Corepressors of agonist-bound nuclear receptors

Abstract

Nuclear receptors (NRs) rely on coregulator proteins to modulate transcription of target genes. NR coregulators can be broadly subdivided into coactivators which potentiate transcription and corepressors which silence gene expression. The prevailing view of coregulator action holds that in the absence of agonist the receptor interacts with a corepressor via the corepressor nuclear receptor (CoRNR, "corner") box motifs within the corepressor. Upon agonist binding, a conformational change in the receptor causes the shedding of corepressor and the binding of a coactivator which interacts with the receptor via NR boxes within the coregulator. This view was challenged with the discovery of RIP140 which acts as a NR corepressor in the presence of agonist and utilizes NR boxes. Since then a number of other corepressors of agonist-bound NRs have been discovered. Among them are LCoR, PRAME, REA, MTA1, NSD1, and COPR1 Although they exhibit a great diversity of structure, mechanism of repression and pathophysiological function, these corepressors frequently have one or more NR boxes and often recruit histone deacetylases to exert their repressive effects. This review highlights these more recently discovered corepressors and addresses their potential functions in transcription regulation, disease pharmacologic responses and xenobiotic metabolism.

Molt cycle regulation of protein synthesis in skeletal muscle of the blackback land crab, Gecarcinus lateralis, and the differential expression of a myostatin-like factor during atrophy induced by molting or unweighting

“…These data provide support for the hypothesis that ecdysteroids repress Gl-Mstn expression during premolt when bound to the EcR-RXR heterodimer. This is contrary to the prevailing view, which holds that heterodimeric hormone receptors, in the absence of hormone, interact with co-repressors to prevent transcription; ligand binding induces a conformational change that causes dissociation of the corepressors (reviewed by Gurevich et al, 2007). The most parsimonious explanation for these data is that the binding of ecdysteroid allows the receptor to interact with a corepressor and block transcription of Gl-Mstn.…”

“…Ecdysteroid and ESA downregulate gene expression in crayfish digestive gland (Shechter et al, 2007), but it is not known whether the effects are direct or indirect. However, a number of co-repressors that require ligand binding to nuclear receptors have been reported in mammals (reviewed by Gurevich et al, 2007). Interestingly, low ecdysteroid levels in intermolt animals permit the upregulation of Gl-Mstn in unweighted thoracic muscle, but this upregulation is overridden by elevated ecdysteroids during premolt (Fig.7).…”

NF-YC Functions as a Corepressor of Agonist-bound Mineralocorticoid Receptor

“…Several models of nuclear receptor-corepressor interaction have been currently delineated (37,38). In the classic model, unliganded non-steroidal receptors, such as thyroid hormone receptor, bind corepressors, the silencing mediator of retinoid and thyroid hormone receptor (SMRT), or N-CoR, thus resulting in basal repression with recruitment of histone deacetylases, whereas ligand binding releases these corepressors and then recruits coactivator complexes and induces hormone-dependent transactivation.…”

“…Recent reports showed a new paradigm that corepressors are recruited to the nuclear receptors even in the presence of agonist. N-CoR and SMRT are shown to be recruited to the vitamin D/retinoid X receptor heterodimers in a vitamin D3-dependent manner (37). Besides these corepressors, new corepressors, such as L-CoR (39) and REA (40), are shown to be involved in agonist-bound estrogen receptor.…”

Thyroid hormones and the central nervous system of mammals (Review)

“…For example, nTRs can inhibit binding to the promoter of transcription factors like AP-1. They can also interact with a recently discovered class of ligand-dependent corepressors (LCoRs) that were found to be able to bind a wide variety of NRs (90). In general, however, the precise changes in chromatin organization that occur during negative regulation by THs are not yet well characterized.…”