RXR-dependent and RXR-independent transactivation by retinoic acid receptors

The binding affinity of retinoic acid receptors (RARs) to their response elements is strongly enhanced in vitro by the formation of heterodimers with retinoid X receptors (RXRs) suggesting that heterodimerization with RXR may be a prerequisite for a RAR-mediated transcriptional response. We found that in Drosophila SL-3 cells that are devoid of endogenous RARs and RXRs the presence of RAR is sufficient to confer a response to all-trans retinoic acid (RA). The transfection of both RAR and RXR and stimulation with their respective ligands all-trans and 9-cis RA leads to a synergistic response. On point mutations of the RAR beta 2 gene promoter RA response element (RARE) the stimulation by RARs showed distinct differences in the absence and presence of RXR. The same differences in transcriptional activity are observed, if mammalian cells containing endogenous RARs and RXRs are stimulated with all-trans RA only or additionally with 9-cis RA. This establishes an RXR-independent and an RXR-dependent pathway of all-trans RA action in Drosophila SL-3 cells as well as in mammalian cells. The presence or absence of 9-cis RA determines by which of the two pathways a response to all-trans RA is mediated.