Gene repression by nuclear hormone receptors

Abstract

Repression by nuclear hormone receptors (NHRs) plays an important role in development, immune response and cellular function. We review mechanisms of how NHRs act as repressors of gene transcription either by direct contact with basal transcription factors or through recruitment of cofactors and enzymic activities that modulate chromatin accessibility. We describe also the role and biochemical mechanism of the cognate hormone that switches a NHR from a transcriptional silencer into an activator. This includes data from crystal structure, functional receptor domain analyses and the role of co-repressors in chromatin modification and remodelling. Furthermore, the comparison of negative response elements with classical response elements unravels the role of co-repressors in this context. We also describe the inhibition of the nuclear factor kappaB and Jun/Fos pathway by NHRs, as well as the molecular mechanism of anti-hormone therapies. Anti-hormones are commonly used in breast and prostate cancer therapy to inhibit cancer proliferation through repression of the oestrogen or androgen receptor, respectively. Here we provide a comprehensive overview of the various mechanism of NHR repression.

Estrogen-induced and TAFII30-mediated gene repression by direct recruitment of the estrogen receptor and co-repressors to the core promoter and its reversal by tamoxifen

“…A classical response element for ER cannot be identified within the P4 promoter. In addition to regulating genes by binding to classical hormone response elements, nuclear receptors have been shown to associate with DNA and repress genes by binding to elements termed 'negative hormone response elements (nHREs)' (Aranda and Pascual, 2001;Moehren et al, 2004). Such elements have been characterized for glucocorticoid and thyroid hormone receptors, and typically occur near the transcription initiation sites of the target genes but may also occur in the 3 0 -untranslated region.…”

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

“…TRs can also regulate target genes indirectly through protein-protein contacts with other transcription factors. TRs, for example, enhance AP-1 activity in the absence of T3, and suppress AP-1 function in the presence of T3 (Desbois et al, 1991;Zhang et al, 1991;Sharif and Privalsky, 1992;Pfahl, 1993;Schmidt et al, 1993;Moehren et al, 2004). TRs are encoded at two distinct loci, a and b, and by alternative mRNA splicing so as to generate three major isoforms: TRa1, TRb1, and TRb2 (Lazar, 1993;Murata, 1998;Zhang and Lazar, 2000).…”

p21WAF1/CIP1 Is a Common Transcriptional Target of Retinoid Receptors

“…For instance, RAR and RXR heterodimer binds to retinoic acid response element (RARE) that contains two or five spacers (DR2 or -5), and RXR homodimer binds to retinoid X response element (RXRE) in which the half-sites are separated by a single nucleotide (DR1) (5). Direct binding of ligands to the receptors is required for transcriptional activation, and in the absence of ligands, this activation is blocked by binding of specific repressors to the receptors (6). Ligand binding triggers a release of the repressors from the complex and promotes interaction with co-activator complexes that forms a bridge between the nuclear receptors and the basic transcriptional machinery (6).…”

“…Direct binding of ligands to the receptors is required for transcriptional activation, and in the absence of ligands, this activation is blocked by binding of specific repressors to the receptors (6). Ligand binding triggers a release of the repressors from the complex and promotes interaction with co-activator complexes that forms a bridge between the nuclear receptors and the basic transcriptional machinery (6). This tight regulatory control of the ligand-dependent transactivation of the nuclear receptor superfamily potentiates a multitude of therapeutic applications for anti-cancer treatments.…”