Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia 31404-3089, USA.
Biol Reprod. 2010 Nov;83(5):842-51. doi: 10.1095/biolreprod.110.085621. Epub 2010 Jul 21.
Forkhead box protein L2 (FOXL2) is the earliest ovarian marker and plays an important role in the regulation of cholesterol and steroid metabolism, inflammation, apoptosis, and ovarian development and function. Mutations and deficiencies of the human FOXL2 gene have been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome as well as premature ovarian failure. Although Foxl2 interacts with steroidogenic factor 1 (Nr5a1) and up-regulates cyp19a1a gene transcription in fish, FOXL2 represses the transcriptional activity of the gene that codes for steroidogenic acute regulatory protein (Star) in mice. Most of the recent studies have heavily focused on the FOXL2 target genes (Star and Cyp19a1) in the ovaries. Hence, it is of importance to search for other downstream targets of FOXL2 and for the possibility of FOXL2 expression in nonovarian tissues. Herein, we demonstrate that the interplay between FOXL2 and NR5A1 regulates Star and melanocortin 2 receptor (Mc2r) gene expression in mammalian systems. Both FOXL2 and NR5A1 are expressed in ovarian and adrenal gland tissues. As expected, FOXL2 represses and NR5A1 enhances the promoter activity of Star. Notably, the promoter activity of Mc2r is activated by FOXL2 in a dose-dependent manner. Surprisingly, we found that FOXL2 and NR5A1 synergistically up-regulate the transcriptional activity of Mc2r. By mapping the Mc2r promoter, we provide evidence that distal NR5A1 response elements (-1410 and -975) are required for synergistic activation by FOXL2 and NR5A1. These results suggest that the interplay between FOXL2 and NR5A1 on the Mc2r promoter functions as a novel mechanism for regulating MC2R-mediated cell signaling as well as steroidogenesis in adrenal glands.
叉头框蛋白 L2（FOXL2）是最早的卵巢标志物，在调节胆固醇和类固醇代谢、炎症、凋亡以及卵巢发育和功能中发挥重要作用。人类 FOXL2 基因的突变和缺失已被证明会导致睑裂狭小-上睑下垂-内眦赘皮倒向综合征以及卵巢早衰。尽管 Foxl2 与类固醇生成因子 1（Nr5a1）相互作用，并在上皮鱼类中上调 cyp19a1a 基因转录，但 FOXL2 会抑制编码类固醇急性调节蛋白（Star）的基因的转录活性在小鼠中。最近的大多数研究都集中在卵巢中的 FOXL2 靶基因（Star 和 Cyp19a1）上。因此，寻找 FOXL2 的其他下游靶标以及 FOXL2 在非卵巢组织中的表达可能性非常重要。在此，我们证明了 FOXL2 和 NR5A1 之间的相互作用调节了哺乳动物系统中的 Star 和黑素皮质素 2 受体（Mc2r）基因表达。FOXL2 和 NR5A1 均在卵巢和肾上腺组织中表达。正如预期的那样，FOXL2 抑制 Star 的启动子活性，而 NR5A1 增强其启动子活性。值得注意的是，FOXL2 以剂量依赖性方式激活 Mc2r 启动子活性。令人惊讶的是，我们发现 FOXL2 和 NR5A1 协同上调 Mc2r 的转录活性。通过对 Mc2r 启动子进行映射，我们提供了证据表明，NR5A1 反应元件的远端（-1410 和-975）对于 FOXL2 和 NR5A1 的协同激活是必需的。这些结果表明，FOXL2 和 NR5A1 之间在 Mc2r 启动子上的相互作用作为一种新的机制，调节肾上腺中 MC2R 介导的细胞信号传导以及类固醇生成。
