Glucocorticoid Receptor Mutants Demonstrate Increased Motility Inside the Nucleus of Living Cells: Time of Fluorescence Recovery After Photobleaching (FRAP) Is an Integrated Measure of Receptor Function

The glucocorticoid receptor (GR) is a constitutively expressed transcriptional regulatory factor (TRF) that controls many distinct gene networks, each uniguely determined by particular cellular and physiological contexts. The precision of GR-mediated responses seems to depend on combinatorial, context-specific assembly of GR-nucleated transcription regulatory complexes at genomic response elements. In turn, evidence suggests that context-driven plasticity is conferred by the integration of multiple signals, each serving as an allosteric effector of GR conformation, a key determinant of regulatory complex composition and activity. This structural and mechanistic perspective on GR regulatory specificity is likely to extend to other eukaryotic TRFs.

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“…Furthermore, ubiquitylation of GR at Lys419 (REF. 85) was shown to stimulate GR nuclear export and subsequent degradation 86 .…”

Section: Allosteric Effectors Of Grmentioning

confidence: 99%

Glucocorticoid receptor control of transcription: precision and plasticity via allostery

Weikum

Knuesel

Ortlund

et al. 2017

Nat Rev Mol Cell Biol

420

419

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“…Thus, ubiquitination and proteasomal degradation regulate the transcriptional activity of GR, by promoting the rapid turnover of the receptor, which leads to down-regulation and a decrease in the transcriptional activity of GR. Ubiquitination also regulates the motility of GR inside the nucleus of living cells (57, 58). Inhibition of the proteasomal activity reduces the motility of the wild-type GRα, as well as the natural mutants GRαD641V, GRαV729I, GRαI747M, and GRαL773P (58).…”

Section: Post-translational Modifications Of Grmentioning

confidence: 99%

The human glucocorticoid receptor: Molecular basis of biologic function

et al. 2010

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The characterization of the subfamily of steroid hormone receptors has enhanced our understanding of how a set of hormonally derived lipophilic ligands controls cellular and molecular functions to influence development and help achieve homeostasis. The glucocorticopid receptor (GR), the first member of this subfamily, is a ubiquitously expressed intracellular protein, which functions as a ligand-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes. The effector domains of the GR mediate transcriptional activation by recruiting coregulatory multi-subunit complexes that remodel chromatin, target initiation sites, and stabilize the RNA polymerase II machinery for repeated rounds of transcription of target genes. This review summarizes the basic aspects of the structure and of the human (h) GR, and the molecular basis of its biologic function.

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“…GR bound to ligands with a low transcriptional activity were found to be more mobile than GR bound to ligands with a high transcriptional activity [16,17]. GR mutants with a lower transcriptional activity also displayed a higher motility [18]. Ligand binding itself is also a highly dynamic process, although receptor clearance from DNA seems to occur independent of ligand dissociation [19].…”

Section: Transactivationmentioning

confidence: 99%