Unique response pathways are established by allosteric interactions among nuclear hormone receptors

Abstract

Heterodimerization is a common paradigm among eukaryotic transcription factors. The 9-cis retinoic acid receptor (RXR) serves as a common heterodimerization partner for several nuclear receptors, including the thyroid hormone receptor (T3R) and retinoic acid receptor (RAR). This raises the question as to whether these complexes possess dual hormonal responsiveness. We devised a strategy to examine the transcriptional properties of each receptor individually or when tethered to a heterodimeric partner. We find that the intrinsic binding properties of RXR are masked in T3R-RXR and RAR-RXR heterodimers. In contrast, RXR is active as a non-DNA-binding cofactor with the NGFI-B/Nurr1 orphan receptors. Heterodimerization of RXR with constitutively active NGFI-B/Nurr1 creates a novel hormone-dependent complex. These findings suggest that allosteric interactions among heterodimers create complexes with unique properties. We suggest that allostery is a critical feature underlying the generation of diversity in hormone response networks.

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

“…First, RXRα acts as a permissive partner of FXR, LXRs, and PPARs, displaying more than an additive effect upon both ligands treatment [25,26]. RXRα is characterized as a conditional permissive partner in the RXRα/RAR heterodimer, as full response to retinoids occurs only in the existence of an RAR agonist [27].…”

“…Conflicting results have been documented regarding the role of RXR in ligand binding and transactivation as a heterodimeric partner of VDR. It has been demonstrated that RXR is silent in the RXR/VDR heterodimers on binding to the DR3 (direct repeats spaced by 3 nucleotides) response element [25]. However, additive or synergistic transcriptional activation has been observed when RXR/VDR heterodimers bind to particular response elements (osteopontin vitamin D response element and DR3) in different cells (human breast cancer cell line MCF-7 and Drosophila SL-3 cells) [30], suggesting that the role of RXR in VDR-mediated transactivation is gene-and cell line-specific.…”

Functional specificity of the two retinoic acid receptor RAR and RXR families in myogenesis

“…Thereby, the di erent responsiveness to RA of the two types of dominant-negative C2 cell transfectants may involve other RXR partners. Possible candidates for such a partnership could be the orphan receptors, LXR (Willy et al, 1995) and NGF1-B-Nur77 or the closely related receptor NURR1 (Forman et al, 1995;Perlmann and Jansson, 1995), which can heterodimerize with RXRs and confer RXR-speci®c ligand activation of transcription. It is thus conceivable that the RA treatment of C2 cells may activate such RXRdependent pathway.…”

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

“…Nuclear Nur77 binds to specific response elements, NBRE and NurRE, either as a monomer or homodimer (Wilson et al, 1991;Philips et al, 1997). In addition, Nur77 regulates transcriptional responses to retinoids by heterodimerizing with orphan nuclear receptor COUP-TF (Wu et al, 1997b) and retinoid X receptor (RXR) (Forman et al, 1995;Perlmann and Jansson, 1995;Wu et al, 1997a).…”