Progesterone and DNA Damage Encourage Uterine Cell Proliferation and Decidualization through Up-regulating Ribonucleotide Reductase 2 Expression during Early Pregnancy in Mice

Abstract

Background: Ribonucleotide reductase M2 (RRM2) is a rate-limiting step for DNA synthesis. It is still unknown how RRM2 is involved in decidualization. Results: RRM2 is highly expressed in the decidua and up-regulated by progesterone and DNA damage. Decidualization is significantly inhibited by specific RRM2 inhibitors. Conclusion: RRM2 is essential for mouse decidualization. Significance: This study will shed light on understanding the mechanism underlying decidualization.

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization

“…32 p-H2A.X, a representative marker of DNA damage, 33 was highly expressed at implantation sites during decidualization compared to inter-implantation sites (Fig. 11E).…”

“…Dtprp is a marker for mouse decidualization. 33 Knockdown of E2f8 failed to reveal any significant effects on Dtprp level under normal in vitro decidualization. However, for stress-treated stromal cells, knockdown of E2f8 led to a reduced expression of Dtprp (Fig.…”

“…Paraquat and CPT were used to induce oxidative stress and DNA damage, respectively. 32,33 Immunofluorescence images showed that a part of the stromal cells switched to polyploidy under the stress conditions even without the induction of decidualization. However, knockdown of E2f8 inhibited the polyploidization of these stress-induced cells (Fig.…”

“…11E). UV irradiation and Camptothecin (CPT, the topoisomerase I inhibitor) were used to induce DNA damage in stromal cells, 33 E2F8 expression was up-regulated by CPT or UV irradiation (Fig. 11F-H).…”

Expression, activation, and role of AKT isoforms in the uterus

“…As FoxO1 is of crucial importance in the regulation of progesterone response in endometrial cells , Kajihara et al 2013, it is plausible that the modulation of AKT activity is of crucial importance in the establishment of decidualization. AKT is further involved in the decidual cell response to progesterone by stimulating the expression of RRM2, a rate-limiting enzyme in the deoxynucleotide production for DNA synthesis, which could induce the characteristic cell proliferation found during mice decidualization (Lei et al 2012). However, the specific mechanisms by which each AKT isoform acts in the process of decidualization remain yet to be elucidated.…”