Background: 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.
Experimental design: 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.
Results: 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.
Conclusions: 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.