Heterodimeric interaction of the retinoic acid and thyroid hormone receptors in transcriptional regulation on the gamma F-crystallin everted retinoic acid response element.

Abstract

Previously, we have identified a hormone response element (γ F-HRE) composed of an everted repeat of the half-site (A/G)GGTCA motif separated by 8 base pairs that mediates retinoic acid (RA) activation of the γ F-crystallin promoter. Here, we report that this element is bound by the thyroid hormone (T 3 ) receptor in the form of heterodimers with either the retinoid X receptor (RXR) or the retinoic acid receptor (RAR). The T 3 R/RXR heterodimer binds to this element with high affinity but the transcriptional activity of the T 3 receptor on this element is effectively antagonized by RAR α. Thus, RAR α exerts a dominant effect on the γ F-HRE-everted repeat by mediating both RA activation and preventing T 3 response. Although RAR/T 3 R heterodimers bind to the γ F-HRE, they do not appear to be involved in transcriptional regulation since they bind with low affinity, and their ability to bind DNA is dramatically decreased by T 3 . Repression requires the DNA- and ligand-binding domains of RAR α and is consistent with a competitive DNA binding model of repression. However, in vitro binding studies indicate that RAR/RXR heterodimers form less stable interactions with the γ F-HRE compared with T 3 R/RXR heterodimers; this suggests that in vivo the binding affinity of RAR/RXR heterodimers may be enhanced by accessory factors. © 1994 by The Endocrine Society.