Inhibitory mechanism of cell proliferation by a novel X-linked tumor suppressor Nrk

1)我们在胎盘中发现了在Akt信号转导通路中抑制PTEN的细胞衰老抑制基因CSIG是一种NRK结合蛋白，提示NRK通过抑制Akt信号通路抑制胎盘海绵状滋养层细胞的增殖。我们还发现，在NRK基因敲除的海绵状滋养细胞中，细胞周期抑制蛋白p27的水平下调，这表明NRK上调了海绵状滋养细胞中p27基因的表达或抑制了p27蛋白的降解。2)我们发现携带NRK基因敲除的雌性小鼠血液和卵巢中的雌激素水平升高，这表明血液中的高雌激素水平导致了NRK基因敲除小鼠的乳腺肿瘤。此外，我们发现NRK在哺乳期和老年(~12个月)野生型小鼠中都有表达，这表明NRK通过下调卵巢中雌激素的合成来抑制乳腺上皮细胞的过度生长。

1) We identified CSIG (cellular senescence-inhibited gene), a protein which inhibits PTEN in the Akt signal transduction pathway, as a Nrk-binding protein in placenta, suggesting that Nrk inhibits the proliferation of spongiotrophoblasts in placenta by inhibiting the Akt signaling pathway. We also found that the level of a cell cycle inhibitor protein p27 is downregulated in Nrk knockout spongiotrophoblasts, suggesting that Nrk increases p27 gene expression or inhibits p27 protein degradation in spongiotrophoblasts.2) We found that the estrogen level is elevated in the blood and ovary of mammary tumor-harboring Nrk knockout female mice, suggesting that the high estrogen level in the blood causes mammary tumors in Nrk knockout mice. In addition, we found that Nrk is expressed in lactating and old (~12 months) wild-type mice, suggesting that Nrk suppresses the overgrowth of mammary epithelial cells by downregulating estrogen synthesis in the ovary.