Wan Y J, Wang L, Wu T C
Department of Pathology, Harbor-UCLA Medical Center, Torrance.
Lab Invest. 1994 Apr;70(4):547-52.
Glucocorticoids and retinoic acid (RA) exert their effects through nuclear receptors; trans-acting factors that regulate the expression of target genes. Both glucocorticoids and retinoic acid have been shown to control hepatocyte phenotype to regulate expression of many liver specific genes such as alpha-fetoprotein and albumin. Two classes of receptors for retinoic acid have been identified, retinoic acid receptor and retinoic x receptor (RXR). RXRs, the receptors for 9-cis-RA (c-RA), are auxiliary factors that form heterodimers with retinoic acid receptors, vitamin D receptors, and thyroid hormone receptors and enhance the binding of the receptors to their cognate responsive elements. Thus, the level of RXR may be a crucial parameter to determine the effects of other hormones.
The current study was designed to analyze the regulation of RXR gene expression by other hormones in hepatoma cells. The effects of c-RA, all-trans-RA, 3,3',5-Triiodo-L-Thyronine, estrogen, and dexamethasone on RXR genes were examined. The expression levels of RXR mRNAs were quantitated by northern hybridization.
Dexamethasone, a crucial agent for hepatocyte differentiation, is the only hormone that up-regulates the levels of liver specific RXR alpha mRNA in three phenotypically different rat hepatoma cell lines. In addition, dexamethasone enhances the expression of RXR gamma mRNA in two cell lines but has no effect on RXR beta gene in any cell line. The regulation of RXR alpha gene is time- and dose-dependent and can be blocked by actinomycin D. However, cycloheximide has no effect on the dexamethasone induced RXR alpha gene expression.
This study demonstrates that dexamethasone enhances the expression of RXR alpha gene probably by increasing the transcription of RXR gene and that glucocorticoids may enhance the differentiation effects of c-RA by increasing the levels of the RXRs in hepatoma cells.
糖皮质激素和视黄酸（RA）通过核受体发挥作用；核受体是调节靶基因表达的反式作用因子。糖皮质激素和视黄酸均已被证明可控制肝细胞表型，以调节许多肝脏特异性基因如甲胎蛋白和白蛋白的表达。已鉴定出两类视黄酸受体，即视黄酸受体和视黄酸X受体（RXR）。RXR是9-顺式视黄酸（c-RA）的受体，是与视黄酸受体、维生素D受体和甲状腺激素受体形成异二聚体并增强这些受体与其同源反应元件结合的辅助因子。因此，RXR的水平可能是决定其他激素作用的关键参数。
本研究旨在分析肝癌细胞中其他激素对RXR基因表达的调节作用。检测了c-RA、全反式视黄酸、3,3',5-三碘-L-甲状腺原氨酸、雌激素和地塞米松对RXR基因的影响。通过Northern杂交定量RXR mRNA的表达水平。
地塞米松是肝细胞分化的关键因子，是唯一能上调三种表型不同的大鼠肝癌细胞系中肝脏特异性RXRα mRNA水平的激素。此外，地塞米松可增强两种细胞系中RXRγ mRNA的表达，但对任何细胞系中的RXRβ基因均无影响。RXRα基因的调节具有时间和剂量依赖性，且可被放线菌素D阻断。然而，环己酰亚胺对地塞米松诱导的RXRα基因表达无影响。
本研究表明，地塞米松可能通过增加RXR基因的转录来增强RXRα基因的表达，并且糖皮质激素可能通过增加肝癌细胞中RXR的水平来增强c-RA的分化作用。
