Figure 1.

Diverse modes of signalling by nuclear receptors. (a) Classical nuclear receptor (NR) signalling. (i) Transcriptional repression through recruitment of corepressor complexes to unliganded nuclear receptors. (ii) Transcriptional activation through recruitment of coactivators to ligand-bound nuclear receptors. (b) Ligand-dependent repression of transcription. (i) Negative response element: direct recruitment to DNA. (1) Nuclear receptor interference with the activation of transcription by other factors. For example, ligand-bound TR prevents the general transcriptional activator SP1 from binding to the β-amyloid precursor gene. (2) Coactivator role reversal leading to transcriptional repression. For example, SRC1 contributes to repression by ligand-bound TR. (3) Inverse recruitment of corepressors to ligand-bound receptors. For example, the corepressor NCoR has been implicated in association with ligand-bound TR on the gene encoding TSHα. (4) Factors such as RIP140 act as inverse regulators because they serve as corepressors yet are recruited to ligand-bound receptors. (5) Synthetic and natural inverse agonists serve as negative ligands because they promote recruitment with corepressor complexes. For example, haem-binding promotes repression by REV-ERB. (ii)Trans-repression by ligand-bound receptors. (6) Ligand-bound GR interacts with and prevents activation of AP1-mediated transcription. (7) Ligand-bound TR contributes to repression of the gene encoding TSHβ through interaction with the GATA2 transcription factor. (iii) Downregulation through off-DNA mechanisms. (8) Genome-wide studies suggest that many downregulated genes do not directly recruit nuclear receptors. Hence, the downregulation observed is likely to be due to squelching effects.