Negative response elements in keratin genes mediate transcriptional repression and the cross-talk among nuclear receptors

Very little is known about the mechanisms responsible for the findings that binding of nuclear receptors (NR) to some promoter elements leads to trans criptional activation, whereas binding to others leads to repression. Case in point is the group of epidermal keratin genes and their DNA sequences re sponsible for repression by NR. Keratin response elements (KREs) interact w ith receptors for retinoic acid, thyroid hormone, and glucocorticoids. KREs , by their structure and sequence, direct the binding of retinoic acid and thyroid hormone as homodimers and glucocorticoids as monomers. Such specifi c DNA-receptor interactions are crucial for the repression signal of transc ription. In this paper we have analyzed the interactions between the KREs a nd NR that lead to such repression. We have found that KREs are promoter-in dependent. They not only provide a docking platform for the receptors, but also play a key role in directing the receptors to bind into particular con figurations and coordinating the interactions among different receptors. Bo th an intact KRE and an intact receptor DNA-binding domain are necessary fo r the regulation to occur, which emphasizes the importance of interaction b etween the DNA and NR. for proper signaling. Furthermore, KREs allow simult aneous binding of multiple receptors, thus providing fine-tuning of transcr iptional regulation. The DNA/DNA-binding domain interactions in keratin pro moters exemplify tissue and gene specificity of hormone action.