scholarly journals Epigenetics meets estrogen receptor: regulation of estrogen receptor by direct lysine methylation

2009 ◽  
Vol 16 (2) ◽  
pp. 319-323 ◽  
Author(s):  
Qun Zhou ◽  
Patrick G Shaw ◽  
Nancy E Davidson
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Nuclear Hormone Receptor ◽  
Cellular Growth ◽  
Breast Cancers ◽  
Lysine Methylation ◽  
Estrogen Response

The nuclear hormone receptor estrogen receptor α (ERα) promotes cellular growth through ligand-dependent activation of specific target genes, a process which is targeted in the treatment of ERα-expressing breast cancers. ERα activity is regulated at the protein level by post-translational modifications including phosphorylation and acetylation. A study now shows that ERα can also be directly methylated at lysine 302 (K302) by SET7, a histone methyltransferase that is known to monomethylate H3K4 and is associated with transcriptional activation. It was shown that K302 methylation stabilizes ERα protein and is suggested to increase sensitivity of ERα to estrogens, enhancing transcription of estrogen response elements. Furthermore, SET7 methylation of K302 is enhanced by a breast cancer-associated mutation at K303 (K303R) in vitro. These findings provide an additional mechanism of SET7 mediated transcriptional activation, as well as potential insight into the complex regulation of ERα stability and ligand sensitivity.

scholarly journals Mediator and p300/CBP-Steroid Receptor Coactivator Complexes Have Distinct Roles, but Function Synergistically, during Estrogen Receptor α-Dependent Transcription with Chromatin Templates

2003 ◽  
Vol 23 (1) ◽  
pp. 335-348 ◽  
Author(s):  
Mari Luz Acevedo ◽  
W. Lee Kraus
Keyword(s):  
Estrogen Receptor ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Steroid Receptor ◽  
Estrogen Receptor Α ◽  
Preinitiation Complex ◽  
Transcription System ◽  
Steroid Receptor Coactivator ◽  
Transcription Reinitiation

ABSTRACT Ligand-dependent transcriptional activation by nuclear receptors involves the recruitment of various coactivators to the promoters of hormone-regulated genes assembled into chromatin. Nuclear receptor coactivators include histone acetyltransferase complexes, such as p300/CBP-steroid receptor coactivator (SRC), as well as the multisubunit mediator complexes (“Mediator”), which may help recruit RNA polymerase II to the promoter. We have used a biochemical approach, including an in vitro chromatin assembly and transcription system, to examine the functional role for Mediator in the transcriptional activity of estrogen receptor α (ERα) with chromatin templates, as well as functional interplay between Mediator and p300/CBP during ERα-dependent transcription. Using three different approaches to functionally inactivate Mediator (immunoneutralization, immunodepletion, and inhibitory polypeptides), we find that Mediator is required for maximal transcriptional activation by ligand-activated ERα. In addition, we demonstrate synergism between Mediator and p300/CBP-SRC during ERα-dependent transcription with chromatin templates, but not with naked DNA. This synergism is important for promoting the formation of a stable transcription preinitiation complex leading to the initiation of transcription. Interestingly, we find that Mediator has an additional distinct role during ERα-dependent transcription not shared by p300/CBP-SRC: namely, to promote preinitiation complex formation for subsequent rounds of transcription reinitiation. These results suggest that one functional consequence of Mediator-ERα interactions is the stimulation of multiple cycles of transcription reinitiation. Collectively, our results indicate an important role for Mediator, as well as its functional interplay with p300/CBP-SRC, in the enhancement of ERα-dependent transcription with chromatin templates.

Protein coregulators that mediate estrogen receptor function

2001 ◽  
Vol 13 (4) ◽  
pp. 221 ◽  
Author(s):  
T. Ratajczak
Keyword(s):  
Estrogen Receptor ◽  
Dna Sequences ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptor ◽  
Estrogen Receptor Β ◽  
Receptor Interaction ◽  
Estrogen Response ◽  
Research Findings

