Temporal variation in estrogen receptor-α protein turnover in the presence of estrogen

Valley, Christopher C.; Solodin, Natalia; Powers, Ginny L.; Ellison, Stephanie J.; Alarid, Elaine T.

doi:10.1677/jme-07-0067

Cited by 57 publications

(67 citation statements)

References 43 publications

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“…ER stability has also been implicated to be regulated by posttranslational modification. For instance, phosphorylation of human ERα at Ser 118 and Ser 167 has been reported to alter ERα stability (20,21), with phosphorylated Ser 118 (pSer 118 )-ERα being resistant to proteasomal degradation (20). We examined pSer 118 -ERα levels in LTED rats and observed a robust decline in hippocampal pSER 118 -ERα levels following LTED; however, when the phospho-ERα levels were corrected with total ERα protein, there was no significant effect of LTED on pSER 118 -ERα levels ( Fig.…”

Section: Discussionmentioning

confidence: 99%

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

Zhang

Han

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

127

132

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Recent work suggests that timing of 17β-estradiol (E2) therapy may be critical for observing a beneficial neural effect. Along these lines, E2 neuroprotection, but not its uterotropic effect, was shown to be lost following long-term E2 deprivation (LTED), and this effect was associated with a significant decrease of estrogen receptor-α (ERα) in the hippocampus but not the uterus. The purpose of the current study was to determine the mechanism underlying the ERα decrease and to determine whether aging leads to a similar loss of hippocampal ERα and E2 sensitivity. The results of the study show that ERα in the rat hippocampal CA1 region but not the uterus undergoes enhanced interaction with the E3 ubiquitin ligase C terminus of heat shock cognate protein 70 (Hsc70)-interacting protein (CHIP) that leads to its ubiquitination/proteasomal degradation following LTED (10-wk ovariectomy). E2 treatment initiated before but not after LTED prevented the enhanced ERα-CHIP interaction and ERα ubiquitination/degradation and was fully neuroprotective against global cerebral ischemia. Administration of a proteasomal inhibitor or CHIP antisense oligonucleotides to knock down CHIP reversed the LTED-induced down-regulation of ERα. Further work showed that these observations extended to natural aging, because aged rats showed enhanced CHIP interaction; ubiquitination and degradation of both hippocampal ERα and ERβ; and, importantly, a correlated loss of E2 neuroprotection against global cerebral ischemia. In contrast, E2 administration to middle-aged rats was still capable of exerting neuroprotection. As a whole, the study provides support for a "critical period" for E2 neuroprotection of the hippocampus and provides important insight into the mechanism underlying the critical period.estradiol | neuroendocrine | steroid | stroke B asic science and clinical observation studies have provided evidence of a beneficial effect of 17β-estradiol (E2) on cardiovascular disease, neuroprotection, and neurodegenerative diseases such as stroke and Alzheimer's disease (1-6). However, the Women's Health Initiative (WHI) surprisingly failed to observe a protective effect of hormone therapy on the cardiovascular system and, in fact, reported a small but significant increase in risk for stroke and dementia (7-9). The average age of subjects in the WHI study was 63 y, far past the onset of menopause. It has been suggested that there may be a "critical period" for the beneficial protective effect of E2 on the brain and that estrogen may need to be administered at perimenopause or earlier to observe a beneficial effect on the cardiovascular and neural system (10-12). In support of a critical period hypothesis for E2 beneficial effects in the brain, work by our laboratory and others has shown that long-term E2 deprivation (LTED) leads to a loss of E2 neuroprotection in animal models of focal and global cerebral ischemia (GCI) (13,14). Intriguingly, recent work by our group showed that the loss of E2 neuroprotection of the hippocampal CA1 region, an area ...

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Section: Discussionmentioning

confidence: 99%

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

Zhang

Han

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

127

132

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“…1). We have previously shown that synthesis of ESR1 is a major component in establishing steadystate levels of ER␣ under chronic E2 treatment (63). Physiologically, ESR1 transcript levels change in response to fluctuations in hormonal status, and a mechanism that incorporates balancing positive (p300 and AIB1) and negative (Sin3A) factors provides a plausible model to achieve such dynamic regulation.…”

Section: Discussionmentioning

confidence: 99%

“…RNA isolation and quantitative real-time PCR (qRT-PCR) were carried out as previously detailed (63). The sequences of the primers used for the different gene targets are available upon request.…”

Section: Methodsmentioning

confidence: 99%

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Repression of ESR1 through Actions of Estrogen Receptor Alpha and Sin3A at the Proximal Promoter

