Complex Human Glucocorticoid Receptor dim Mutations Define Glucocorticoid Induced Apoptotic Resistance in Bone Cells

Jewell, Christine M.; Scoltock, Alyson B.; Hamel, Brant L.; Yudt, Matthew R.; Cidlowski, John A.

doi:10.1210/me.2011-1116

Cited by 59 publications

(62 citation statements)

References 42 publications

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“…5C). While GR drives more transcription than GR dim at the WT-selective sites, GR dim compares favorably at the common regions, agreeing with earlier studies demonstrating in vitro activity for GR dim (Adams et al 2003;Meijsing et al 2009;Jewell et al 2012). Mutation of the GR half-site sequence within the common regions destroys GR and GR dim activity, demonstrating that transcriptional activation by monomeric GR requires a half-site motif.…”

Section: Gr Dim Partitions the Gr Cistrome Similarly In Primary Macrosupporting

confidence: 87%

“…Early interpretations proposed no DNAbinding functions for GR dim (Reichardt et al 1998), but our data show that GR dim occupies a majority of sites comprising the GR cistromes in a primary cell type and native tissue and displays little or no selective binding. Recently, the inability of GR dim to form homodimers has been challenged through forced expression of GFP-or YFP-tagged GR dim and monitoring dimerization by immunoprecipitation (Jewell et al 2012) or a number and brightness assay (Presman et al 2014). We detect little, if any, dimeric occupancy for GR dim , indicating that it interacts with the genome primarily as a monomer under physiological conditions.…”

Section: Discussionmentioning

confidence: 85%

“…This was in part due to the inability of GR dim to induce GR-dependent antiinflammatory genes (Vandevyver et al 2012). Although its DNA-binding properties are compromised relative to GR (Gebhardt et al 2013;Watson et al 2013), the inability of GR dim to dimerize and bind DNA has been challenged by in vitro studies (Jewell et al 2012;Presman et al 2014;Sedwick 2014).…”

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confidence: 99%

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Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

et al. 2015

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Glucocorticoids (GCs) are commonly prescribed drugs, but their anti-inflammatory benefits are mitigated by metabolic side effects. Their transcriptional effects, including tissue-specific gene activation and repression, are mediated by the glucocorticoid receptor (GR), which is known to bind as a homodimer to a palindromic DNA sequence. Using ChIP-exo in mouse liver under endogenous corticosterone exposure, we report here that monomeric GR interaction with a half-site motif is more prevalent than homodimer binding. Monomers colocalize with lineage-determining transcription factors in both liver and primary macrophages, and the GR half-site motif drives transcription, suggesting that monomeric binding is fundamental to GR's tissue-specific functions. In response to exogenous GC in vivo, GR dimers assemble on chromatin near ligand-activated genes, concomitant with monomer evacuation of sites near repressed genes. Thus, pharmacological GCs mediate gene expression by favoring GR homodimer occupancy at classic palindromic sites at the expense of monomeric binding. The findings have important implications for improving therapies that target GR.

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Section: Gr Dim Partitions the Gr Cistrome Similarly In Primary Macrosupporting

confidence: 87%

Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

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Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

et al. 2015

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“…Of note, in transient transfection studies it was shown that by the GR dim mutation, dimerisation is not entirely absent (Jewell et al, 2012;Watson et al, 2013;Presman et al, 2014). The residual dimerisation of the GR dim mutant is due to the fact that promoters may engage several dimerisation interfaces of the GR that are still present in the GR dim mutation (e.g., in the LBD) (Savory et al, 2001;Bledsoe et al, 2002;Jewell et al, 2012;Presman et al, 2014).…”

Section: Lessons From Gr Dim Micementioning

confidence: 99%

The glucocorticoid receptor in inflammatory processes: transrepression is not enough

Hübner¹,

Dejager²,

Libert³

et al. 2015

Biological Chemistry

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Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases. However, steroid therapies are accompanied by severe side-effects during long-term treatment. The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNAbound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. Recent discoveries using conditional GR mutant mice and genomic approaches reveal that transactivation of antiinflammatory acting genes is essential to suppress many inflammatory disease models. This novel view radically changes the concept to design selective acting GR ligands with a reduced side-effect profile.

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“…However, this paradigm has been established exclusively from in vitro studies, working mostly with the DBD fragment (8)(9)(10), only using the whole GR protein in rare cases (11,12). The small number of experiments performed in live cells only addresses the entire nuclear population, lacking specific information regarding the GR fraction bound to chromatin (13)(14)(15)(16). Furthermore, these studies were unable to discriminate between dimers or higher oligomeric states.…”

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confidence: 99%

DNA binding triggers tetramerization of the glucocorticoid receptor in live cells

Presman

Ganguly

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

118

190

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Transcription factors dynamically bind to chromatin and are essential for the regulation of genes. Although a large percentage of these proteins appear to self-associate to form dimers or higher order oligomers, the stoichiometry of DNA-bound transcription factors has been poorly characterized in vivo. The glucocorticoid receptor (GR) is a ligandregulated transcription factor widely believed to act as a dimer or a monomer. Using a unique set of imaging techniques coupled with a cell line containing an array of DNA binding elements, we show that GR is predominantly a tetramer when bound to its target DNA. We find that DNA binding triggers an interdomain allosteric regulation within the GR, leading to tetramerization. We therefore propose that dynamic changes in GR stoichiometry represent a previously unidentified level of regulation in steroid receptor activation. Quaternary structure analysis of other members of the steroid receptor family (estrogen, androgen, and progesterone receptors) reveals variation in oligomerization states among this family of transcription factors. Because GR's oligomerization state has been implicated in therapy outcome, our findings open new doors to the rational design of novel GR ligands and redefine the quaternary structure of steroid receptors. Steroid receptors are transcription factors regulated by physiological stimuli that dynamically bind to chromatin and control complex biological pathways (1). In particular, the glucocorticoid receptor (GR) is essential for life and is one of the most targeted proteins in the pharmacological industry due to its powerful antiinflammatory and immunosuppressive activities (2). Current pharmaceutical approaches are based on a recently challenged (3) binary model wherein direct binding of GR dimers and indirect binding of GR monomers via other proteins determine the transcriptional output (4).Upon hormone activation, GR associates to a subset of glucocorticoid response elements (GREs) across the genome, depending on the accessibility of the chromatin landscape (5). GR is a modular protein organized into three structural and functional domains; the N-terminal ligand-independent activation function-1 domain (NTD), the central DNA-binding domain (DBD), and the C-terminal ligand-binding domain (LBD) (6). GR, and all steroid receptors, are widely believed to bind DNA directly as homodimers (7). However, this paradigm has been established exclusively from in vitro studies, working mostly with the DBD fragment (8-10), only using the whole GR protein in rare cases (11,12). The small number of experiments performed in live cells only addresses the entire nuclear population, lacking specific information regarding the GR fraction bound to chromatin (13-16). Furthermore, these studies were unable to discriminate between dimers or higher oligomeric states.For the present study, we combine an experimental model where GR-DNA interaction can be observed in real time with techniques that allow the quantification of the oligomeric state of proteins inside living...

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Complex Human Glucocorticoid Receptor dim Mutations Define Glucocorticoid Induced Apoptotic Resistance in Bone Cells

Cited by 59 publications

References 42 publications

Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

The glucocorticoid receptor in inflammatory processes: transrepression is not enough

DNA binding triggers tetramerization of the glucocorticoid receptor in live cells

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