title: Up-regulation of NDRG2 through nuclear factor-kappa B is required for Leydig cell apoptosis in both human and murine infertile testes.
abstract: Many pro-apoptotic factors, such as nuclear factor-kappa B (NF-κB) 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-κB was activated by EDS administration, bound to the ndrg2 promoter, and further increased in expression, effects that were abolished by NF-κB 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.
authors.affiliation: Department of Human Anatomy, Histology and Embryology, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.forename: Gong-Hao
authors.initials: GH
authors.lastname: He
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Chu-Chao
authors.initials: CC
authors.lastname: Zhu
authors.forename: Wu-Gang
authors.initials: WG
authors.lastname: Hou
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jin-Shan
authors.initials: JS
authors.lastname: Zhang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Xin-Ping
authors.initials: XP
authors.lastname: Liu
authors.forename: Li-Bo
authors.initials: LB
authors.lastname: Yao
authors.forename: Yuan-Qiang
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism*; D007985:Leydig Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008698:Mesylates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054331:Sertoli Cell-Only Syndrome / Q000235:genetics / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008698:Mesylates; C466228:NDRG2 protein, human; D016328:NF-kappa B; C485172:Ndr2 protein, mouse; C507213:Ndrg2 protein, rat; D009419:Nerve Tissue Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C002994:ethylene dimethanesulfonate