Retinoic acid receptors (RARs) and
retinoid X receptors (RXRs) mediate the effects of
retinoids on gene expression by binding to response elements in
retinoid-sensitive genes. RAR- but not RXR-selective
retinoids were found in many previous studies to suppress the growth of various cells, implicating RXR-RAR in these effects. Using a co-expression vector for identifying cells that expressed
retinoid receptors transiently and 5'-bromo-2'-deoxyuridine incorporation for labeling
DNA-synthesizing cells, we found that RXR-selective
retinoids inhibited
DNA synthesis in
squamous carcinoma 1483 cells transfected with RXRalpha but not with RARs.
Ligand-induced transcription of the reporter
luciferase gene via the activation of RXR-RXR but not RXR-RAR correlated with growth suppression. Studies with RXRalpha deletion mutants indicated that the
DNA binding and the
ligand binding domains are essential for mediating growth inhibition. A point mutation in the
ligand binding domain (L430F) that decreased RXRalpha homodimerization compromised its growth inhibitory function. Further, RXRalpha mutant (F313A), which functions as a constitutively active receptor, inhibited
DNA synthesis in the absence of
ligand. These results demonstrate that RXR homodimer activation leads to growth inhibition and suggest that transfection of RXRalpha and treatment with RXR-selective
retinoids or the transfection of constitutively activated RXRalpha mutant alone may have a therapeutic potential.