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J Cell Mol Med. 2010 Jun;14(6B):1793-805. doi: 10.1111/j.1582-4934.2009.00802.x. Epub 2009 Jun 16.

Retinoids regulate human amniotic tissue-type plasminogen activator gene by a two-step mechanism.

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  • 1Génétique Reproduction et Développement (GReD), UMR CNRS 6247, Clermont Université, INSERM U931, Faculté de Médecine, Clermont-Ferrand, France.


The collagenolytic effects of the tissue-type plasminogen activator (t-PA) leading to extracellular matrix degradation are clearly involved in the physiopathology of human foetal membranes rupture. Nevertheless, the regulation of t-PA gene expression in extraembryonic developmental contexts remains unknown. The aim of our study is to propose the retinoic acids (RAs) as molecular regulators of t-PA expression in foetal membranes. RA induced t-PA mRNA and proteins in a time-dependent manner in amniotic membrane explants and Wistar Institute Susan Hayflick (WISH) cells. Furthermore, the use of cycloheximide revealed a two-step regulation of t-PA gene. Gene reporter assays confirmed that the RA-induced t-PA gene expression occurred through interactions of retinoid receptors (RARs and RXRs) with a DR5 response element located at -7 kb from the transcription site. Site-directed mutagenesis of this region of the t-PA promoter showed that SP1 factor was also retinoid-mediated induction, and immunoprecipitation assays revealed that SP1 and RAR/RXR interacted physically. Chromatin immunoprecipitation demonstrated that interactions between RARs, RXRs and t-PA promoter were time dependent: RAR-alpha/RXR-alpha bound DR5 motif before and up to 12 hrs of RA exposure, and RAR-beta/RXR-alpha bound DR5 response element after 12 hrs of RA treatment. Finally, experiments using shRNA and RAR-beta-specific antagonist revealed that reducing RAR-beta induction decreased t-PA induction. Altogether, our results established that the RA-mediated regulation of t-PA in human foetal membranes occurred through two steps, with a major role played by RAR-beta.

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