Technion—Israel Institute of Technology, Haifa, Israel.
Mol Cell Biol. 2011 Dec;31(24):5023-36. doi: 10.1128/MCB.06083-11. Epub 2011 Oct 10.
Gonadotropin-releasing hormone (GnRH) regulates the expression of all three gonadotropin genes, encoding the common α subunit (αGSU) and hormone-specific β subunits, through the activation of several signal transduction pathways. We have shown that GnRH also upregulates calcineurin, and we hypothesized that calcineurin mediates the effects of GnRH on the transcription of the αGSU and follicle-stimulating hormone β (FSHβ) genes through two of its targets: nuclear factor of activated T cells (NFAT) and CREB-regulated transcription coactivator (TORC). We show that calcineurin is essential for GnRH-induced expression of both genes but that NFAT and TORC1 play quite distinct roles in activating each gene. GnRH induces calcineurin-dependent nuclear import of NFAT3, which activates the αGSU promoter, while TORC1 also mediates GnRH activation of this promoter, but not through CREB. GnRH initially stimulates the degradation of TORC1 but protects the N terminus of the newly synthesized protein to enhance its activity. Calcineurin induces Nur77 expression, likely via NFAT3, and Nur77 interacts synergistically with TORC1 and CREB to increase FSHβ promoter activity. Although TORC plays a role in the basal activity of the FSHβ promoter, it does not interact with phosphorylated CREB and probably does not play a major role in direct GnRH signaling to this gene. TORC may be part of an alternatively regulated pathway, possibly involving cross talk with other stimulatory hormones.
促性腺激素释放激素 (GnRH) 通过激活几种信号转导途径来调节所有三种促性腺激素基因的表达,这些基因编码共同的 α 亚基 (αGSU) 和激素特异性的 β 亚基。我们已经表明,GnRH 还上调钙调神经磷酸酶,并且我们假设钙调神经磷酸酶通过其两个靶标:激活 T 细胞的核因子 (NFAT) 和 CREB 调节的转录共激活因子 (TORC) 来介导 GnRH 对 αGSU 和卵泡刺激素 β (FSHβ) 基因转录的影响。我们表明,钙调神经磷酸酶对于 GnRH 诱导的这两个基因的表达都是必需的,但是 NFAT 和 TORC1 在激活每个基因方面起着截然不同的作用。 GnRH 诱导钙调神经磷酸酶依赖性 NFAT3 的核内易位,从而激活 αGSU 启动子,而 TORC1 也通过 CREB 介导 GnRH 对该启动子的激活,但不是通过 CREB。 GnRH 最初刺激 TORC1 的降解,但保护新合成蛋白质的 N 端以增强其活性。钙调神经磷酸酶诱导 Nur77 表达,可能通过 NFAT3,Nur77 与 TORC1 和 CREB 协同作用,增加 FSHβ 启动子活性。虽然 TORC 在 FSHβ 启动子的基础活性中起作用,但它不与磷酸化的 CREB 相互作用,并且可能在 GnRH 对该基因的直接信号转导中不起主要作用。 TORC 可能是另一种调节途径的一部分,可能涉及与其他刺激激素的串扰。