Expression of PSG genes is increased upon differentiation of cytotrophoblast to syncytiotrophoblast by an unknown mechanism. Retinoid receptors,RXR a and RAR a ,regulate the differentiation of cytotrophoblast, activating gene transcription mainly by a ligand-induced manner. In addition, they interact with Sp1,enhancing its binding to CACCC-boxes and therefore increasing the Sp1-mediated activation of genes lacking canonical RAREs. Here we show that endogenous PSG expression in trophoblast-derived cells is induced by 9-cis retinoic acid (9cRA).Moreover, RXRa ,RARa  and Testicular Receptor (TR)4 activates the PSG5 promoter, which is recognized through a composite RARE/CACCC motif by RXRa and TR4,thereby confirming the potential role of the RARE. Most importantly, RXR a activates the PSG5 promoter in a ligand-dependent or independent manner at different expression levels. Accordingly, RXRa enhances Sp1 binding to the CACCC-box, but increasing concentrations of RXRa impairs this interaction and the Sp1-mediated activation, independently of its own DNA binding. These results suggests that the RARE/CACCC motif can integrate different regulatory signals,being able of switching from a Sp1-inducible to a retinoid-responsive state, suggesting for the first time, a mechanism explaining how is reached the high expression of PSG genes during trophoblast differentiation.