The recent discovery of estrogen receptor β as a biological partner with estrogen receptor β in mediating the estrogen response has come at precisely the same time as intensive research is revealing the role played by downstream coregulator proteins in linking nuclear hormone receptor activity to general transcription machinery involved in gene transcriptional activation. In what is a rapidly evolving area of research, findings to date have led to a proposed model of hormonal action, in which a receptor activated by estrogen or cell-membrane-derived phosphorylation-dependent signaling pathways promotes recruitment of selected members of the multifunctional steroid receptor coactivator family and the cointegrators, p300/CBP and P/CAF. The intrinsic histone acetylase activity mediated by these coactivator and cointegrator proteins, alters chromatin structure giving rise to increased transcriptional efficiency. On the other hand, antiestrogen-bound receptors favour the assembly of receptor-corepressor complexes containing the sequence-related corepressors N-CoR (nuclear receptor corepressor) or SMRT (silencing mediator of retinoid and thyroid hormone receptors), localizing histone deacetylase activity to the promoter and leading to transcriptional repression. The model predicts that a change in the balance between corepressor and coactivator expression in favour of coactivators, might result in antiestrogen resistance. Together with available crystal structure data for estrogen- and antiestrogen-bound receptors, these studies have provided valuable insights into events that occur subsequent to receptor interaction with specific DNA sequences and have helped define the molecular basis of estrogen and antiestrogen activity.

scholarly journals Review of: BRCA1 and cyclin D1: gate keepers in hormone responsive tissues?

2006 ◽  
Vol 9 (4) ◽  
pp. 1-3 ◽  
Author(s):  
A. Griekspoor ◽  
T. C. Margarido ◽  
W. Zwart ◽  
R. Michalides
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Susceptibility Gene ◽  
Mammary Tumorigenesis ◽  
Estrogen Receptor Α ◽  
Cellular Growth ◽  
Human Breast

Citation of original article:C. Wang et al. Cancer Research 2005; 65(15): 6557–6567.Abstract of the original article:The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor α(ERα)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERα binding. Cyclin D1 and BRCA1 were both capable of binding ERα in a common region of the ERα hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERα and for rescue of BRCA1-mediated ERα transcriptional repression. In chromatin immunoprecipitation assays, 17β-estradiol (E2) enhanced ERα and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ERα recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ERα recruitment at 12 h. Cyclin D1 expression antagonized BRCA1 inhibition of ERα recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ERα repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.

scholarly journals Rho GDP dissociation inhibitor α interacts with estrogen receptor α and influences estrogen responsiveness

2007 ◽  
Vol 39 (4) ◽  
pp. 249-259 ◽  
Author(s):  
Saad El Marzouk ◽  
Jennifer R Schultz-Norton ◽  
Varsha S Likhite ◽  
Ian X McLeod ◽  
John R Yates ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Negative Regulator ◽  
Guanosine Diphosphate ◽  
Estrogen Response ◽  
Endogenous Estrogen ◽  
Coregulatory Proteins ◽  
Gdp Dissociation Inhibitor ◽  
Mcf 7

AbstractEstrogen receptor α (ERα) is a ligand-activated transcription factor that regulates expression of estrogen-responsive genes. Upon binding of the ligand-occupied ERα to estrogen response elements (EREs) in DNA, the receptor interacts with a variety of coregulatory proteins to modulate transcription of target genes. We have isolated and identified a number of proteins associated with the DNA-bound ERα. One of these proteins, Rho guanosine diphosphate (GDP) dissociation inhibitor α (RhoGDIα), is a negative regulator of the Rho family of GTP-binding proteins. In this study, we demonstrate that endogenously expressed RhoGDIα is present in the nucleus as well as the cytoplasm of MCF-7 breast cancer cells, and that RhoGDIα binds directly to ERα, alters the ERα–ERE interaction, and influences the ability of ERα to regulate transcription of a heterologous estrogen-responsive reporter plasmid in transient transfection assays as well as endogenous, estrogen-responsive genes in MCF-7 cells. Our studies suggest that, in addition to the activity of RhoGDIα in the cytoplasm, it also influences ERα signaling in the nucleus.

scholarly journals Phosphorylation of Estrogen Receptor α at Serine 118 Directs Recruitment of Promoter Complexes and Gene-Specific Transcription

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2517-2526 ◽  
Author(s):  
Tamika T. Duplessis ◽  
Christopher C. Williams ◽  
Steven M. Hill ◽  
Brian G. Rowan
Keyword(s):  
Estrogen Receptor ◽  
Cyclin D1 ◽  
Transcriptional Activation ◽  
Protein Complexes ◽  
Estrogen Receptor Α ◽  
Gene Promoters ◽  
Interacting Protein ◽  
Steroid Receptor Coactivator ◽  
Estrogen Response ◽  
Transcriptional Coregulators

