Some new twists in the regulation of gene expression by thyroid hormone and retinoic acid receptors

Recent studies indicate that heterodimeric nuclear receptors utilize several novel mechanisms for increasing the complexity of transcriptional responses to hormonal stimuli. By binding as heterodimers, these receptors can potentially respond to more than one activating ligand. Allosteric interactions between the ligand binding domains of RXR and its heterodimeric partners regulate the binding of RXR ligands, resulting in either selective or dual transcriptional responses. Regulation of the relative levels of expression of different heterodimeric partners that permit signaling through RXR is likely further to expand the patterns of transcriptional responses that can occur through a given response element. Heterodimeric nuclear receptors also bind to asymmetric response elements with specific polarities that result from the formation of cooperative interfaces between DNA binding domains. The DNA binding interface serves to determine the response element specificity of different heterodimers based on the spacing between half sites. The specific polarity of DNA binding has also been shown to provide a mechanism for regulating the transcriptional responses of retinoic acid receptors to activating ligands through the differential control of co-repressor interactions. The identification and characterization of co-activator and co-repressor molecules is likely to provide a very interesting next chapter to the mechanisms of steroid hormone action.