The multiple untranslated first exons system of the human estrogen receptor beta (ERβ) gene

Hirata, Shuji; Shoda, Tomoko; Kato, Junzo; Hoshi, Kazuhiko

doi:10.1016/s0960-0760(01)00071-1

Cited by 70 publications

(73 citation statements)

References 26 publications

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“…The molecular weights of the two bands were determined to be 55 and 60 kDa by digital molecular weight analysis (Fig. 2E), a finding consistent with previous reports demonstrating expression of multiple ER␤ isoforms in most tissues (Hirata et al, 2001;Leung et al, 2006). Weak ER␤ signals were found in liver and brain capillary membranes.…”

Section: E2supporting

confidence: 90%

Estrogen Receptor β Signaling through Phosphatase and Tensin Homolog/Phosphoinositide 3-Kinase/Akt/Glycogen Synthase Kinase 3 Down-Regulates Blood-Brain Barrier Breast Cancer Resistance Protein

Hartz¹,

Madole²,

Miller³

et al. 2010

J Pharmacol Exp Ther

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Breast cancer resistance protein (BCRP) is an ATP-driven efflux pump at the blood-brain barrier that limits central nervous system pharmacotherapy. Our previous studies showed rapid loss of BCRP transport activity in rat brain capillaries exposed to low concentrations of 17-␤-estradiol (E2); this occurred without acute change in BCRP protein expression. Here, we describe a pathway through which sustained, extended exposure to E2 signals down-regulation of BCRP at the blood-brain barrier. Six-hour exposure of isolated rat and mouse brain capillaries to E2 reduced BCRP transport activity and BCRP monomer and dimer expression. Experiments with brain capillaries from estrogen receptor (ER)␣ and ER␤ knockout mice and with ER agonists and antagonists showed that E2 signaled through ER␤ to down-regulate BCRP expression. In rat brain capillaries, E2 increased unphosphorylated, active phosphatase and tensin homolog (PTEN); decreased phosphorylated, active Akt; and increased phosphorylated, active glycogen synthase kinase (GSK)3. Consistent with this, inhibition of phosphoinositide 3-kinase (PI3K) or Akt decreased BCRP activity and protein expression, and inhibition of PTEN or GSK3 reversed the E2 effect on BCRP. Lactacystin, a proteasome inhibitor, abolished E2-mediated BCRP down-regulation, suggesting internalization followed by transporter degradation. Dosing mice with E2 reduced BCRP activity in brain capillaries within 1 h; this reduction persisted for 24 h. BCRP protein expression in brain capillaries was unchanged 1 h after E2 dosing but was substantially reduced 6 and 24 h after dosing. Thus, E2 signals through ER␤, PTEN/PI3K/Akt/GSK3 to stimulate proteasomal degradation of BCRP. These in vitro and in vivo findings imply that E2-mediated down-regulation of bloodbrain barrier BCRP has the potential to increase brain uptake of chemotherapeutics that are BCRP substrates.

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Section: E2supporting

confidence: 90%

Estrogen Receptor β Signaling through Phosphatase and Tensin Homolog/Phosphoinositide 3-Kinase/Akt/Glycogen Synthase Kinase 3 Down-Regulates Blood-Brain Barrier Breast Cancer Resistance Protein

Hartz¹,

Madole²,

Miller³

et al. 2010

J Pharmacol Exp Ther

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“…(7,12) Two novel ERβ mRNA isoforms containing distinct 5′-untranslated regions, exons 0K and 0N, have recently been demonstrated to be generated by alternative splicing of exon 1. (13) These results indicate that the transcription of the human ERβ gene occurs from at least two different promoters, those of 0N and 0K.…”

mentioning

confidence: 77%

Loss of estrogen receptor β isoform expression and its correlation with aberrant DNA methylation of the 5′‐untranslated region in human epithelial ovarian carcinoma

