Glucocorticoid receptor mutants that are constitutive activators of transcriptional enhancement

Godowski, Paul J.; Rusconi, Sandro; Miesfeld, Roger L.

doi:10.1038/325365a0

Cited by 419 publications

(214 citation statements)

References 32 publications

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“…Thus, additional mechanisms must operate to enable the GR to selectively recognize a (+)GRE DBS, an IR nGRE DBS, or p65 (NF-κB)/c-jun (AP1) proteins. As the GR ABCD is a constitutive activator of transcription (11,21), GR binding to a (+)GRE only requires a GC-dependent conformational modification of the LBD, which unmasks the DNA binding domain (DBD), whereas the binding of GR to an IR nGRE requires a GC ligand, which by binding to the LBD, allows the unmasking of both the DBD and the NTD SUMOylation site, therefore allowing the formation of a SMRT/NCoR1 repressing complex on the IR nGRE (11). In this respect, note that GR ABCD, but not its SUMOylation mutant GR ABCD K293R, is readily SUMOylated to assemble a repressing complex on an IR nGRE (Fig.…”

Section: Which Mechanisms Allow a Single Gr To Exert Three Main Functmentioning

confidence: 99%

Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex

Hua

Ganti

Chambon

2015

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

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Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GCinduced tethered indirect transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression functions, while still exerting a tethered indirect transrepression activity and could therefore be clinically lesser debilitating on long-term GC therapy.glucocorticoid receptor | SUMOylation | NF-κB/AP1-mediated GC-induced tethered repression

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Section: Which Mechanisms Allow a Single Gr To Exert Three Main Functmentioning

confidence: 99%

Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex

Hua

Ganti

Chambon

2015

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

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“…GR contains three functional domains: the NH 2 -terminal part or modulating domain involved in modulation of gene transcription (14); the DNA-binding domain involved in DNA binding, receptor dimerization (15), and gene transcription enhancement (16); and the ligand-binding domain that controls the activity of the receptor as a whole through its interaction with other proteins and glucocorticoids. In addition to ligand binding, the ligand-binding domain contains a receptor dimerization function (17,18) as well as domains for silencing of the receptor in the absence of the hormone (19,20).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cells

Sánchez-Vega

Krett

Rosen

et al. 2006

Molecular Cancer Therapeutics

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Although glucocorticoids play an important role in the treatment of multiple myeloma, some patients do not respond or develop resistance. The glucocorticoid receptor (GR), a single gene, mediates the effects of glucocorticoids. Using a model system of a multiple myeloma cell line sensitive to glucocorticoids and its early and late resistant variants, we have analyzed mutations in the GR gene, detected the presence of different transcriptional isoforms, quantified their levels of expression, and identified the promoters that regulate their expression.

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“…The GR regulates transcription of target genes by binding DNA at specific hormone response elements and͞or by interacting with other transcription factors (5)(6)(7)(8). Although the structural organization of steroid receptors into N-terminal domain (NTD), DNA binding domain (DBD), and ligand binding domain is well characterized (9)(10)(11)(12)(13)(14), precisely how transcription is regulated by them is largely unknown. For all steroid receptors, this is in part due to the lack of information about their transcription activating domain AF1, located in the NTD (9,10).…”

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confidence: 99%

TATA box binding protein induces structure in the recombinant glucocorticoid receptor AF1 domain

Kumar

Volk

et al. 2004

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

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A number of transcription factor proteins contain domains that are fully or partially unstructured. The means by which such proteins acquire naturally folded conformations are not well understood. When they encounter their proper binding partner(s), several of these proteins adopt a folded conformation through an induced-fit mechanism. The glucocorticoid receptor (GR) is a ligand-activated transcription factor. Expressed independently as a recombinant peptide, the N-terminal transactivation domain (AF1) of the GR shows little structure and appears to exist as a collection of random coil configurations. The GR AF1 is known to interact with other transcription factors, including a critical component of the general transcription machinery proteins, the TATA box binding protein (TBP). We tested whether this interaction can lead to acquisition of structure in the GR AF1. Our results show that recombinant GR AF1 acquires a significant amount of helical content when it interacts with TBP. These structural changes were monitored by Fourier transform infrared and NMR spectroscopies, and by proteolytic digestions. Our results support a model in which TBP binding interaction with the GR AF1 induces significantly greater helical structure in the AF1 domain. This increased helical content in the GR AF1 appears to come mostly at the expense of random coil conformation. These results are in accordance with the hypothesis that an induced-fit mechanism gives structure to the GR AF1 when it encounters TBP.glucocorticoid receptor ͉ N-terminal activation function ͉ coregulatory protein ͉ protein folding T he glucocorticoid receptor (GR) is a ligand-activated transcription factor with the domain structural arrangement typical of the nuclear hormone receptors superfamily (1-4). The GR regulates transcription of target genes by binding DNA at specific hormone response elements and͞or by interacting with other transcription factors (5-8). Although the structural organization of steroid receptors into N-terminal domain (NTD), DNA binding domain (DBD), and ligand binding domain is well characterized (9-14), precisely how transcription is regulated by them is largely unknown. For all steroid receptors, this is in part due to the lack of information about their transcription activating domain AF1, located in the NTD (9, 10). The GR AF1 sequence resembles those of acidic transactivation domains of several transcription factors (15, 16). When expressed independently, the GR AF1 shows little structure and seems to exist as an ensemble of largely unstructured conformers (17, 18). The GR AF1 is known to interact with other transcription factors, and conditional folding has been suggested to be the key for these interactions (19)(20)(21)(22).It has been reported that in the presence of trifluoroethanol, the ''core'' of AF1 (AF1 c , amino acids 187-242), located toward the C-terminal end of AF1, adopts three helical segments (17). Independent experiments have shown that substitution of the ␣-helixbreaking amino acid proline for natural residues a...

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Glucocorticoid receptor mutants that are constitutive activators of transcriptional enhancement

Cited by 419 publications

References 32 publications

Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex

Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex

Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cells

TATA box binding protein induces structure in the recombinant glucocorticoid receptor AF1 domain

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