Chen J Y, Penco S, Ostrowski J, Balaguer P, Pons M, Starrett J E, Reczek P, Chambon P, Gronemeyer H
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.
EMBO J. 1995 Mar 15;14(6):1187-97. doi: 10.1002/j.1460-2075.1995.tb07102.x.
Using retinoic acid receptor (RAR) reporter cells specific for either RAR alpha, beta or gamma, we have identified synthetic retinoids which specifically induce transactivation by RAR beta, while antagonizing RA-induced transactivation by RAR alpha and RAR gamma. Like RA, these synthetic retinoids allow all three RAR types to repress AP1 (c-Jun/c-Fos) activity, demonstrating that the transactivation and transrepression functions of RARs can be dissociated by properly designed ligands. Using AP1 reporter cells, we also show that glucocorticoids or vitamin D3, together with either RA or these 'dissociating' synthetic retinoids, can synergistically repress phorbol ester-induced AP1 activity. RA, but not these 'dissociating' retinoids, induced transcription of an interleukin-6 promoter-based reporter gene transiently transfected into HeLa cells together with RARs. Using Ki-ras-transformed 3T3 cells as a model system, we show that both RA and the 'dissociating' retinoids inhibit anchorage-independent cell proliferation, suggesting that retinoid-induced growth inhibition may be related to AP1 transrepression.
利用对视黄酸受体（RAR）α、β或γ具有特异性的RAR报告基因细胞，我们鉴定出了合成类视黄醇，它们能特异性地诱导RARβ的反式激活，同时拮抗视黄酸（RA）诱导的RARα和RARγ的反式激活。与RA一样，这些合成类视黄醇能使所有三种RAR类型抑制AP1（c-Jun/c-Fos）活性，表明通过合理设计配体可使RAR的反式激活和反式抑制功能分离。利用AP1报告基因细胞，我们还表明糖皮质激素或维生素D3与RA或这些“解离性”合成类视黄醇一起，可协同抑制佛波酯诱导的AP1活性。RA而非这些“解离性”类视黄醇可诱导与RARs一起瞬时转染到HeLa细胞中的基于白细胞介素-6启动子的报告基因的转录。以Ki-ras转化的3T3细胞作为模型系统，我们表明RA和“解离性”类视黄醇均抑制非锚定依赖性细胞增殖，提示类视黄醇诱导的生长抑制可能与AP1反式抑制有关。
