N-myc Downstream-regulated Gene 2, a Novel Estrogen-targeted Gene, Is Involved in the Regulation of Na+/K+-ATPase

• DOI: 10.1074/jbc.m111.247825
• Publication Date: 2011-07-20T01:42:23Z
• Authors: Yan Li; Jiandong Yang; Shaoqing Li; Jian Zhang; Jin Zheng; Wugang Hou; Huadong Zhao; Yanyan Guo; Xinping Liu; Kefeng Dou; Zhenqiang Situ; Libo Yao
• Keywords: 0303 health sciences; Ion Transport; Estradiol; Transcription, Genetic; Tumor Suppressor Proteins; Sodium; Estrogens; Up-Regulation; 03 medical and health sciences; Estrogen Receptor beta; Homeostasis; Humans; Sodium-Potassium-Exchanging ATPase; HeLa Cells

Na(+)/K(+)-ATPase, a plasma membrane protein abundantly expressed in epithelial tissues, has been identified and linked to numerous biological events, including ion transport and reabsorption. In Na(+)/K(+)-ATPase, the β-subunit plays a fundamental role in the structural integrity and functional maturation of holoenzyme. Estrogens are important circulating hormones that can regulate Na(+)/K(+)-ATPase abundance and activity; however, the specific molecules participating in this process are largely unknown. Here, we characterize that N-myc downstream-regulated gene 2 (NDRG2) is an estrogen up-regulated gene. 17β-Estradiol binds with estrogen receptor β but not estrogen receptor α to up-regulate NDRG2 expression via transcriptional activation. We also find that NDRG2 interacts with the β1-subunit of Na(+)/K(+)-ATPase and stabilizes the β1-subunit by inhibiting its ubiquitination and degradation. NDRG2-induced prolongation of the β1-subunit protein half-life is accompanied by a similar increase in Na(+)/K(+)-ATPase-mediated Na(+) transport and Na(+) current in epithelial cells. In addition, NDRG2 silencing largely attenuates the accumulation of β1-subunit regulated by 17β-estradiol. Our results demonstrate that estrogen/NDRG2/Na(+)/K(+)-ATPase β1 pathway is important in promoting Na(+)/K(+)-ATPase activity and suggest this novel pathway might have substantial roles in ion transport, fluid balance, and homeostasis.