Ellison-Zelski

Solodin

Alarid

2009

Molecular and Cellular Biology

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Gene expression results from the coordinated actions of transcription factor proteins and coregulators. Estrogen receptor alpha (ER␣) is a ligand-activated transcription factor that can both activate and repress the expression of genes. Activation of transcription by estrogen-bound ER␣ has been studied in detail, as has antagonist-induced repression, such as that which occurs by tamoxifen. How estrogen-bound ER␣ represses gene transcription remains unclear. In this report, we identify a new mechanism of estrogen-induced transcriptional repression by using the ER␣ gene, ESR1. Upon estrogen treatment, ER␣ is recruited to two sites on ESR1, one distal (ENH1) and the other at the proximal (A) promoter. Coactivator proteins, namely, p300 and AIB1, are found at both ER␣-binding sites. However, recruitment of the Sin3A repressor, loss of RNA polymerase II, and changes in histone modifications occur only at the A promoter. Reduction of Sin3A expression by RNA interference specifically inhibits estrogen-induced repression of ESR1. Furthermore, an estrogen-responsive interaction between Sin3A and ER␣ is identified. These data support a model of repression wherein actions of ER␣ and Sin3A at the proximal promoter can overcome activating signals at distal or proximal sites and ultimately decrease gene expression.Downregulation of receptors by their ligands is a fundamental process by which cells control sensitivity to stimuli. For steroid hormones, this involves lipophilic ligands binding to intracellular receptors to induce a decline in receptor number. Regulation of estrogen (E2) receptor alpha (ER␣) by E2 is one example. The E2-induced decline in ER␣ is, in part, mediated through direct regulation of the protein. It is well documented that decreases in ER␣ protein levels in response to E2 occur via the ubiquitin-proteasome pathway (1, 42). The mRNA levels of ER␣ also decrease, but the mechanism responsible for E2-induced repression of the ER␣ gene, ESR1, is not established (5, 49, 52).ER␣ is a ligand-activated transcription factor that mediates the effects of E2 by regulating gene expression. Activation by ER␣ has been studied in detail, but little is understood about how E2-bound ER␣ represses transcription. E2-induced repression is, however, of significant biological importance. Microarray analyses of E2-treated breast cancer cell lines show that the number of repressed genes is greater than or near the number of activated genes (10,19,29,32). Yet, there are limited reports investigating E2-induced repression, and no generalized mechanism has emerged (6,13,22,25,43,47,59,60,71,74). Antagonistinduced repression by selective ER modulators involves conformational changes that prevent coactivator binding to ER␣ (55). Such a conformational blockade does not occur with agonist binding and thus cannot account for E2-induced gene repression.Many repressive complexes exist to restrict gene expression in response to cellular signals. One example is the Sin3 complex, which was identified in yeast but is conserved in mammals (41, ...

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“…5) Although the transcriptional mechanism of autoregulation is not fully understood, studies have shown that ligand-mediated protein degradation via 26S proteasome is involved. 6) The ubiquitin proteasome system has been implicated in cellcycle control, signal transduction, and transcription.…”

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confidence: 99%

Effects of Inhibiting the Proteasomal Degradation of Estrogen Receptor .ALPHA. on Estrogen Receptor .ALPHA. Activation under Hypoxic Conditions

Park

Cho

Koo

et al. 2009

Biological & Pharmaceutical Bulletin

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Estrogen receptor (ER) a is a member of the nuclear receptor superfamily. Upon binding to 17b-estradiol (E2), ERa undergoes conformational changes and modulates the transcription of target genes.1) The magnitude of this estrogen-induced response depends on the initial concentration of ERa 2) and is modulated by numerous regulatory proteins.3) Furthermore, the differential regulation of coactivator activity modulates ER signal transduction pathways via direct or indirect interactions.4) Despite considerable progress, the exact mechanism of E2-induced transcriptional activation has yet to be elucidated.Down-regulation of ERa in response to estrogen is one of the earliest and most distinct functional readouts of estrogen binding and was first observed more than four decades ago. 5)Although the transcriptional mechanism of autoregulation is not fully understood, studies have shown that ligand-mediated protein degradation via 26S proteasome is involved. 6)The ubiquitin proteasome system has been implicated in cellcycle control, signal transduction, and transcription.7) The somewhat paradoxical correlation between receptor turnover and transcriptional activation of estrogen target genes raises the possibility that ER down-regulation is intimately related to ERa-mediated transactivation. 8) Lonard et al. 9) showed that the ubiquitin-proteasome function is required for ERa to serve as a transcriptional activator. In addition, they showed that protein interactions with ERa coactivator-binding surfaces are important for ligand-mediated ER down-regulation, suggesting that receptor and coactivator turnover contributes to ERa transcriptional activity. However, a different experimental system found that these two phenomena are distinct responses.9,10) Thus, further studies, using various experimental systems, are required.ER is also degraded in response to stimuli other than estrogens.11,12) We and others have reported that under hypoxic conditions, ER is degraded via a proteasome-dependent pathway. 13,14) Hypoxia plays an important role in normal physiological processes and development as well as in tumorigenesis.15) Hypoxia-inducible factor-1 (HIF-1), a heterodimer composed of the HIF-1a subunit and the aryl hydrocarbon receptor nuclear translocator b-subunit, is a key transcription factor that regulates the expression of various genes involved in the physiological response to changes in cellular oxygen tension. For example, HIF-1 modulates erythropoietin expression during erythropoiesis; glucose transporter-1, aldolase A, enolase 1, and lactate dehydrogenase expression during glycolysis; vascular endothelial growth factor expression during vasculogenesis; and nitric oxide synthase and hemoxigenase expression during vasodilation.16) We previously demonstrated that HIF-1a is sufficient to induce proteasomedependent ER down-regulation, which involves interactions between these proteins.13) In addition, hypoxia-induced HIF1a can activate ERa in the absence of a estrogenic ligand. Here we used the proteasome inhibitor MG132 t...

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Temporal variation in estrogen receptor-α protein turnover in the presence of estrogen

Cited by 57 publications

References 43 publications

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

Repression of ESR1 through Actions of Estrogen Receptor Alpha and Sin3A at the Proximal Promoter

Effects of Inhibiting the Proteasomal Degradation of Estrogen Receptor .ALPHA. on Estrogen Receptor .ALPHA. Activation under Hypoxic Conditions

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