Up-regulation of NDRG2 through nuclear factor-kappa B is required for Leydig cell apoptosis in both human and murine infertile testes
Up-regulation of NDRG2 through nuclear factor-kappa B is required for Leydig cell apoptosis in both human and murine infertile testes
复制标题
在人类和小鼠不育睾丸中，Leydig 细胞凋亡需要通过核因子 kappa B 上调 NDRG2。
DOI：
10.1016/j.bbadis.2011.11.013
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发表时间：
2012-02-01
影响因子：
6.2
通讯作者：
Zhang, Yuan-Qiang
中科院分区：
文献类型：
--
作者：
Li, Teng;Hu, Jing;Zhang, Yuan-Qiang
核因子-κ B（NF-kappa B）和Fas等促凋亡因子在睾丸间质细胞凋亡过程中发挥重要作用，最终导致男性不育，如Sertoli细胞综合征（SCO）和精子生成不足。然而，这种凋亡的分子机制尚不清楚。N-myc下游调节基因2（ndrg 2）的研究表明其参与细胞的分化、发育和凋亡。NDRG 2在SCO和低精子生成睾丸中的独特表达表明其在这些疾病中的关键作用。在这项研究中，我们分析了NDRG 2的表达谱在睾丸的正常精子发生患者，hypospermatogenesis患者，和SCO患者，以及在体内和体外模型，这是Sprague-Dawley大鼠和睾丸间质细胞特异性毒物乙-二甲磺酸盐（EDS）处理的睾丸间质细胞系TM 3。我们的数据证实，NDRG 2通常只位于Leydig细胞的细胞质中，并且在人类和小鼠睾丸中在凋亡刺激下上调并易位到细胞核中。同时，EDS给药激活转录因子NF-κ B，与ndrg 2启动子结合，并进一步增加表达，NF-κ B抑制剂吡咯烷二硫代氨基甲酸酯（PDTC）消除了这种作用。此外，siRNA敲低ndrg 2导致TM 3细胞增殖增加或凋亡减少，而过量表达ndrg 2则具有相反的效果。本研究揭示ndrg 2是一个参与睾丸间质细胞凋亡的新基因，在睾丸细胞中具有重要功能，并提示其在睾丸间质细胞凋亡和男性生育中可能发挥作用。(C)2011爱思唯尔有限公司版权所有。
Many pro-apoptotic factors, such as nuclear factor-kappa B (NF-kappa B) and Fas, play crucial roles in the process of Leydig cell apoptosis, ultimately leading to male sterility, such as in Sertoli cell only syndrome (SCO) and hypospermatogenesis. However, the molecular mechanism of such apoptosis is unclear. Recent reports on N-myc downstream-regulated gene 2 (ndrg2) have suggested that it is involved in cellular differentiation, development, and apoptosis. The unique expression of NDRG2 in SCO and hypospermatogenic testis suggests its pivotal role in those diseases. In this study, we analyzed NDRG2 expression profiles in the testes of normal spermatogenesis patients, hypospermatogenesis patients, and SCO patients, as well as in vivo and in vitro models, which were Sprague-Dawley rats and the Leydig cell line TM3 treated with the Leydig cell-specific toxicant ethane-dimethanesulfonate (EDS). Our data confirm that NDRG2 is normally exclusively located in the cytoplasm of Leydig cells and is up-regulated and translocates into the nucleus under apoptotic stimulations in human and murine testis. Meanwhile, transcription factor NF-kappa B was activated by EDS administration, bound to the ndrg2 promoter, and further increased in expression, effects that were abolished by NF-kappa B inhibitor Pyrrolidine dithiocarbamate (PDTC). Furthermore, siRNA knock-down of ndrg2 led to increased proliferative or decreased apoptotic TM3 cells, while over-expression of ndrg2 had the reverse effect. This study reveals that ndrg2 is a novel gene that participates in Leydig cell apoptosis, with essential functions in testicular cells, and suggests its possible role in apoptotic Leydig cells and male fertility. (C) 2011 Elsevier B.V. All rights reserved.