Phosphorylation of estrogen receptor α (ERα) is important for receptor function, although the role of specific ERα phosphorylation sites in ERα-mediated transcription remains to be fully evaluated. Transcriptional activation by ERα involves dynamic, coordinate interactions with coregulators at promoter enhancer elements to effect gene expression. To determine whether ERα phosphorylation affects recruitment of unique protein complexes at gene-specific promoters, changes in ERα Ser118 phosphorylation were assessed for effects on receptor and coregulator recruitment and transcription of ERα-regulated genes. Chromatin immunoprecipitation assays to measure promoter association found a 17β-estradiol (E2)-dependent recruitment of ERα at 150 min to ERα-regulated promoters, whereas ERα phosphorylated at Ser118 was dissociated from promoters after E2 treatment. Mutation of Ser118 to alanine (S118A) altered unliganded and ligand-induced association of ERα and p160 coregulators with ERα target promoters when compared with wild-type (WT)-ERα transfection. S118A and WT-ERα exhibited a similar level of recruitment to the estrogen response element-driven pS2 promoter and induced pS2 mRNA after E2 treatment. Although WT-ERα was recruited to c-myc and cyclin D1 promoters after E2 treatment and induced mRNA expression, S118A exhibited reduced interaction with c-myc and cyclin D1 promoters, and E2 did not induce c-myc and cyclin D1 mRNA. In addition, S118A resulted in increased recruitment of steroid receptor coactivator-1, glucocorticoid receptor interacting protein-1, and activated in breast cancer-1 to pS2, c-myc, and cyclin D1 irrespective of the presence of E2. Together, these data indicate that site specific phosphorylation of ERα directs gene-specific recruitment of ERα and transcriptional coregulators to ERα target gene promoters.

scholarly journals The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response

2009 ◽  
Vol 106 (37) ◽  
pp. 15732-15737 ◽  
Author(s):  
Leandro Castellano ◽  
Georgios Giamas ◽  
Jimmy Jacob ◽  
R. Charles Coombes ◽  
Walter Lucchesi ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Target Genes ◽  
Transcriptional Response ◽  
Regulatory System ◽  
Protein Translation ◽  
Mature Mirnas ◽  
Estrogen Receptor Α ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Wide Range

Following estrogenic activation, the estrogen receptor-α (ERα) directly regulates the transcription of target genes via DNA binding. MicroRNAs (miRNAs) modulated by ERα have the potential to fine tune these regulatory systems and also provide an alternate mechanism that could impact on estrogen-dependent developmental and pathological systems. Through a microarray approach, we identify the subset of microRNAs (miRNAs) modulated by ERα, which include upregulation of miRNAs derived from the processing of the paralogous primary transcripts (pri-) mir-17–92 and mir-106a-363. Characterization of the mir-17–92 locus confirms that the ERα target protein c-MYC binds its promoter in an estrogen-dependent manner. We observe that levels of pri-mir-17–92 increase earlier than the mature miRNAs derived from it, implicating precursor cleavage modulation after transcription. Pri-mir-17–92 is immediately cleaved by DROSHA to pre-miR-18a, indicating that its regulation occurs during the formation of the mature molecule from the precursor. The clinical implications of this novel regulatory system were confirmed by demonstrating that pre-miR-18a was significantly upregulated in ERα-positive compared to ERα-negative breast cancers. Mechanistically, miRNAs derived from these paralogous pri-miRNAs (miR-18a, miR-19b, and miR-20b) target and downregulate ERα, while a subset of pri-miRNA-derived miRNAs inhibit protein translation of the ERα transcriptional p160 coactivator, AIB1. Therefore, different subsets of miRNAs identified act as part of a negative autoregulatory feedback loop. We propose that ERα, c-MYC, and miRNA transcriptional programs invoke a sophisticated network of interactions able to provide the wide range of coordinated cellular responses to estrogen.

scholarly journals A Novel Estrogen Receptor α-Associated Protein Alters Receptor-Deoxyribonucleic Acid Interactions and Represses Receptor-Mediated Transcription

2004 ◽  
Vol 18 (11) ◽  
pp. 2649-2659 ◽  
Author(s):  
Margaret A. Loven ◽  
Roger E. Davis ◽  
Carol D. Curtis ◽  
Nemone Muster ◽  
John R. Yates ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Thyroid Hormone Receptor ◽  
Estrogen Receptor Α ◽  
Target Cells ◽  
Estrogen Response Element ◽  
Response Element ◽  
Estrogen Response ◽  
Mcf 7

