Steroid Hormone Regulation of PIK3IP1, a Known Suppressor of PI3K Induced Cell Division and Survival, in the Mouse Uterus
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The ovarian steroid hormones, estrogen and progesterone, are essential regulators of uterine functions necessary for development, embryo implantation, and normal pregnancy. AT-rich interaction domain 1A protein (ARIDIA) plays an important role in steroid hormone signaling in endometrial function and pregnancy. Reduction of ARIDIA is seen in women with endometriosis, a disease in which endometrial tissue is found outside of the uterus. The exact mechanism behind this disease remains unclear. Phosphatidylinositol-3-kinase interacting protein 1(Pik3ipl) a known negative regulator ofPI3K induced cell division and survival, has been identified as a direct downstream target ofARID1A,making it a gene of interest in investigating this pathway. In the present study we aim to show PIK3IP1 is a target of ARIDIA, the progesterone receptor (PGR), is regulated by ovarian steroid hormones, and evaluate PIK3IP1 expression during mouse early pregnancy. In order to analyze our hypotheses we performed real-time RT-PCR and immunohistochemistry. To mimic endometriosis within a mouse model, mice were utilized with conditional ablation of Aridla, knocking out its expression within only the uterus. Results revealed strong expression of PIK3IP1 within wild type mice, however expression was reduced within mice with conditional ablation of Aridla. Next, progesterone receptor knockout mice (PRKO) were used in order to analyze PGR's regulation ofPIK3IP1, revealing reduced PIK3IP1 expression within stromal cells of the PRKO mouse uterus. PIK3IP1 expression was tightly regulated during early pregnancy, showing strongest expression 2.5 days after establishment of pregnancy. There was an increase in PIK3IP1 expression after progesterone and estrogen treatments, indicating PIK3IP1 is regulated by steroid hormones. Our results allow us to identify PIK3IP1 as a novel target of ARIDIA and PGR in the murine uterus. These results provide insight into a new protein of interest, specifically in regard to uterine disease mechanisms, such as that of endometriosis.