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

Abstract

Previously, we have identified a hormone response element (γF-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 γF- 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 3R/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 RARα. Thus, RARα exerts a dominant effect on the γF-HRE-everted repeat by mediating both RA activation and preventing T 3 response. Although RAR/T 3R heterodimers bind to the γF-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 RARα 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 γF-HRE compared with T 3R/RXR heterodimers; this suggests that in vivo the binding affinity of RAR/RXR heterodimers may be enhanced by accessory factors.