{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nResearch in mice has revealed that Nrk—an X‐linked serine/threonine kinase predominantly expressed in the placenta—is essential for proper placental development and for triggering labor. In Nrk‐deficient placentas, the spongiotrophoblast layer exhibits dysregulated overgrowth without corresponding alterations in maternal progesterone or estrogen levels, suggesting the presence of a novel fetoplacental signal that induces labor. These findings support a role for Nrk in coordinating placental signals required for the timely onset of parturition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn studies on trophoblast cells derived from murine embryonic stem cells, Nrk has been shown to regulate cell proliferation. Disruption of Nrk results in enhanced proliferation of differentiated trophoblasts that correlates with upregulated AKT phosphorylation at Ser473. Inhibition of this phosphorylation rescues the proliferative phenotype, indicating that Nrk normally acts to modulate AKT activity and thus ensure balanced trophoblast growth during placental development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther investigations have demonstrated that Nrk also plays a critical role in the mammary gland during pregnancy. Normally, Nrk expression contributes to suppressing estrogen-dependent proliferation of mammary epithelial cells during the late gestation period. However, Nrk mutant mice exhibit sustained expression of estrogen receptor α and elevated blood estrogen levels, leading to mammary hyperplasia and the development of noninvasive tubular adenocarcinomas in parous females. This indicates that Nrk is an important negative regulator of mammary epithelial proliferation during pregnancy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kimitoshi Denda, Kanako Nakao-Wakabayashi, Naoki Okamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nrk, an X-linked protein kinase in the germinal center kinase family, is required for placental development and fetoplacental induction of labor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.258160"}], "href": "https://doi.org/10.1074/jbc.M111.258160"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21715335"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21715335"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kimitoshi Denda, Kanako Ida, Masataka Tanno, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proteomic analysis of Nrk gene-disrupted placental tissue cells explains physiological significance of NRK."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Res Notes (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13104-019-4818-7"}], "href": "https://doi.org/10.1186/s13104-019-4818-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31783915"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31783915"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yuka Morioka, Jin-Min Nam, Takashi Ohashi "}, {"type": "b", "children": [{"type": "t", "text": "Nik-related kinase regulates trophoblast proliferation and placental development by modulating AKT phosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0171503"}], "href": "https://doi.org/10.1371/journal.pone.0171503"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28152035"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28152035"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Takayo Yanagawa, Kimitoshi Denda, Takuya Inatani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency of X-Linked Protein Kinase Nrk during Pregnancy Triggers Breast Tumor in Mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajpath.2016.06.005"}], "href": "https://doi.org/10.1016/j.ajpath.2016.06.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27634343"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27634343"}]}]}]}