The State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
Mol Cell Endocrinol. 2013 Jul 15;374(1-2):108-16. doi: 10.1016/j.mce.2013.04.012. Epub 2013 Apr 28.
SET has multiple cell functions including nucleosome assembly, histone binding, transcription control, and cell apoptosis. In ovaries SET is predominantly expressed in theca cells and oocytes. In our study, SET overexpression in theca cells stimulated testosterone production whereas SET knockdown decreased testosterone production. Moreover, SET negatively regulated PP2A activity. Treatment with PP2A inhibitor okadaic acid (OA) led to increased testosterone synthesis, while treatment with PP2A activators resulted in the decreased testosterone synthesis. Furthermore, PP2A knockdown confirmed the key role of PP2A in the testosterone synthesis, and OA was able to block the AdH1-SiRNA/SET-mediated inhibition of testosterone production. The central role of PP2A in SET-mediated regulation of testosterone production was confirmed by the finding that SET promoted the lyase activity of P450c17 and that PP2A inhibited its lyase activity. Taken together, these results reveal a specific, SET-initiated, PP2A-mediated, pathway that leads to the increased lyase activity of P450c17 and testosterone biosynthesis.
SET 具有多种细胞功能，包括核小体组装、组蛋白结合、转录调控和细胞凋亡。在卵巢中，SET 主要在卵泡膜细胞和卵母细胞中表达。在我们的研究中，SET 在卵泡膜细胞中的过表达刺激了睾酮的产生，而 SET 的敲低则减少了睾酮的产生。此外，SET 负调控 PP2A 活性。用 PP2A 抑制剂 okadaic acid（OA）处理会导致睾酮合成增加，而用 PP2A 激活剂处理则会导致睾酮合成减少。此外，PP2A 的敲低证实了 PP2A 在睾酮合成中的关键作用，OA 能够阻断 AdH1-SiRNA/SET 介导的对睾酮产生的抑制作用。SET 促进 P450c17 的裂解酶活性，而 PP2A 抑制其裂解酶活性，这一发现证实了 PP2A 在 SET 介导的睾酮产生调控中的核心作用。综上所述，这些结果揭示了一种特定的、由 SET 启动、PP2A 介导的途径，导致 P450c17 的裂解酶活性增加和睾酮生物合成。
