The hormone and vitamin A metabolite retinoic acid (RA) is best known for its actions promoting cell differentiation, arrest of the cell division cycle, or apoptosis, and it has even been proposed as an anticancer agent. These effects are mediated by the nuclear hormone receptor known as the retinoic acid receptor (RAR). But, in some tissues, RA can promote cell survival and even enhance formation of tumors, for example, in the skin. Shug et al. propose that these nearly opposite effects of RA can be explained by its association with and activation of another nuclear receptor called PPARβ (or, alternatively, PPARδ). Their experiments monitoring transcription in cultured cells confirmed that RA could act through both RAR and PPARβ. Furthermore, the choice of which receptor RA activates appeared to be dictated by a set of proteins that work with the receptors, carrying ligands from the cytosol to the nucleus where they pass them off to nuclear receptors. The proteins CRABP-II (cellular retinoic acid-binding protein II) and FABP5 (fatty acid-binding protein 5, also sometimes called K-FABP, eFABP, or mal1) work selectively with RAR or PPARβ, respectively. The authors showed that altering the ratio of these binding proteins in a cell (with RNAi or overexpression in transfected cells) determined which receptor was primarily engaged by RA and, thus, what the ultimate biological effect would be. When amounts of CRABP-II were high, RA acted primarily through RAR in cultured keratinocytes and promoted apoptosis. But if FABP5 was more abundant, RA acted through PPARβ and favored cell survival. Thus, the authors propose that in most cells, high affinity interactions of RA with CRABP-II and RAR [with Kds (dissociation constants) of about 0.1nM] predominate, but in certain cell types, PPARβ and FABP5 (which bind RA with Kds of 10 to 50 nM) are sufficiently abundant to take over and produce the "nontraditional" proliferative effects of the hormone.
T. T. Schug, D. C. Berry, N. S. Shaw, S. N. Travis, N. Noy, Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 129, 723-733 (2007). [Online Journal]