Riaz Muhammad Assad, Stammler Angelika, Borgers Mareike, Konrad Lutz
Center of Gynecology and Obstetrics, Medical Faculty, Feulgenstr. 12, Justus-Liebig-University Giessen 35392, Giessen, Germany.
Institute of Anatomy and Cell Biology, Signaling Group, Justus-Liebig-University Giessen 35392, Giessen, Germany.
Am J Transl Res. 2017 Mar 15;9(3):1266-1276. eCollection 2017.
Clusterin (CLU) is a ubiquitously expressed heterodimeric glycoprotein that is involved in a variety of functions like cell-cell interactions, apoptosis, epithelial-mesenchymal transition, carcinogenesis, and chaperone function. In the testis, CLU is strongly expressed especially in Sertoli cells but very little is known about its testicular function, regulation of secretion and most enigmatic, its receptor(s). In this study, we approached these questions with a special emphasis on the link between CLU and meiosis. In cultured seminiferous tubules, we found that secretion of CLU protein is upregulated by transforming growth factor-betas (TGF-β1-3) and observed inhibition of staurosporine-induced apoptosis by recombinant CLU. Clusterin signaling in testicular cells seems to be modulated by very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), because these members of the low density lipoprotein (LDL) receptor family are present in rat germ cells. Furthermore, inhibition of VLDLR/ApoER2 by a specific inhibitor abrogates CLU-mediated phosphorylation of Akt, which mediates VLDLR/ApoER2 signaling. We could also show in tubules treated with recombinant CLU a significant upregulation of several meiosis-associated proteins such as V-myb avian myeloblastosis viral oncogene homolog-like 1 (Mybl1), stimulated by retinoic acid gene 8 (Stra8), lactate dehydrogenase C (LDHC), cAMP response element-binding protein (CREB) and histone H3 (H3S10P). Collectively, our data show for the first time the involvement of CLU in upregulation of meiosis through VLDLR/ApoER2 in male germ cells.
簇集素（CLU）是一种广泛表达的异二聚体糖蛋白，参与多种功能，如细胞间相互作用、细胞凋亡、上皮-间质转化、致癌作用和伴侣功能。在睾丸中，CLU尤其在支持细胞中强烈表达，但其睾丸功能、分泌调节以及最神秘的其受体情况却知之甚少。在本研究中，我们特别关注CLU与减数分裂之间的联系来探讨这些问题。在培养的生精小管中，我们发现转化生长因子-β（TGF-β1 - 3）可上调CLU蛋白的分泌，并观察到重组CLU可抑制星形孢菌素诱导的细胞凋亡。睾丸细胞中的簇集素信号似乎受到极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体2（ApoER2）的调节，因为这些低密度脂蛋白（LDL）受体家族成员存在于大鼠生殖细胞中。此外，用特异性抑制剂抑制VLDLR/ApoER2可消除CLU介导的Akt磷酸化，而Akt介导VLDLR/ApoER2信号传导。我们还发现在用重组CLU处理的小管中，几种减数分裂相关蛋白显著上调，如维甲酸基因8（Stra8）刺激的V - myb禽成髓细胞瘤病毒癌基因同源物样1（Mybl1）、乳酸脱氢酶C（LDHC）、环磷酸腺苷反应元件结合蛋白（CREB）和组蛋白H3（H3S10P）。总体而言，我们的数据首次表明CLU通过VLDLR/ApoER2参与雄性生殖细胞减数分裂的上调。
