Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid

Abstract

Retinoid response pathways are mediated by two classes of receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). A central question is whether distinct response pathways are regulated by these two classes of receptors. The observation that the stereoisomer 9-cis-retinoic acid binds with high affinity to RXRs suggested that this retinoid has a distinct role in controlling RXR activity, but it was almost simultaneously discovered that RXRs function as auxiliary receptors for RARs and related receptors, and are essential for DNA binding and function of those receptors. Hence, although RARs seem to operate effectively only as heterodimeric RAR/RXR complexes, RXRs themselves apparently function predominantly, if not exclusively, as auxiliary receptors. Here we report that 9-cis-retinoic acid induces RXR homodimer formation. Our results demonstrate a new mechanism for retinoid action by which a ligand-induced homodimer mediates a distinct retinoid response pathway.

Retinoid-suppressed phosphorylation of RARα mediates the differentiation pathway of osteosarcoma cells

“…By overexpressing RARa and phosphorylation-defective RARaS77A in parallel in either RARa mutant or RARaÀ/À cells, we along with others have found that RARaS77A, but not RARa, inhibits proliferation and induces differentiation in either normal or cancer cells (Taneja et al, 1997;Rochette-Egly et al, 2000;Crowe and Kim, 2002;Luo et al, 2007;Wang et al, 2009). RA-bound RARs and/or RXRs function as transcription factors to induce transactivation by modulating protein-DNA interactions at the RA responsive element (RARE) in the promoters of target genes (Mangelsdorf et al, 1991;Zhang et al, 1992;Chambon, 1996), although the underlying mechanisms remain to be dissected.…”

Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.

“…While retinoid-dependent transactivation by RXR is mediated in part by RXR homodimers (66), RXR is also able to form heterodimers with TR and VDR (7,18,36,37,46,48,64,65). In each case, target gene binding by the nuclear hormone receptor is greatly enhanced by its partnership with RXR.…”

“…First, we performed transient transfections in JEG-3 cells, which express low levels of endogenous RARs. A CAT reporter gene containing the palindromic (inverted repeat) element TREp, which can be activated by both RARs and RXRs (47,66), was used. Figure 2A shows that as expected, RA and 9-cis RA activated transcription by both RARs and RXRs (38,44,47,66).…”

“…A CAT reporter gene containing the palindromic (inverted repeat) element TREp, which can be activated by both RARs and RXRs (47,66), was used. Figure 2A shows that as expected, RA and 9-cis RA activated transcription by both RARs and RXRs (38,44,47,66). However, SR11237 selectively activated RXRot-dependent transcription -22-fold over the control (vehicle alone) level, and RXR-y mRNAs were barely detectable in JEG-3 cells by Northern analysis (data not shown).…”

Retinoids induce Fas(CD95) ligand cell surface expression via RARγ and nur77 in T cells

“…In the presence of RA, retinoid receptors can function in the form of either RAR-RXR heterodimers or RXR-RXR homodimers [10]. In addition, RXR can form heterodimers with various other members of the steroid/thyroid/retinoid receptor family, including nur77 [11].…”