Progesterone is primary regulator of Cdk2ap1 gene expression and tissue-specific expression in the uterus

Proliferation of endometrial cells is a prerequisite step for functional differentiation in the uterus. A tumor suppressor gene, Cyclin-dependent kinase 2-associated protein 1 (Cdk2ap1) mRNA was detected in the pregnant uterus and was suggested to be involved in cell proliferation. However, its roles and the mechanisms regulating its expression are largely unknown. In this study, the role of steroid hormones in the expression of Cdk2ap1 was examined using RT-PCR, Northern blotting and in situ hybridization methods. Cdk2ap1 mRNA was highly expressed during the proestrus phase and was mainly localized in the epithelium and subepithelium. Its expression was induced by a single injection of estradiol and progesterone, but the effect of progesterone was stronger than that of estradiol. Injections of progesterone (P1,2) on 2 consecutive days induced Cdk2ap1 expression in the endometrium with the same patterns observed in the proestrus phase, but injections of estradiol (E1,2) on 2 consecutive days did not induce expression. The Cdk2ap1 mRNA level was decreased by combined treatment of progesterone and estradiol (E1+P2,3). RU486 suppressed completely the Cdk2ap1 mRNA expression in P1,2 while ICI 182,780 did not in E1+P2,3. In the uteri on day 4 of gestation, expression of Cdk2ap1 also was regulated by progesterone as expected. Cdk2ap1 mRNA expression was totally suppressed by RU486 but not by ICI 182,780. Thus, it is suggested that Cdk2ap1 expression is primarily regulated by progesterone and the progesterone receptor in uterus and is mainly localized to proliferating tissues.