title: N-myc downstream-regulated gene 2, a novel estrogen-targeted gene, is involved in the regulation of Na+/K+-ATPase.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jiandong
authors.initials: J
authors.lastname: Yang
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Zheng
authors.forename: Wugang
authors.initials: W
authors.lastname: Hou
authors.forename: Huadong
authors.initials: H
authors.lastname: Zhao
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Guo
authors.forename: Xinping
authors.initials: X
authors.lastname: Liu
authors.forename: Kefeng
authors.initials: K
authors.lastname: Dou
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Situ
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
mesh_terms: D004958:Estradiol / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D047629:Estrogen Receptor beta; D004967:Estrogens; C466228:NDRG2 protein, human; D025521:Tumor Suppressor Proteins; D004958:Estradiol; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase