measuring allelic ESR1 mRNA expression in human brain tissues with marker SNPs in exon4 representing ESR1-008 (or ESRα-36), and in the 3’UTR of ESR1-203, two main ESR1 isoforms in brain. In prefrontal cortex from subjects with bipolar disorder, schizophrenia, and controls (n = 35 each; Stanley Foundation brain bank), allelic ESR1 mRNA ratios deviated from unity up to tenfold at the exon4 marker SNP, with large allelic ratios observed primarily in bipolar and schizophrenic subjects. SNP scanning and targeted sequencing identified rs2144025, associated with large allelic mRNA ratios (p = 1.6E10-6). Moreover, rs2144025 was significantly associated with ESR1 mRNA levels in the Brain eQTL Almanac and in brain regions in the Genotype-Tissue Expression project. In four GWAS cohorts, rs2104425 was significantly associated with behavioral traits, including: hypomanic episodes in female bipolar disorder subjects (GAIN bipolar disorder study; p = 0.0004), comorbid psychological symptoms in both males and females with attention deficit hyperactivity disorder (GAIN ADHD, p = 0.00002), psychological diagnoses in female children (eMERGE study of childhood health, subject age ≥9, p = 0.0009), and traits in schizophrenia (e.g., grandiose delusions, GAIN schizophrenia, p = 0.0004). The first common ESR1 variant (MAF 12–33% across races) linked to regulatory functions, rs2144025 appears conditionally to affect ESR1 mRNA expression in the brain and modulate traits in behavioral disorders.

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Section: Resultsmentioning

confidence: 84%

Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits

et al. 2017

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“…Human total RNAs were purchased from Takara Bio and Thermo Fisher Scientific. The information of human total RNAs sources was described previously [35]. Human and rat total RNAs were reverse-transcribed using oligo(dT) 15 primers.…”

Section: Total Rna Extraction 5 -Race and Rt-pcrmentioning

confidence: 99%

“…The cells were cultured in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS; Equitech-Bio, Kerrville, TX, USA) and 1% penicillin/streptomycin solution (Fujifilm Wako Pure Chemical Corporation, Osaka, Japan). The cells were maintained according to our previous studies [35,36]. For transfection, cells were cultured on appropriate culture plates or dishes, with lipofection of plasmid vectors using TransFast Transfection Reagents (Promega) according to the manufacturer's protocols.…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

Applicability of Anti-Human Estrogen Receptor β Antibody PPZ0506 for the Immunodetection of Rodent Estrogen Receptor β Proteins

Ishii

Otsuka

Kanaya

et al. 2019

IJMS

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Several lines of controversial evidence concerning estrogen receptor β (ERβ) remain to be solved because of the unavailability of specific antibodies against ERβ. The recent validation analysis identified a monoclonal antibody (PPZ0506) with sufficient specificity against human ERβ. However, the specificity and cross-reactivity of PPZ0506 antibody against ERβ proteins from laboratory animals have not been confirmed. In the present study, we aimed to validate the applicability of PPZ0506 to rodent studies. The antibody exhibited specific cross-reactivity against mouse and rat ERβ proteins in immunoblot and immunocytochemical experiments using transfected cells. In immunohistochemistry for rat tissue sections, PPZ0506 showed immunoreactive signals in the ovary, prostate, and brain. These immunohistochemical profiles of rat ERβ proteins in rat tissues accord well with its mRNA expression patterns. Although the antibody was reported to show the moderate signals in human testis, no immunoreactive signals were observed in rat testis. Subsequent RT-PCR analysis revealed that this species difference in ERβ expression resulted from different expression profiles related to the alternative promoter usage between humans and rats. In conclusion, we confirmed applicability of PPZ0506 for rodent ERβ studies, and our results provide a fundamental basis for further examination of ERβ functions.

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“…In this manner, steroid hormones regulate the expression of the target genes over a time period of hours or days (for review, see Hewitt et al, 2016). As genes that encode steroid hormone receptors have several transcripts and splice variants, this brings additional complexity to their mechanisms of action (for review, see Prossnitz and Barton, 2011; Thomas and Gustafsson, 2011; Hattori et al, 2016). …”

Section: Intracrine Actions Of Steroid Hormonesmentioning

confidence: 99%

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

2017

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Endometrial and ovarian cancers predominately affect women after menopause, and are more frequently observed in developed countries. These are considered to be hormone-dependent cancers, as steroid hormones, and estrogens in particular, have roles in their onset and progression. After the production of estrogens in the ovary has ceased, estrogen synthesis occurs in peripheral tissues. This depends on the cellular uptake of estrone-sulfate and dehydroepiandrosterone-sulfate, as the most important steroid precursors in the plasma of postmenopausal women. The uptake through transporter proteins, such as those of the organic anion-transporting polypeptide (OATP) and organic anion-transporter (OAT) families, is followed by the synthesis and action of estradiol E2. Here, we provide an overview of the current understanding of this intracrine action of steroid hormones, which depends on the availability of the steroid precursors and transmembrane transporters for precursor uptake, along with the enzymes for the synthesis of E2. The data is also provided relating to the selected transmembrane transporters from the OATP, OAT, SLC51, and ABC-transporter families, and the enzymes involved in the E2-generating pathways in cancers of the endometrium and ovary. Finally, we discuss these transporters and enzymes as potential drug targets.Keywords: sulfatase, aromatase, 17beta-hydroxysteroid dehydrogenase, transporters, OATP, ABC-transporter HORMONE-DEPENDENT CANCERSSteroid hormones have important roles in human physiology, and the disruption of androgen, estrogen, and progesterone actions are implicated in the development of hormone-dependent cancers and benign hormone-dependent diseases. Hormone-dependent cancers include prostate, breast, endometrial, and ovarian cancers, which comprise more than 20% of all cancers in humans, and more than 35% of cancers in women (Ferlay et al., 2013). Indeed, in women, breast cancer is the most frequent cancer in the developed world. In 2012, 1,671,149 new cases of breast cancer were estimated worldwide, with 521,907 associated deaths. In the developed world, endometrial cancer is the most common among gynecological cancers. Worldwide, there were 319,605 new cases and 76,160 deaths from endometrial cancer in 2012 alone (Ferlay et al., 2013). The most deadly of the hormone-dependent cancers is ovarian cancer. Worldwide, there were 238,719 new cases and 151,905 deaths from ovarian cancer in 2012 (Ferlay et al., 2013).

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Human C-terminally truncated ERα variants resulting from the use of alternative exons in the ligand-binding domain

Cited by 14 publications

References 53 publications

Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits

Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits

Applicability of Anti-Human Estrogen Receptor β Antibody PPZ0506 for the Immunodetection of Rodent Estrogen Receptor β Proteins

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

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