Suzuki¹,

Akahira²,

Miura³

et al. 2008

Cancer Science

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Evidence exists that sex steroids such as estrogens affect epithelial ovarian cancer. The expression profiles of the estrogen receptors (ER) and ERb in particular have not been fully described. Therefore, in our present study, we examined the methylation status of the promoters 0K and 0N, and the expression of ERb isoforms in human epithelial ovarian carcinoma. We then correlated methylation status with ER expression status. Twelve ovarian carcinoma cell lines, six primary cultures of ovarian surface epithelial cells (OSE), and 64 cases of ovarian carcinoma tissues were examined. Bisulfite sequencing and quantitative reverse transcription-polymerase chain reaction were used to evaluate methylation status and expression of ERb isoforms. The relative abundance of exon 0N, ERb1, ERb2, and ERb4 mRNA was significantly lower in ovarian cancer cell lines and tissues than in their corresponding normal counterparts. However, O f the gynecological malignancies, epithelial ovarian cancer is the leading cause of death in the great majority of developed countries.(1) Sex steroid hormones have been implicated in the etiology and progression of some epithelial ovarian cancers. Human epithelial ovarian carcinomas can express both estrogen receptors (ER) and progesterone receptors (PR). (2,3) In endometrioid endometrial and breast carcinomas, steroid hormone receptor status is correlated well with response to hormonal manipulation and prognosis.(4-6) However, in epithelial ovarian carcinoma, the prognostic significance of tumor ER and PR status remains controversial. (2,7,8) Forty to 60% of ovarian cancers express ERα, but only a small proportion of patients (7-18%) respond clinically to anti-estrogen treatment. (9,10) Most estrogen actions are mediated through its binding to two ER proteins, ERα and ERβ, which belong to a large family of transcription factors, the nuclear receptor family.(11) Wild-type ERβ (ERβ1) encodes the full-length, 530 amino-acid receptor protein, whereas ERβ2 (ERβcx) to ERβ5, which utilize alternative exons, encode variant receptors with different C-and Ntermini. (7,12) Two novel ERβ mRNA isoforms containing distinct 5′-untranslated regions, exons 0K and 0N, have recently been demonstrated to be generated by alternative splicing of exon 1.(13) These results indicate that the transcription of the human ERβ gene occurs from at least two different promoters, those of 0N and 0K.DNA methylation has an essential regulatory function in mammalian development, suppressing gene activity by changing chromatin structure. (14,15) Aberrant DNA methylation of promoter region CpG islands may therefore serve as an alternate mechanism that leads to the inactivation of tumor-suppressor genes in human cancers.(16) Therefore, the identification of genes regulated by methylation-associated silencing could lead to the characterization of novel regulators of the initiation and progression of human neoplasia.In the mammary gland, ERβ1 mRNA is downregulated during breast tumorigenesis. (17)(18)(19) Decreases in the mRNA expressio...

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“…Alternative usage of promoters in the 5 0 -flanking region of non-coding exons (0N or 0K) and a coding exon M resulted in two types of full-length human ERb transcripts spliced with exon 0N or 0K (Hirata et al, 2001) and a truncated transcript spliced with exon M, respectively (Shoda et al, 2002). An B2 kb 5 0 -flanking region of each promoter was cloned and evaluated by luciferase reporter assay using PC-3 cells (Figure 2a).…”

Section: Identification Of Erb 0n Promoter As the Predominant Promotementioning

confidence: 99%

AP-2 regulates the transcription of estrogen receptor (ER)-β by acting through a methylation hotspot of the 0N promoter in prostate cancer cells

Zhang

Leung

2007

Oncogene

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We reported previously that the loss of expression of estrogen receptor (ER)-b during the development of prostate cancer (PCa) is associated with methylation of a CpG island located in the 5 0 -flanking sequence of the 0N promoter. Three methylation hotspots, referred to as centers 1, 2 and 3, were identified in the CpG island. In this study, we demonstrated that a 581-bp region with these three centers within it is sufficient for the promoter activity in PCa cells. Deletion analyses indicated that center 1 (16 bp), with a putative activator protein-2 (AP-2) binding site, is essential for gene transactivation. Chromatin immunoprecipitation assays showed that AP-2a occupies a short sequence containing center 1. Forced expression of AP-2a or -2c, but not -2b, increased activity of the ERb 0N promoter and the accumulation of mRNA. Conversely, siRNA-mediated AP-2a and -2c knockdown reduced levels of ERb transcript and promoter activity. Quantitative reverse transcription-PCR showed that AP-2a and -2c are the predominant transcripts expressed in PCa cells, and levels of ERb transcript correlate with levels of these AP-2 transcripts among different PCa cell lines. These results provide the first evidence that ERb is an AP-2-regulated gene. They also support the hypothesis that certain cis-acting elements are methylation hotspots susceptible to epigenetic modifications during cancer progression.

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The multiple untranslated first exons system of the human estrogen receptor beta (ERβ) gene

Cited by 70 publications

References 26 publications

Estrogen Receptor β Signaling through Phosphatase and Tensin Homolog/Phosphoinositide 3-Kinase/Akt/Glycogen Synthase Kinase 3 Down-Regulates Blood-Brain Barrier Breast Cancer Resistance Protein

Estrogen Receptor β Signaling through Phosphatase and Tensin Homolog/Phosphoinositide 3-Kinase/Akt/Glycogen Synthase Kinase 3 Down-Regulates Blood-Brain Barrier Breast Cancer Resistance Protein

Loss of estrogen receptor β isoform expression and its correlation with aberrant DNA methylation of the 5′‐untranslated region in human epithelial ovarian carcinoma

AP-2 regulates the transcription of estrogen receptor (ER)-β by acting through a methylation hotspot of the 0N promoter in prostate cancer cells

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