2 DISTINCT ACTIONS OF RETINOID-RECEPTOR LIGANDS

SIGNALLING by all-trans retinoic acid is mediated through RXR-RAR reti noid receptor heterodimers(1,2), in which RXR has been considered to a ct as a transcriptionally silent partner(3-5), However, we show here t hat in cultured NB4 (ref. 6) human acute promyelocytic leukaemia(7-9) cells treated with either an RAR-alpha-selective agonist alone, or cer tain RAR-alpha antagonists in combination with an RXR agonist, recepto r-DNA binding is induced in vivo, resulting in expression of the targe t genes of retinoic acid as well as acute promyelocytic leukaemia prot ein (PML) relocation to nuclear bodies(10-12) and differentiation befo re apoptosis, These results indicate that RAR-alpha ligands can induce two separate events: one enables RXR-RAR-alpha heterodimers to bind t o DNA in vivo and allows RXR agonists to act; the other induces transc riptional activity of RAR-alpha. The availability of receptor-specific synthetic retinoids that can induce distinct receptor functions has p otential in extending the therapeutic repertoire of retinoids.