Activation Functions 1 and 2 of Nuclear Receptors: Molecular Strategies for Transcriptional Activation

Wärnmark, Anette; Treuter, Eckardt; Wright, Anthony P. H.; Gustafsson, Jan Åke

doi:10.1210/me.2002-0384

Cited by 243 publications

(181 citation statements)

References 96 publications

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“…We suggest that the SRC1 and TR␤2 N termini confer conformations on their respective proteins that permit and help stabilize higher affinity interactions between them. Unfortunately little is currently known about the secondary or tertiary structure of these N-terminal nuclear receptor domains, which are believed to be relatively disordered in solution and to assume an induced-fit conformation only in response to contacts with other proteins (62,63).…”

Section: A Pas-b Motif In the Src1 Unexpectedly Modulates Isoformspecmentioning

confidence: 99%

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

Privalsky

Lee²,

Hahm³

et al. 2009

Journal of Biological Chemistry

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Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that play multiple roles in vertebrate endocrinology and development. TRs are expressed as a series of distinct receptor isoforms that mediate different biological functions. The TR␤2 isoform is expressed primarily in the hypothalamus, pituitary, cochlea, and retina, and displays an enhanced response to hormone agonist relative to the other TR isoforms. We report here that the unusual transcriptional properties of TR␤2 parallel the ability of this isoform to bind p160 coactivators cooperatively through multiple contact surfaces; the more broadly expressed TR␤1 isoform, in contrast, utilizes a single contact mechanism. Intriguingly, the PAS-B domain in the p160 N terminus plays a previously unanticipated role in permitting TR␤2 to recruit coactivator at limiting triiodothyronine concentrations. The PAS-B sequences also play an important role in coactivator binding by estrogen receptor-␣. We propose that the PAS-B domain of the p160 coactivators is an important modulator of coactivator recruitment for a specific subset of nuclear receptors, permitting stronger transcriptional activation at lower hormone concentrations than would otherwise occur, and allowing isoform-specific mRNA splicing to customize the hormone response in different tissues.

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Section: A Pas-b Motif In the Src1 Unexpectedly Modulates Isoformspecmentioning

confidence: 99%

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

Privalsky

Lee²,

Hahm³

et al. 2009

Journal of Biological Chemistry

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“…Estrogen receptors (ERs) 3 share their modular domain structure with the other members of the steroid and nuclear receptor superfamily and are comprised of an N-terminal domain characterized by a ligand-independent activation function (AF-1), a central DNA binding domain (DBD) followed by a hinge region, and a C-terminal ligand binding domain (LBD), which contains a ligand-dependent activation function (AF-2) important for coregulator recruitment (4,5).…”

mentioning

confidence: 99%

Estrogen-occupied Estrogen Receptor Represses Cyclin G2 Gene Expression and Recruits a Repressor Complex at the Cyclin G2 Promoter

Stossi

Likhite

Katzenellenbogen

et al. 2006

Journal of Biological Chemistry

111

107

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Estrogens, acting through their nuclear receptors have a broad impact on target cells, eliciting a transcriptional response program that involves gene repression as well as gene stimulation. While much is known about the mechanisms by which the estrogen-occupied estrogen receptor (ER) stimulates gene expression, the molecular events that lead to gene repression by the hormone-ER complex are largely unknown. Because estradiol represses expression of the cyclin G2 gene, which encodes a negative regulator of the cell cycle, our aim was to understand the mechanism by which cyclin G2 is repressed by estrogen. We show that cyclin G2 is a primary ER target gene in MCF-7 breast cancer cells that is rapidly and robustly down-regulated by estrogen. Promoter analysis reveals a responsive region containing a halfestrogen response element and GC-rich region that interact with ER and Sp1 proteins. Mutation of the half-ERE abrogates hormone-mediated repression. Mutational mapping of receptor reveals a requirement for its N-terminal region and DNA binding domain to support cyclin G2 repression. Following estradiol treatment of cells, chromatin immunoprecipitation analyses reveal recruitment of ER to the cyclin G2 regulatory region, dismissal of RNA polymerase II, and recruitment of a complex containing N-CoR and histone deacetylases, leading to a hypoacetylated chromatin state. Our study provides evidence for a mechanism by which the estrogen-occupied ER is able to actively repress gene expression in vivo and indicates a role for nuclear receptor corepressors and associated histone deacetylase activity in mediating negative gene regulation by this hormone-occupied nuclear receptor.In target cells, estrogen hormones act via their nuclear receptors to elicit a diverse transcriptional response program that involves gene repression as well as gene stimulation (1-3). Estrogen receptors (ERs) 3 share their modular domain structure with the other members of the steroid and nuclear receptor superfamily and are comprised of an N-terminal domain characterized by a ligand-independent activation function (AF-1), a central DNA binding domain (DBD) followed by a hinge region, and a C-terminal ligand binding domain (LBD), which contains a ligand-dependent activation function (AF-2) important for coregulator recruitment (4, 5).In the mammary gland, the actions of estrogens are essential for normal growth and development. In breast cancer, the presence of ERs is associated with likely response to endocrine therapy, most usually treatment with antiestrogens such as tamoxifen, or estrogen depletion by the use of aromatase inhibitors (6). Estrogens enhance the proliferation of ER-positive breast cancer cells, and recent studies have shown that this enhancement of proliferation involves both stimulation of the expression of many genes associated with cell cycle progression, as well as the suppression of genes that block the cell cycle (7). Most previous studies, focusing on the mechanisms that lead to stimulation of gene expression, have demonstrat...

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“…Similar to other nuclear receptors, the GR consists structurally of a C-terminal ligand binding domain (LBD), a DNA binding domain with a dimerization interface in the center of the molecule and two transcription activation domains, AF-1 and AF-2 (Wärnmark et al, 2003). In the ligand-activated state, the receptor modulates gene expression either positively (transactivation) or negatively (transrepression).…”

Section: Glucocorticoid Receptor and Its Molecular Actionsmentioning

confidence: 99%

Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index

Schäcke

Berger

Rehwinkel

et al. 2007

Molecular and Cellular Endocrinology

214

190

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A c c e p t e d M a n u s c r i p t Nevertheless, recent understanding of the molecular mechanisms of the GR has triggered several drug discovery programs and these have led to the identification of dissociated GR-ligands. Such selective GR agonists (SEGRAs) are likely to enter clinical testing soon.

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Activation Functions 1 and 2 of Nuclear Receptors: Molecular Strategies for Transcriptional Activation

Cited by 243 publications

References 96 publications

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

Estrogen-occupied Estrogen Receptor Represses Cyclin G2 Gene Expression and Recruits a Repressor Complex at the Cyclin G2 Promoter

Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index

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