Retinoid signaling regulates Pregnancy Specific Glycoprotein gene transcription through a functional Retinoic Acid Responsive Element.

LOPEZ-DIAZ F; PANZETTA-DUTARI G; PATRITO L; BOCCO JL

City of Hope. Duarte – California. USA

Simposio; The 17th International CEA Symposium; 2007

Beckman Research Institute

Human pregnancy-specific glycoproteins (PSG) are major placental polypeptides encoded by eleven highly conserved genes expressed by the syncytiotrophoblast.  The minimal promoter region of all PSG genes contains a putative Retinoic Acid Responsive Element (RARE) though the ability of retinoids to regulate PSG gene expression has not been established.  Retinoid signaling pathway plays a key role for overall placenta biology and is essential for trophoblast differentiation.  In this work, we investigated the participation of the RARE motif in the regulation of PSG5 gene transcription by retinoic acid and its receptors.  The minimal promoter region of PSG5 gene was activated by RXRa but not by RARa, in a ligand-dependent manner. The RARE sequence of PSG5 gene promoter was recognized by endogenous RXRa present in placental nuclear extracts as well as by RXRa either over expressed in cultured non-placental cells or in vitro translated. Mutations at specific nucleotides within the RARE motif abrogated both RXRa DNA binding and transcriptional activation of PSG5 promoter mediated by RXRa. Moreover, endogenous PSG expression was significantly induced in trophoblast-derived Jeg-3 cells upon 9-cis retinoic acid treatment.  Interestingly, the induction level was higher following methotrexate-induced differentiation of Jeg-3 cells to syncytiotrophoblast-like structures. Altogether, these data provide the first evidences demonstrating that transcriptional activity of PSG5 gene is responsive to an external signal involving the retinoids-RXRa axis through a conserved RARE motif shared by all PSG gene family members.