Chen J Y, Clifford J, Zusi C, Starrett J, Tortolani D, Ostrowski J, Reczek P R, Chambon P, Gronemeyer H
Institut de Génetique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, College de France, Strasbourg, France.
Nature. 1996 Aug 29;382(6594):819-22. doi: 10.1038/382819a0.
Signalling by all-trans retinoic acid is mediated through RXR-RAR retinoid receptor heterodimers, in which RXR has been considered to act as a transcriptionally silent partner. However, we show here that in cultured NB4 (ref. 6) human acute promyelocytic leukaemia cells treated with either an RAR-alpha-selective agonist alone, or certain RAR-alpha antagonists in combination with an RXR agonist, receptor-DNA binding is induced in vivo, resulting in expression of the target genes of retinoic acid as well as acute promyelocytic leukaemia protein (PML) relocation to nuclear bodies and differentiation before apoptosis. These results indicate that RAR-alpha ligands can induce two separate events: one enables RXR-RAR-alpha heterodimers to bind to DNA in vivo and allows RXR agonists to act; the other induces transcriptional activity of RAR-alpha. The availability of receptor-specific synthetic retinoids that can induce distinct receptor functions has potential in extending the therapeutic repertoire of retinoids.
全反式维甲酸的信号传导是通过RXR-RAR类视黄醇受体异二聚体介导的，其中RXR被认为是一个转录沉默伴侣。然而，我们在此表明，在培养的NB4（参考文献6）人急性早幼粒细胞白血病细胞中，单独用RAR-α选择性激动剂处理，或某些RAR-α拮抗剂与RXR激动剂联合处理，可在体内诱导受体与DNA结合，导致维甲酸靶基因表达以及急性早幼粒细胞白血病蛋白（PML）重新定位到核体并在凋亡前分化。这些结果表明，RAR-α配体可诱导两个独立事件：一个使RXR-RAR-α异二聚体在体内与DNA结合并使RXR激动剂发挥作用；另一个诱导RAR-α的转录活性。能够诱导不同受体功能的受体特异性合成类视黄醇的可用性在扩展类视黄醇的治疗范围方面具有潜力。
