Molecular Biology

X.-k. Zhang, B. Hoffmann, P.B.V. Tran, G. Graupner, M. Pfahl, "Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors," Nature, 355:441-6, 1992. Magnus Pfahl (La Jolla Cancer Research Foundation, Calif.): "Thyroid hormones as well as the vitamin A-derived hormones (retinoids) influence a myriad of biological processes, including such complex programs as metamorphosis and morphogenesis. Retinoids have also drawn particular attention in recent years because of their effectiveness against a number of skin diseases (including wrinkles) and their potential as anti- cancer and cancer-preventive agents. However, use of retinoids and thyroid hormones as therapeutics has been hampered by undesirable side effects-- which, for instance, in the case of retinoids range all the way from slight skin irritations to malformation in fetuses. Because of the manifold roles of both thyroid and retinoid hormones, and their potential as therapeutics, their mechanism of action has been of particular interest. "A major advance toward understanding this was achieved by the cloning of specific nuclear receptors. The receptors turned out to belong to a large family of transcription factors that also included the steroid hormone receptors. In concert with their multiple biological roles, multiple receptors were found to exist: two thyroid hormone receptors (TRa and TRb) and six retinoid receptors. The retinoid receptors fall into two groups, the retinoic acid receptors (RARa, b, and g) and the retinoid X receptors (RXRa, b, and g). Since these receptors were structurally related to the steroid hormone receptors, it was first believed that they also functioned like those--that is, bind as homodimers to specific DNA sequences (hormone response elements). However, it turned out that TRs and RARs (as well as RXRs) were relatively poor DNA binders but that their binding in vitro could be enhanced by nuclear protein extracts. This indicated that the mechanism of action was more complex and required another protein for efficient DNA recognition. "In our paper we show that RXR is this nuclear factor. Thus, RXR, itself a retinoid receptor that requires 9-cis retinoic acid for activation, can serve as a coreceptor for TRs and RARs, receptors that belong to the same subfamily but are activated by very different hormones. An RXR homologue is already found in Drosophila (while TRs and RARs do not exist in insects) and has now also been shown to function there as the partner for the ecdysone receptor. Not surprisingly, then, its role in higher vertebrates turned out to be very broad, as RXRs were found to heterodimerize with the vitamin D3 receptor (VDR) as well as with the peroxisome proliferator-activated receptors (PPAR). Thus, RXRs play a very central role; by heterodimerizing with several hormone and vitamin receptors, they may in fact allow crosstalk between a variety of hormonal pathways and allow an enormous diversity of transcriptional controls. This may account for the pleiotropic effects of these hormones and vitamins. "Because of RXR's central role, we were also particularly interested in the effect of RXR-specific ligands. Surprisingly, we observed 9-cis RA-induced RXR homodimers that act on a subset of retinoic acid-responsive genes (X.- k. Zhang, et al., Nature, 358:587-91, 1992). Thus, an additional retinoid response pathway exists that is controlled by homodimers. We subsequently were able to design retinoids that are selective for RXR homodimers (J.M. Lehmann, et al., Science, 258:1944-46, 1992). Retinoids that induce RXR homodimers can decrease the RXR availability for heterodimerization, and we have recently observed that, indeed, 9-cis RA- and synthetic RXR-selective retinoids can inhibit the thyroid hormone response (J.M. Lehmann, X.-k. Zhang, G. Graupner, et al., Molecular and Cellular Biology, 13:7698-7707, 1993). "Overall, the discovery that RXR is an essential partner for a number of hormone and vitamin receptors by us (and several other laboratories at essentially the same time) reignited tremendously research in this area. A major challenge for the future will be to harness this knowledge into hormone/vitamin-derived therapeutics with optimal efficacy and minimal side effects. For the retinoids, this seems at last now to be feasible."

Molecular Biology

The Scientist Staff

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