title: Progesterone and DNA damage encourage uterine cell proliferation and decidualization through up-regulating ribonucleotide reductase 2 expression during early pregnancy in mice.
abstract: Embryo implantation into the maternal uterus is a crucial step for the successful establishment of mammalian pregnancy. Following the attachment of embryo to the uterine luminal epithelium, uterine stromal cells undergo steroid hormone-dependent decidualization, which is characterized by stromal cell proliferation and differentiation. The mechanisms underlying steroid hormone-induced stromal cell proliferation and differentiation during decidualization are still poorly understood. Ribonucleotide reductase, consisting of two subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and plays an important role in cell proliferation and tumorgenicity. Based on our microarray analysis, Rrm2 expression was significantly higher at implantation sites compared with interimplantation sites in mouse uterus. However, the expression, regulation, and function of RRM2 in mouse uterus during embryo implantation and decidualization are still unknown. Here we show that although both RRM1 and RRM2 expression are markedly induced in mouse uterine stromal cells undergoing decidualization, only RRM2 is regulated by progesterone, a key regulator of decidualization. Further studies showed that the induction of progesterone on RRM2 expression in stromal cells is mediated by the AKT/c-MYC pathway. RRM2 can also be induced by replication stress and DNA damage during decidualization through the ATR/ATM-CHK1-E2F1 pathway. The weight of implantation sites and deciduoma was effectively reduced by specific inhibitors for RRM2. The expression of decidual/trophoblast prolactin-related protein (Dtprp), a reliable marker for decidualization in mice, was significantly reduced in deciduoma and steroid-induced decidual cells after HU treatment. Therefore, RRM2 may be an important effector of progesterone signaling to induce cell proliferation and decidualization in mouse uterus.
authors.affiliation: Department of Biology, Shantou University, Shantou 515063, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lei
authors.forename: Xu-Hui
authors.initials: XH
authors.lastname: Feng
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Deng
authors.forename: Hua
authors.initials: H
authors.lastname: Ni
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Jia
authors.forename: Xin-Ling
authors.initials: XL
authors.lastname: Yang
authors.forename: Tong-Song
authors.initials: TS
authors.lastname: Wang
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Liu
authors.forename: Ren-Wei
authors.initials: RW
authors.lastname: Su
authors.forename: Xiao-Huan
authors.initials: XH
authors.lastname: Liang
authors.forename: Qian-Rong
authors.initials: QR
authors.lastname: Qi
authors.forename: Zeng-Ming
authors.initials: ZM
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004249:DNA Damage; D003656:Decidua / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D010064:Embryo Implantation / Q000187:drug effects / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006918:Hydroxyurea / Q000494:pharmacology; D008297:Male; D051379:Mice; D010052:Ovariectomy; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics* / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014599:Uterus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011374:Progesterone; D012264:Ribonucleotide Reductases; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; C498690:Rrm1 protein, mouse; D006918:Hydroxyurea