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 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.

Nuclear Hormone Receptors and Gene Expression

2001 ◽  
Vol 81 (3) ◽  
pp. 1269-1304 ◽  
Author(s):  
Ana Aranda ◽  
Angel Pascual
Keyword(s):  
Gene Expression ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Hormone Receptors ◽  
Target Genes ◽  
Specific Interaction ◽  
Nuclear Hormone Receptor ◽  
Transcriptional Responses ◽  
Orphan Receptors

The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different “orphan” receptors of unknown ligand. Ligands for some of these receptors have been recently identified, showing that products of lipid metabolism such as fatty acids, prostaglandins, or cholesterol derivatives can regulate gene expression by binding to nuclear receptors. Nuclear receptors act as ligand-inducible transcription factors by directly interacting as monomers, homodimers, or heterodimers with the retinoid X receptor with DNA response elements of target genes, as well as by “cross-talking” to other signaling pathways. The effects of nuclear receptors on transcription are mediated through recruitment of coregulators. A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand. Corepressors are found within multicomponent complexes that contain histone deacetylase activity. Deacetylation leads to chromatin compactation and transcriptional repression. Upon ligand binding, the receptors undergo a conformational change that allows the recruitment of multiple coactivator complexes. Some of these proteins are chromatin remodeling factors or possess histone acetylase activity, whereas others may interact directly with the basic transcriptional machinery. Recruitment of coactivator complexes to the target promoter causes chromatin decompactation and transcriptional activation. The characterization of corepressor and coactivator complexes, in concert with the identification of the specific interaction motifs in the receptors, has demonstrated the existence of a general molecular mechanism by which different receptors elicit their transcriptional responses in target genes.

scholarly journals Mouse Estrogen Receptor β Forms Estrogen Response Element-Binding Heterodimers with Estrogen Receptor α

1997 ◽  
Vol 11 (10) ◽  
pp. 1486-1496 ◽  
Author(s):  
Katarina Pettersson ◽  
Kaj Grandien ◽  
George G. J. M. Kuiper ◽  
Jan-Åke Gustafsson
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Estrogen Receptor Β ◽  
Estrogen Response Element ◽  
Response Element ◽  
Estrogen Response

scholarly journals Reading and Function of a Histone Code Involved in Targeting Corepressor Complexes for Repression

2005 ◽  
Vol 25 (1) ◽  
pp. 324-335 ◽  
Author(s):  
Ho-Geun Yoon ◽  
Youngsok Choi ◽  
Philip A. Cole ◽  
Jiemin Wong
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Hormone Receptors ◽  
Critical Role ◽  
Pericentric Heterochromatin ◽  
Histone Code ◽  
Stable Association ◽  
And Function

ABSTRACT A central question in histone code theory is how various codes are recognized and utilized in vivo. Here we show that TBL1 and TBLR1, two WD-40 repeat proteins in the corepressor SMRT/N-CoR complexes, are functionally redundant and essential for transcriptional repression by unliganded thyroid hormone receptors (TR) but not essential for transcriptional activation by liganded TR. TBL1 and TBLR1 bind preferentially to hypoacetylated histones H2B and H4 in vitro and have a critical role in targeting the corepressor complexes to chromatin in vivo. We show that targeting SMRT/N-CoR complexes to the deiodinase 1 gene (D1) requires at least two interactions, one between unliganded TR and SMRT/N-CoR and the other between TBL1/TBLR1 and hypoacetylated histones. Neither interaction alone is sufficient for the stable association of the corepressor complexes with the D1 promoter. Our data support a feed-forward working model in which deacetylation exerted by initial unstable recruitment of SMRT/N-CoR complexes via their interaction with unliganded TR generates a histone code that serves to stabilize their own recruitment. Similarly, we find that targeting of the Sin3 complex to pericentric heterochromatin may also follow this model. Our studies provide an in vivo example that a histone code is not read independently but is recognized in the context of other interactions.

scholarly journals Inhibition of Estrogen Receptor Action by the Orphan Receptor SHP (Short Heterodimer Partner)

1998 ◽  
Vol 12 (10) ◽  
pp. 1551-1557 ◽  
Author(s):  
Wongi Seol ◽  
Bettina Hanstein ◽  
Myles Brown ◽  
David D. Moore
Keyword(s):  
Estrogen Receptor ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Estrogen Signaling ◽  
Dependent Manner ◽  
Interaction Domain ◽  
Short Heterodimer Partner

Abstract SHP (short heterodimer partner) is an unusual orphan receptor that lacks a conventional DNA-binding domain. Previous results have shown that it interacts with several other nuclear hormone receptors, including the retinoid and thyroid hormone receptors, and inhibits their ligand-dependent transcriptional activation. Here we show that SHP also interacts with estrogen receptors and inhibits their function. In mammalian and yeast two-hybrid systems as well as glutathione-S-transferase pull-down assays, SHP interacts specifically with estrogen receptor-α (ERα) in an agonist-dependent manner. The same assay systems using various deletion mutants of SHP map the interaction domain with ERα to the same SHP sequences required for interaction with the nonsteroid hormone receptors such as retinoid X receptor and thyroid hormone receptor. In transient cotransfection assays, SHP inhibits estradiol -dependent activation by ERα by about 5-fold. In contrast, SHP interacts with ERβ independent of ligand and reduces its ability to activate transcription by only 50%. These data suggest that SHP functions to regulate estrogen signaling through a direct interaction with ERα.

scholarly journals Allosteric Modulation of Estrogen Receptor Conformation by Different Estrogen Response Elements

