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 ?-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. 17?-Estradiol binds with estrogen receptor ? but not estrogen receptor ? to up-regulate NDRG2 expression via transcriptional activation. We also find that NDRG2 interacts with the ?1-subunit of Na(+)/K(+)-ATPase and stabilizes the ?1-subunit by inhibiting its ubiquitination and degradation. NDRG2-induced prolongation of the ?1-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 ?1-subunit regulated by 17?-estradiol. Our results demonstrate that estrogen/NDRG2/Na(+)/K(+)-ATPase ?1 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.

SUBMITTER: Li Y 

PROVIDER: S-EPMC3173200 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature