RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors.

Abstract

Retinoic acid receptor (RAR), thyroid hormone receptor (T3R) and vitamin D3 receptor (VD3R) differ from steroid hormone receptors in that they bind and transactivate through responsive elements organized as direct rather than inverted repeats. We now show that recombinant RAR and T3R are monomers in solution and cannot form stable homodimeric complexes on their responsive elements. Stable binding of the receptors to their responsive elements requires heterodimerization with a nuclear factor. This auxiliary factor is tightly associated with RAR and T3R in the absence of DNA and co‐purifies with both receptors. As demonstrated by extensive purification, the same auxiliary factor is required for stable DNA binding of RAR as for that of T3R; the factor also facilitates the formation of a stable VD3R‐DNA complex. The auxiliary factor is identical to the retinoid X receptor alpha (RXR alpha) by biochemical and functional criteria. The identification of RXR alpha as a dimerization partner for the RARs, T3Rs and VD3R has important implications as to the function of these receptors and their ligands in development, homeostasis and neoplasia.

Deregulation of NPM and PLZF in a variant t(5;17) case of acute promyelocytic leukemia

“…Recently it has been shown that both PML-RARa and PLZF-RARa silence the transcription of RA responsive genes under physiological concentrations of RA (Grignani et al, 1998;He et al, 1998;Lin et al, 1998). In light of these studies, as well as the fact that RAR/RXR heterodimerization is required for RAR function Bugge et al, 1992;Zhang et al, 1992), it is surprising that PML-RARa/RXRa heterodimers do not appear essential for PML-RARa's e ect on di erentiation (Grignani et al, 1996). Taken together, however, it appears that PML-RARa, PLZF-RARa, and possibly NPM-RARa disrupt wildtype RARa function by sequestering RXRa to co-repressor complexes.…”

Inhibition of ligand induced promoter occupancy in vivo by a dominant negative RXR

“…We have previously shown that in parental P19 EC cells none of these elements are occupied before RA treatment, but occupancy is induced at these elements after RA treatment without requiring new protein synthesis (except for the Inr which exhibits delayed occupancy). Thus, even though unliganded RXR/RAR heterodimers bind to the RARE in vitro (Yu et al 1991;Leid et al 1992;Marks et al 1992;Bugge et al 1992;Kliewer et al 1992), RARE occupancy in this promoter in vivo is ligand dependent (as defined within the constraint of the genomic footprinting method employed here, see the summary figure). Figures 5A and 5B show the results of genomic footprinting analysis performed for a control and 1 C2 clone before and after RA treatment.…”

Neurogenesis in the Fish Retina

“…Genes in this family are activated by small molecule hydrophobic ligands and form homodimers and heterodimers that then interact with specific response elements in regulatory regions of target genes (Applebury et al, 2000;Bugge et al, 1992). This family includes genes encoding the retinoid receptors (RARs and RXRs), thyroid hormone receptors (TRs), and a number of "orphan" receptors for which ligands have not been identified.…”