Figure 1. Retinoid X receptor-α (RXRα) intranuclear localization is a critical factor in retinoid responsiveness. RXRα localizes throughout the nucleoplasm in retinoid-sensitive normal cells and MCF-7 cells of low malignancy. In contrast, RXRα is sequestered in the splicing factor compartment (SFC) and silenced in MDA-MB-231 cells; consequently, retinoid signaling is shut off in these cells. To reverse the lack of responsiveness to retinoid, which itself is attributable to the sequestration of RXRα, two separate approaches were taken. RXRα C-terminus–specific peptide to MDA-MB-231 cells facilitated redistribution of RXRa throughout the nucleus, increasing RXR-homodimer–mediated transactivation upon RXR-ligand treatment. Also, nucleoplasmic overexpression of RXRα in MDA-MB-231 cells infected with RXRα adenovirus resulted in apoptosis in accordance with increased p21 and decreased Bcl-2 expression, restoring the retinoid sensitivity. RA, retinoids; RXRE and RARE, response elements.