| Abstrakt: |
Cellular responsiveness to retinoic acid and its metabolites is conferred through two distinct families of receptors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Herein, we report on the identification and characterization of several conformationally restricted retinoids, which selectively bind and activate RX receptors. Under the influence of retinoids, HL-60 myelocytic leukemia cells differentiate into granulocytes. This effect is mediated by RARα, as has been demonstrated through the use of a selective RARα antagonist (Apfel, C., Bauer, F., Crettaz, M., Forni, L., Kamber, M., Kaufmann, F., LeMotte, P., Pirson, W., and Klaus, M.(1992) Proc. Natl. Acad. Sci. U. S. A.89, 7129-7133). Here, we show that conformationally restricted RXR-specific retinoids, at doses that are per seinactive, are able to potentiate by up to one order of magnitude the pro-differentiating effects of all-transretinoic acid and an RARα-selective synthetic retinoid. We also present evidence that these RXR-selective ligands are able to bind to a DNA RXR•RAR heterodimer complex. This finding demonstrates that agonists for RARs and RXRs can synergistically promote HL-60 differentiation, which could be mediated through a heterodimer of these receptors. |
