Dual transcriptional activities underlie opposing effects of retinoic acid on cell survival

Transcriptional activation of the nuclear receptor RAR by retinoic acid (RA) often leads to inhibition of cell growth. However, in some tissues, RA promotes cell survival and hyperplasia, activities that are unlikely to be mediated by RAR. Here we show that, in addition to functioning through RAR, RA activates the ‘orphan’ nuclear receptor PPARβ/δ, which, in turn, induces the expression of pro-survival genes. Partitioning of RA between the two receptors is regulated by the intracellular lipid-binding proteins CRABP-II and FABP5. These proteins specifically deliver RA from the cytosol to nuclear RAR and PPARβ/δ, respectively, thereby selectively enhancing the transcriptional activity of their cognate receptors. Consequently, RA functions through RAR and is a pro-apoptotic agent in cells with high CRABP-II/FABP5 ratio, but it signals through PPARβ/δ and promotes survival in cells that highly express FABP5. Opposing effects of RA on cell growth thus emanate from alternate activation of two different nuclear receptors.