Nuclear Hormone Receptors and Gene Expression

Abstract

The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different "orphan" receptors of unknown ligand. Ligands for some of these receptors have been recently identified, showing that products of lipid metabolism such as fatty acids, prostaglandins, or cholesterol derivatives can regulate gene expression by binding to nuclear receptors. Nuclear receptors act as ligand-inducible transcription factors by directly interacting as monomers, homodimers, or heterodimers with the retinoid X receptor with DNA response elements of target genes, as well as by "cross-talking" to other signaling pathways. The effects of nuclear receptors on transcription are mediated through recruitment of coregulators. A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand. Corepressors are found within multicomponent complexes that contain histone deacetylase activity. Deacetylation leads to chromatin compactation and transcriptional repression. Upon ligand binding, the receptors undergo a conformational change that allows the recruitment of multiple coactivator complexes. Some of these proteins are chromatin remodeling factors or possess histone acetylase activity, whereas others may interact directly with the basic transcriptional machinery. Recruitment of coactivator complexes to the target promoter causes chromatin decompactation and transcriptional activation. The characterization of corepressor and coactivator complexes, in concert with the identification of the specific interaction motifs in the receptors, has demonstrated the existence of a general molecular mechanism by which different receptors elicit their transcriptional responses in target genes.

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…Ligand binding regulates NR conformation, nuclear localization, binding to specific response elements and recruitment of coactivators/corepressors (Moras & Gronemeyer 1998, Weatherman et al . 1999, Aranda & Pascual 2001, Sanchez et al . 2002, White et al .…”

Class II histone deacetylases: versatile regulators

“…Both SMRT and N-CoR interact with unbound nuclear receptors and with a growing list of other transcription factors (reviewed in Ref. [51]). In addition, both SMRT and N-CoR participate in the formation of a stable multiprotein complex consisting of HDAC3, transducin (b)-like 1 (TBL1) [52,53] and GPS2, a protein involved in intracellular signaling [54].…”

Retinoid-suppressed phosphorylation of RARα mediates the differentiation pathway of osteosarcoma cells

“…The FGF8 promoter contains functional binding sites of RARa, whereas RARa interacts with these DNA binding sites, leading to induction of CAT activity (Brondani et al, 2002). According to the current model of gene regulation by retinoids (Bastien and Rochette-Egly, 2004), unliganded and DNA-bound retinoid receptors repress transcription through the recruitment of corepressors; whereas ligand-induced conformational changes in the receptors cause dissociation of corepressors and recruitment of coactivators (Melnick and Licht, 1999;Aranda and Pascual, 2001;Bastien and Rochette-Egly, 2004). Such chromatin remodeling leads to decompaction of repressive chromatin and facilitating the recruitment of TFIIH complexes to the promoter of target genes to initiate Osteosarcoma cell differentiation P Luo et al transcription (Bastien and Rochette-Egly, 2004).…”