Progesterone and cAMP synergistically induce SHP2 expression via PGR and CREB1 during uterine stromal decidualization.

Decidualization of endometrial stroma is a key step in embryo implantation and its abnormality often leads to pregnancy failure. Stromal decidualization is a very complex process that is co-regulated by estrogen, progesterone, and many local factors. Our previous study found that the signaling protein SHP2 encoded by PTPN11 is dynamically expressed in decidualized endometrial stroma and mediates and integrates various signals to govern the decidualization. Here, we further investigate the mechanism of the PTPN11 gene transcription. Estrogen, progesterone, and cyclic AMP (cAMP) co-induced decidualization of human endometrial stromal cell (hESC) in vitro, but only progesterone and cAMP induced SHP2 expression. Using the luciferase reporter, we refined a region from -229bp to +1bp in the PTPN11 gene promoter is the transcriptional core regions that responded to progesterone and cAMP. Then, Progesterone receptor (PGR) and Cyclic AMP-Responsive Element-Binding Protein 1 (CREB1) were predicted to be transcription factors in this core region by bioinformatic methods. The direct binding of PGR and CREB1 on the PTPN11 promoter was confirmed by electrophoretic mobility (EMSA) and chromatin immunoprecipitation (ChIP) in vitro. Furthermore, the knockdown of PGR and CREB1 protein significantly inhibited the expression of SHP2 induced by MPA and cAMP. These results demonstrated that transcription factors PGR and CREB1 bind to the PTPN11 promoter to regulate the expression of SHP2 responded decidual signals. Our results explained the transcriptional expression mechanism of SHP2 during decidualization and promoted the understanding of the mechanism of decidualization of stromal cells.