Giannini G, Dawson M I, Zhang X, Thiele C J
Cell and Molecular Biology Section, Pediatric Oncology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892-1928, USA.
J Biol Chem. 1997 Oct 17;272(42):26693-701. doi: 10.1074/jbc.272.42.26693.
Naturally occurring retinoids, like all-trans retinoic acid and 9-cis retinoic acid, are known to affect proliferation and differentiation of sensitive neuroblastoma cell lines. Cellular responsiveness to retinoic acid depends on its interaction with two distinct classes of receptors, the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs). Both receptor classes have three different subtypes (RARalpha, RARbeta, and RARgamma and RXRalpha, RARbeta, and RARgamma) that act as ligand-dependent transcription factors. To examine the involvement of the different receptor classes and subtypes in the biological responses of neuroblastoma cells to retinoids, we analyzed the effects of a panel of receptor-selective retinoids on cell growth, differentiation, and gene expression on in vitro cultured KCNR cells. Any association of per se inactive RXR-selective with RAR-selective ligands efficiently regulates growth inhibition, differentiation (neurite extension), and expression of RARbeta, TrkB, and N-myc. SR11383 alone, a very potent retinoid, entirely reproduces the pattern of biological responses induced by naturally occurring retinoids. In contrast to other tumor cell lines, the growth of neuroblastoma cell lines is not altered using AP1-antagonistic retinoids. These studies raise the possibility that three distinct RXR/RAR heterodimers mediate the effects of retinoids on neuroblastoma cells through an AP-1 antagonism-independent mechanism.
天然存在的类视黄醇，如全反式维甲酸和9-顺式维甲酸，已知会影响敏感神经母细胞瘤细胞系的增殖和分化。细胞对视黄酸的反应性取决于它与两类不同受体的相互作用，即维甲酸受体（RARs）和维甲酸X受体（RXRs）。这两类受体都有三种不同的亚型（RARα、RARβ和RARγ以及RXRα、RXRβ和RXRγ），它们作为配体依赖性转录因子发挥作用。为了研究不同受体类别和亚型在神经母细胞瘤细胞对类视黄醇的生物学反应中的作用，我们分析了一组受体选择性类视黄醇对体外培养的KCNR细胞的细胞生长、分化和基因表达的影响。本身无活性的RXR选择性配体与RAR选择性配体的任何联合都能有效调节生长抑制、分化（神经突延伸）以及RARβ、TrkB和N-myc的表达。单独使用SR11383，一种非常有效的类视黄醇，能完全重现天然存在的类视黄醇诱导的生物学反应模式。与其他肿瘤细胞系不同，使用AP1拮抗类视黄醇不会改变神经母细胞瘤细胞系的生长。这些研究提出了一种可能性，即三种不同的RXR/RAR异二聚体通过一种不依赖AP-1拮抗的机制介导类视黄醇对神经母细胞瘤细胞的作用。