Abstract Estrogen receptor α (ERα) serves as a ligand-activated transcription factor, turning on transcription of estrogen-responsive genes in target cells. Numerous regulatory proteins interact with the receptor to influence ERα-mediated transactivation. In this study, we have identified pp32, which interacts with the DNA binding domain of ERα when the receptor is free, but not when it is bound to an estrogen response element. Coimmunoprecipitation experiments demonstrate that endogenously expressed pp32 and ERα from MCF-7 breast cancer cells interact. Although pp32 substantially enhances the association of the receptor with estrogen response element-containing DNA, overexpression of pp32 in MCF-7 cells decreases transcription of an estrogen-responsive reporter plasmid. pp32 Represses p300-mediated acetylation of ERα and histones in vitro and inhibits acetylation of ERα in vivo. pp32 Also binds to other nuclear receptors and inhibits thyroid hormone receptor β-mediated transcription. Taken together, our studies provide evidence that pp32 plays a role in regulating transcription of estrogen-responsive genes by modulating acetylation of histones and ERα and also influences transcription of other hormone-responsive genes as well.

scholarly journals pp90rsk1 Regulates Estrogen Receptor-Mediated Transcription through Phosphorylation of Ser-167

1998 ◽  
Vol 18 (4) ◽  
pp. 1978-1984 ◽  
Author(s):  
Peteranne B. Joel ◽  
Jeffrey Smith ◽  
Thomas W. Sturgill ◽  
Tracey L. Fisher ◽  
John Blenis ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Activation ◽  
Ectopic Expression ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Kinase Domain ◽  
Stable Complex ◽  
Wild Type

ABSTRACT The estrogen receptor α (ER), a member of the steroid receptor superfamily, contains an N-terminal hormone-independent transcriptional activation function (AF-1) and a C-terminal hormone-dependent transcriptional activation function (AF-2). Here, we used in-gel kinase assays to determine that pp90rsk1 activated by either epidermal growth factor (EGF) or phorbol myristate acetate specifically phosphorylates Ser-167 within AF-1. In vitro kinase assays demonstrated that pp90rsk1 phosphorylates the N terminus of the wild-type ER but not of a mutant ER in which Ser-167 was replaced by Ala. In vivo, EGF stimulated phosphorylation of Ser-167 as well as Ser-118. Ectopic expression of active pp90rsk1increased the level of phosphorylation of Ser-167 compared to that of either a mutant pp90rsk1, which is catalytically inactive in the N-terminal kinase domain, or to that of vector control. The ER formed a stable complex with the mutant pp90rsk1in vivo. Transfection of the mutant pp90rsk1 depressed ER-dependent transcription of both a wild-type ER and a mutant ER that had a defective AF-2 domain (ER TAF-1). Furthermore, replacing either Ser-118 or Ser-167 with Ala in ER TAF-1 showed similar decreases in transcription levels. A double mutant in which both Ser-118 and Ser-167 were replaced with Ala demonstrated a further decrease in transcription compared to either of the single mutations. Taken together, our results strongly suggest that pp90rsk1 phosphorylates Ser-167 of the human ER in vivo and that Ser-167 aids in regulating the transcriptional activity of AF-1 in the ER.

scholarly journals Genome-wide Estrogen Receptor-α activation is sustained, not cyclical

2018 ◽  
Author(s):  
Andrew N Holding ◽  
Amy E Cullen ◽  
Florian Markowetz
Keyword(s):  
Estrogen Receptor ◽  
Binding Affinity ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Genome Wide ◽  
Main Driver ◽  
Precise Quantification ◽  
Key Driver ◽  
Parallel Factor

AbstractEstrogen Receptor-α (ER) is the key driver of 75% of all breast cancers. Upon stimulation by its ligand estra-2-diol, ER forms a transcriptionally active complex binding chromatin. Previous studies have reported that ER binding follows a cyclical binding pattern with a periodicity of 90 minutes. However, these studies have been limited to individual ER target genes and most were done without replicates. Thus, the robustness and generality of ER cycling are not well understood.Here we present a comprehensive genome-wide analysis of the time dependence of ER binding affinity up to 90 minutes after activation, based on 6 replicates at 10 time points using our previously reported method for precise quantification of binding, Parallel-Factor ChIP-seq (pfChIP-seq). In contrast to previously described cyclical binding, our approach identifies a unidirectional sustained increase in ER binding affinity, as well as a class of estra-2-diol independent binding sites. Our results are corrob-orated by a quantitative re-analysis of data from multiple independent studies.Our new model reconciles the results of multiple conflicting studies into the activation of ER at the TFF1 promoter. We provide a detailed understanding of ER’s response to estra-2-diol in the context of the receptor’s fundamental role as both the main driver and therapeutic target of breast cancer.

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