2001 ◽  
Vol 15 (7) ◽  
pp. 1114-1126 ◽  
Author(s):  
Jennifer R. Wood ◽  
Varsha S. Likhite ◽  
Margaret A. Loven ◽  
Ann M. Nardulli
Keyword(s):  
Estrogen Receptor ◽  
Dna Interaction ◽  
Allosteric Modulation ◽  
Proteinase K ◽  
Receptor Interaction ◽  
Interacting Protein ◽  
Deoxyribonuclease I ◽  
Estrogen Response ◽  
Nuclear Extracts ◽  
Regulated Gene Expression

Abstract Estrogen-regulated gene expression is dependent on interaction of the estrogen receptor (ER) with the estrogen response element (ERE). We assessed the ability of the ER to activate transcription of reporter plasmids containing either the consensus vitellogenin A2 ERE or the imperfect pS2, vitellogenin B1, or oxytocin (OT) ERE. The A2 ERE was the most potent activator of transcription. The OT ERE was significantly more effective in activating transcription than either the pS2 or B1 ERE. In deoxyribonuclease I (DNase I) footprinting experiments, MCF-7 proteins protected A2 and OT EREs more effectively than the pS2 and B1 EREs. Limited protease digestion of the A2, pS2, B1, or OT ERE-bound receptor with V8 protease or proteinase K produced distinct cleavage products demonstrating that individual ERE sequences induce specific changes in ER conformation. Receptor interaction domains of glucocorticoid receptor interacting protein 1 and steroid receptor coactivator 1 bound effectively to the A2, pS2, B1, and OT ERE-bound receptor and significantly stabilized the receptor-DNA interaction. Similar levels of the full-length p160 protein amplified in breast cancer 1 were recruited from HeLa nuclear extracts by the A2, pS2, B1, and OT ERE-bound receptors. In contrast, significantly less transcriptional intermediary factor 2 was recruited by the B1 ERE-bound receptor than by the A2 ERE-bound receptor. These studies suggest that allosteric modulation of ER conformation by individual ERE sequences influences the recruitment of specific coactivator proteins and leads to differential expression of genes containing divergent ERE sequences.

scholarly journals Estrogen receptor acetylation and phosphorylation in hormone responses

2005 ◽  
Vol 8 (9) ◽  
Author(s):  
C. Wang ◽  
M. Fu ◽  
R. G. Pestell
Keyword(s):  
Estrogen Receptor ◽  
Dna Sequences ◽  
Transcriptional Repression ◽  
Estrogen Receptor Alpha ◽  
Estrogen Therapy ◽  
Estrogen Signaling ◽  
Hormone Signaling ◽  
Post Translational Modification ◽  
Lysine Residues ◽  
Hormone Responses

Histone acetylation is thought to facilitate binding of transcription factors (TFs) to specific target DNA sequences by destabilizing nucleosomes bound to the promoter region of a target gene. In addition, non-histone proteins including a subset of TFs and co-activators are acetylated by p300/CBP and P/CAF. The regulation of estrogen signaling by direct estrogen receptor alpha (ERα) post-translational modification reveals a novel role for histone acetyltransferase in hormone signaling. ERα is acetylated and phosphorylated and phosphorylation occurs at multiple sites in response to kinase signaling. The finding that mutations with the ERα hinge domain lysine residues enhance hormone sensitivity suggests these residues may be involved in ligand-dependent transcriptional repression or transcriptional attenuation. Phosphorylation and acetylation of the ER regulates hormone signaling and is being assessed for a role in resistance to anti-estrogen therapy of ERα-positive patients.

scholarly journals Functional Interaction between the Estrogen Receptor and CTF1: Analysis of the Vitellogenin Gene B1 Promoter in Yeast

1998 ◽  
Vol 12 (10) ◽  
pp. 1525-1541 ◽  
Author(s):  
Monika Tsai-Pflugfelder ◽  
Susan M. Gasser ◽  
Walter Wahli
Keyword(s):  
Estrogen Receptor ◽  
Chromatin Structure ◽  
Transcriptional Activation ◽  
Transactivation Domain ◽  
Functional Interaction ◽  
Estrogen Response ◽  
Eukaryotic Gene Expression ◽  
Eukaryotic Gene ◽  
Human Estrogen Receptor ◽  
Vitellogenin Gene

Abstract Eukaryotic gene expression depends on a complex interplay between the transcriptional apparatus and chromatin structure. We report here a yeast model system for investigating the functional interaction between the human estrogen receptor (hER) and CTF1, a member of the CTF/NFI transcription factor family. We show that a CTF1-fusion protein and the hER transactivate a synthetic promoter in yeast in a synergistic manner. This interaction requires the proline-rich transactivation domain of CTF1. When the natural estrogen-dependent vitellogenin B1 promoter is tested in yeast, CTF1 and CTF1-fusion proteins are unable to activate transcription, and no synergy is observed between hER, which activates the B1 promoter, and these factors. Chromatin structure analysis on this promoter reveals positioned nucleosomes at −430 to −270 (±20 bp) and at −270 to− 100 (±20 bp) relative to the start site of transcription. The positions of the nucleosomes remain unchanged upon hormone-dependent transcriptional activation of the promoter, and the more proximal nucleosome appears to mask the CTF/NFI site located at −101 to −114. We conclude that a functional interaction of hER with the estrogen response element located upstream of a basal promoter occurs in yeast despite the nucleosomal organization of this promoter, whereas the interaction of CTF1 with its target site is apparently precluded by a nucleosome.

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