N-myc Downstream-regulated Gene 2, a Novel Estrogen-targeted Gene, Is Involved in the Regulation of Na+/K+-ATPase
N-myc Downstream-regulated Gene 2, a Novel Estrogen-targeted Gene, Is Involved in the Regulation of Na+/K+-ATPase
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N-myc 下游调节基因 2 是一种新型雌激素靶向基因，参与 Na /K -ATP 酶的调节。
DOI：
10.1074/jbc.m111.247825
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发表时间：
2011-09-16
影响因子：
4.8
通讯作者：
Yao, Libo
中科院分区：
文献类型：
--
作者：
Li, Yan;Yang, Jiandong;Yao, Libo
Na+/K+-ATP酶是一种在上皮组织中大量表达的质膜蛋白，已被鉴定并与许多生物学事件相关，包括离子转运和重吸收。在Na+/K+-ATP酶中，β亚基对全酶的结构完整性和功能成熟起着重要作用。雌激素是一种重要的循环激素，它可以调节Na（+）/K+-ATP酶的丰度和活性，然而，参与这一过程的具体分子在很大程度上是未知的。在这里，我们的特点，N-myc下游调节基因2（NDRG 2）是一个雌激素上调基因。17 β-雌二醇与雌激素受体β结合，但不与雌激素受体α结合，通过转录激活上调NDRG 2表达。我们还发现NDRG 2与Na+/K+-ATP酶的β 1-亚基相互作用，并通过抑制其泛素化和降解来稳定β 1-亚基。NDRG 2诱导的β 1亚基蛋白半衰期延长伴随着上皮细胞中Na+/K+-ATP酶介导的Na+转运和Na+电流的类似增加。此外，NDRG 2沉默在很大程度上减弱了由17 β-雌二醇调节的β 1亚基的积累。我们的研究结果表明，雌激素/NDRG 2/Na+/K+-ATP酶β 1途径在促进Na+/K+-ATP酶活性方面是重要的，并表明这一新的途径可能在离子转运，液体平衡和稳态中起重要作用。
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 beta-subunit plays a fundamental role in the structural integrity and functional maturation of holoenzyme. Estrogens are important circulating hormones that can regulateNa(+)/K+-ATPase abundance and activity; however, the specific molecules participating in this process are largely unknown. Here, we characterize that N-myc down-stream-regulated gene 2 (NDRG2) is an estrogen up-regulated gene. 17 beta-Estradiol binds with estrogen receptor beta but not estrogen receptor alpha to up-regulate NDRG2 expression via transcriptional activation. We also find that NDRG2 interacts with the beta 1-subunit of Na+/K+-ATPase and stabilizes the beta 1-subunit by inhibiting its ubiquitination and degradation. NDRG2-induced prolongation of the beta 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 beta 1-subunit regulated by 17 beta-estradiol. Our results demonstrate that estrogen/NDRG2/Na+/K+-ATPase beta 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.