Estrogen Receptors α and β as Determinants of Gene Expression: Influence of Ligand, Dose, and Chromatin Binding

Chang, Edmond Chin‐Ping; Charn, Tze Howe; Park, Sung Hee; Helferich, William G.; Komm, Barry S.; Katzenellenbogen, John A.; Katzenellenbogen, Benita S.

doi:10.1210/me.2007-0356

Cited by 160 publications

(151 citation statements)

References 41 publications

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“…We used different acetylation assays to illustrate that Tip60 is incapable of acetylating ER␤1. This is consistent with studies of other coregulators of ER␤1 that possess HAT activity, but none of them was found to acetylate ER␤1 (9,13,16,45,48). Moreover, acetylation of nuclear receptors is assumed to occur at a conserved motif "(K/R)XKK" (13), which is absent in ER␤1 (data not shown).…”

Section: Discussionsupporting

confidence: 90%

“…Estrogen signaling is mediated primarily by ER␣ and ER␤1, whereas ER␤1 is able to activate a distinct set of target genes and also to antagonize ER␣ transactivation (45)(46)(47)(48)(49). Although ERs share many common coregulators, the differential interaction between the coregulatory proteins and ERs may be responsible for their distinct functions (8).…”

Section: Discussionmentioning

confidence: 99%

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Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

Lee¹,

Leung

Chung³

et al. 2013

Journal of Biological Chemistry

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Background:The interactions between estrogen receptor ␤ (ER␤1) and different coregulators are responsible for the distinct functions of ER␤1. Results: Tip60 enhances ER␤1 transactivation at the AP-1 site but inhibits it at ERE sites. Conclusion: Tip60 is either a coactivator or a corepressor for ER␤1 in a regulatory element-dependent manner. Significance: Tip60 is the first multifaceted coregulator of the transcriptional activity of ER␤1 that has been identified.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

Lee¹,

Leung

Chung³

et al. 2013

Journal of Biological Chemistry

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“…The therapeutic importance of this regulation stems from the strong inverse correlation between ER␣ and Skp2 levels in human breast tumors. Interestingly, Skp2 was found to selectively target ER␣ and not the closely related receptor ER␤ or several other nuclear hormone receptors and transcription factors that we examined, making it an attractive target for pharmacological intervention, because ER␤ in breast tumors shows antiproliferative activity, whereas ER␣ is proproliferative (11,18).…”

Section: Discussionmentioning

confidence: 98%

Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen ReceptorαTurnover and Functional Activity via the SCF^Skp2Proteasomal Complex

Bhatt

Xiao

Meng

et al. 2012

Molecular and Cellular Biology

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The nuclear hormone receptor estrogen receptor ␣ (ER␣) mediates the actions of estrogens in target cells and is a master regulator of the gene expression and proliferative programs of breast cancer cells. The presence of ER␣ in breast cancer cells is crucial for the effectiveness of endocrine therapies, and its loss is a hallmark of endocrine-insensitive breast tumors. However, the molecular mechanisms underlying the regulation of the cellular levels of ER␣ are not fully understood. Our findings reveal a unique cellular pathway involving the p38 mitogen-activated protein kinase (p38MAPK)-mediated phosphorylation of ER␣ at Ser-294 that specifies its turnover by the SCF Skp2 proteasome complex. Consistently, we observed an inverse relationship between ER␣ and Skp2 or active p38MAPK in breast cancer cell lines and human tumors. ER␣ regulation by Skp2 was cell cycle stage dependent and critical for promoting the mitogenic effects of estradiol via ER␣. Interestingly, by the knockdown of Skp2 or the inhibition of p38MAPK, we restored functional ER␣ protein levels and the control of gene expression and proliferation by estrogen and antiestrogen in ER␣-negative breast cancer cells. Our findings highlight a novel pathway with therapeutic potential for restoring ER␣ and the responsiveness to endocrine therapy in some endocrine-insensitive ER␣-negative breast cancers. T he nuclear hormone receptor estrogen receptor ␣ (ER␣) is a master regulator of gene expression and the proliferative program of breast cancer cells (18,29,36,38,50,54) and, hence, is the main target of endocrine therapies. Approximately 70% of human breast tumors express ER␣ and depend on estrogens for growth, rendering these tumors amenable to treatment with drugs such as selective estrogen receptor modulators/antiestrogens (such as tamoxifen) and aromatase inhibitors, which are quite effective and have relatively few side effects. These ER␣-targeted therapies (7,27,28,40,41) have resulted in a steady decline in the rate of mortality due to breast cancer but show effectiveness only against ER-positive breast tumors, while ER-negative tumors fail to respond. The regulation of the cellular level of ER␣ is therefore key to the effectiveness of endocrine therapies in breast cancer, and an understanding of its underlying mechanism is critical for the identification of novel drug targets for the design of combinatorial therapies.ER␣ is unusual among nuclear hormone receptors in being a rapidly turning-over protein with a half-life of ca. 4 h in breast cancer cells and in normal target tissues such as the uterus (2, 16, 39), indicating dynamic regulation by modulating factors. The degradation of ER␣, and several other nuclear receptors, has been shown to be under the control of the ubiquitin (Ub) proteasome system (2, 31, 32, 48, 51), yet many important aspects of this regulation remain unclear. In view of the importance of ER␣ in many target tissues and in breast cancer biology, prognosis, and responses to endocrine treatments, we have investigated the underlyin...

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“…On binding of agonistic ligands, the DNA-bound receptor recruits cofactors, which enables the receptor to transmit its regulatory information to the cellular transcription complex, including RNA polymerase II (transactivation). ERa and ERb mediate distinct profiles of gene expression (Chang et al, 2008;Williams et al, 2008). This is due to a combination of differential ligand response (Barkhem et al, 1998;Paech et al, 1997;Paige et al, 1999;Van Den Bemd et al, 1999), distinct interaction with coactivators (Kraichely et al, 2000) and binding to specific estrogen response elements (EREs) (Klinge et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The hinge region of the human estrogen receptor determines functional synergy between AF-1 and AF-2 in the quantitative response to estradiol and tamoxifen

Zwart

Leeuw

Rondaij

et al. 2010

Journal of Cell Science

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SummaryHuman estrogen receptors a and b (ERa and ERb) greatly differ in their target genes, transcriptional potency and cofactor-binding capacity, and are differentially expressed in various tissues. In classical estrogen response element (ERE)-mediated transactivation, ERb has a markedly reduced activation potential compared with ERa; the mechanism underlying this difference is unclear. Here, we report that the binding of steroid receptor coactivator-1 (SRC-1) to the AF-1 domain of ERa is essential but not sufficient to facilitate synergy between the AF-1 and AF-2 domains, which is required for a full agonistic response to estradiol (E2). Complete synergy is achieved through the distinct hinge domain of ERa, which enables combined action of the AF-1 and AF-2 domains. AF-1 of ERb lacks the capacity to interact with SRC-1, which prevents hinge-mediated synergy between AF-1 and AF-2, thereby explaining the reduced E2-mediated transactivation of ERb. Transactivation of ERb by E2 requires only the AF-2 domain. A weak agonistic response to tamoxifen occurs for ERa, but not for ERb, and depends on AF-1 and the hinge-region domain of ERa.Key words: Estrogen receptor alpha, Estrogen receptor beta, Activation domain 1, Activation domain 2, Hinge region, SRC-1, Transcriptional capacity, Tamoxifen agonism Journal of Cell Science1254 the non-classical pathway (Gustafsson, 2000). The molecular mechanism underlying these differences in transcription by the ER subtypes is still unclear.The precise process of transactivation of genes by ERs is still unresolved. ER can dimerize and bind to its cofactors even when not bound to DNA, which occurs also in the absence of ligands (Carroll et al., 2006;Padron et al., 2007;Zwart et al., 2007a). For proper recruitment of RNA polymerase II, however, the ER needs to be bound to an ERE (Carroll et al., 2006;Sharp et al., 2006;Zwart et al., 2007a). Effective transactivation of ERa requires interaction between the N-terminal and C-terminal regions of ERa (Merot et al., 2004;Metivier et al., 2001), which is accomplished by the binding of ERa to cofactors (Metivier et al., 2001). The antiestrogen tamoxifen inhibits ERa-mediated transactivation by arresting the conformation of ERa such that the groove that interacts with the steroid receptor coactivator-1 (SRC-1) cofactor remains covered by the twelfth a helix of the LBD (Shiau et al., 1998). However, tamoxifen also has weak agonistic activity. This mild agonistic behavior can be enhanced by phosphorylation of serine 305 in the hinge region of ERa by protein kinase A (Michalides et al., 2004).Here, we investigate the differences between human ERa and ERb with regard to E2-driven transactivation and the agonistic effect of tamoxifen. We show that a specific interaction of the AF-1 domain of ERa with SRC-1 is required, but by itself not sufficient, to induce a maximal response to E2. The maximal response to E2 demands, in addition, the hinge region of ERa. Human ERb lacks an active AF-1 domain. The weak agonistic response to tamoxifen is dependent...

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Estrogen Receptors α and β as Determinants of Gene Expression: Influence of Ligand, Dose, and Chromatin Binding

Cited by 160 publications

References 41 publications

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen ReceptorαTurnover and Functional Activity via the SCF^Skp2Proteasomal Complex

The hinge region of the human estrogen receptor determines functional synergy between AF-1 and AF-2 in the quantitative response to estradiol and tamoxifen

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Estrogen Receptors α and β as Determinants of Gene Expression: Influence of Ligand, Dose, and Chromatin Binding

Cited by 160 publications

References 41 publications

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen ReceptorαTurnover and Functional Activity via the SCFSkp2Proteasomal Complex

The hinge region of the human estrogen receptor determines functional synergy between AF-1 and AF-2 in the quantitative response to estradiol and tamoxifen

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Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen ReceptorαTurnover and Functional Activity via the SCF^Skp2Proteasomal Complex