Estrogen-related receptor β (ERRβ) – renaissance receptor or receptor renaissance?

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Abstract

Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα and ERRγ at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ, however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor.

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A signature motif in transcriptional co-activators mediates binding to nuclear receptors.

D Heery, E Kalkhoven, S. Hoare … (1997)

The binding of lipophilic hormones, retinoids and vitamins to members of the nuclear-receptor superfamily modifies the DNA-binding and transcriptional properties of these receptors, resulting in the activation or repression of target genes. Ligand binding induces conformational changes in nuclear receptors and promotes their association with a diverse group of nuclear proteins, including SRC-1/p160, TIF-2/GRIP-1 and CBP/p300 which function as co-activators of transcription, and RIP-140, TIF-1 and TRIP-1/SUG-1 whose functions are unclear. Here we report that a short sequence motif LXXLL (where L is leucine and X is any amino acid) present in RIP-140, SRC-1 and CBP is necessary and sufficient to mediate the binding of these proteins to liganded nuclear receptors. We show that the ability of SRC-1 to bind the oestrogen receptor and enhance its transcriptional activity is dependent upon the integrity of the LXXLL motifs and on key hydrophobic residues in a conserved helix (helix 12) of the oestrogen receptor that are required for its ligand-induced activation function. We propose that the LXXLL motif is a signature sequence that facilitates the interaction of different proteins with nuclear receptors, and is thus a defining feature of a new family of nuclear proteins.

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Dissecting self-renewal in stem cells with RNA interference.

Natalia Ivanova, Radu Dobrin, Rong lu … (2006)

We present an integrated approach to identify genetic mechanisms that control self-renewal in mouse embryonic stem cells. We use short hairpin RNA (shRNA) loss-of-function techniques to downregulate a set of gene products whose expression patterns suggest self-renewal regulatory functions. We focus on transcriptional regulators and identify seven genes for which shRNA-mediated depletion negatively affects self-renewal, including four genes with previously unrecognized roles in self-renewal. Perturbations of these gene products are combined with dynamic, global analyses of gene expression. Our studies suggest specific biological roles for these molecules and reveal the complexity of cell fate regulation in embryonic stem cells.

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Rembrandt: helping personalized medicine become a reality through integrative translational research.

Subha Madhavan, Jean-Claude Zenklusen, Yuri Kotliarov … (2009)

Finding better therapies for the treatment of brain tumors is hampered by the lack of consistently obtained molecular data in a large sample set and the ability to integrate biomedical data from disparate sources enabling translation of therapies from bench to bedside. Hence, a critical factor in the advancement of biomedical research and clinical translation is the ease with which data can be integrated, redistributed, and analyzed both within and across functional domains. Novel biomedical informatics infrastructure and tools are essential for developing individualized patient treatment based on the specific genomic signatures in each patient's tumor. Here, we present Repository of Molecular Brain Neoplasia Data (Rembrandt), a cancer clinical genomics database and a Web-based data mining and analysis platform aimed at facilitating discovery by connecting the dots between clinical information and genomic characterization data. To date, Rembrandt contains data generated through the Glioma Molecular Diagnostic Initiative from 874 glioma specimens comprising approximately 566 gene expression arrays, 834 copy number arrays, and 13,472 clinical phenotype data points. Data can be queried and visualized for a selected gene across all data platforms or for multiple genes in a selected platform. Additionally, gene sets can be limited to clinically important annotations including secreted, kinase, membrane, and known gene-anomaly pairs to facilitate the discovery of novel biomarkers and therapeutic targets. We believe that Rembrandt represents a prototype of how high-throughput genomic and clinical data can be integrated in a way that will allow expeditious and efficient translation of laboratory discoveries to the clinic.

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Author and article information

Journal

Journal ID (nlm-ta): Nucl Recept Signal

Journal ID (iso-abbrev): Nucl Recept Signal

Journal ID (publisher-id): NRS

Title: Nuclear Receptor Signaling

Publisher: Nuclear Receptor Signaling Atlas

ISSN (Electronic): 1550-7629

Publication date Collection: 2016

Publication date (Electronic): 21 June 2016

Volume: 14

Electronic Location Identifier: e002

Affiliations

[1]Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC (SDD, DMT, AF, RBR)

Author notes

Corresponding Author: RBR, rbr7@ 123456georgetown.edu

Article

Publisher ID: nrs14002

DOI: 10.1621/nrs.14002

PMC ID: 4978380

PubMed ID: 27507929

SO-VID: 0f764665-fa5f-4ea1-8e6e-8abace3f598c

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 05 November 2015

Date accepted : 25 March 2016

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Estrogen-related receptor β (ERRβ) – renaissance receptor or receptor renaissance?

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Higher order chromatin architecture

Most cited references 96

A signature motif in transcriptional co-activators mediates binding to nuclear receptors.

Dissecting self-renewal in stem cells with RNA interference.

Rembrandt: helping personalized medicine become a reality through integrative translational research.

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