Non-canonical progesterone signaling in granulosa cell function.
Non-canonical progesterone signaling in granulosa cell function.
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DOI：
10.1530/rep-13-0582
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Pru JK
中科院分区：
文献类型：
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作者：
Peluso JJ;Pru JK
三十多年来，人们都知道黄体酮 (P4) 会抑制卵泡生长。人们认为 P4 直接作用于发育中的卵泡的颗粒细胞以减缓其发育，因为 P4 抑制培养的颗粒细胞的有丝分裂和凋亡。然而，小鼠、大鼠、猴子和人类发育中的卵泡的颗粒细胞不表达经典黄体酮核受体 (PGR) 的 A 或 B 形式。相比之下，这些颗粒细胞表达其他孕酮结合蛋白，其中一种称为孕酮受体膜成分 1 (PGRMC1)。 PGRMC1 以高亲和力特异性结合 P4，并介导 P4 的抗有丝分裂和抗凋亡作用，PGRMC1 耗尽的细胞中缺乏这些 P4 依赖性作用就证明了这一点。此外，颗粒细胞中 PGRMC1 条件性缺失的小鼠表现出卵泡发育减弱。虽然 PGRMC1 的 P4 激活影响颗粒细胞功能的机制尚未明确，但 PGRMC1 似乎部分通过以 T 细胞特异性转录因子/淋巴增强因子 (Tcf/Lef) 依赖性方式调节基因表达来控制颗粒细胞功能。临床上，PGRMC1 表达的改变与卵巢早衰/功能不全、多囊卵巢综合征和不孕症相关。这些集体研究提供了强有力的证据，证明 PGRMC1 在颗粒细胞中充当 P4 受体，并且表达的改变会导致生殖能力受损。正在进行的研究试图确定信号转导级联的组成部分，通过 PGRMC1 的 P4 激活来调节颗粒细胞功能。
It has been known for over three decades that progesterone (P4) suppresses follicle growth. It has been assumed that P4 acts directly on granulosa cells of developing follicles to slow their development, since P4 inhibits both mitosis and apoptosis of cultured granulosa cells. However, granulosa cells of developing follicles of mice, rats, monkeys and humans do not express the A or B form of the classic nuclear receptor for progesterone (PGR). In contrast, these granulosa cells express other progesterone binding proteins, one of which is referred to as Progesterone Receptor Membrane Component 1 (PGRMC1). PGRMC1 specifically binds P4 with high affinity and mediates P4’s anti-mitotic and anti-apoptotic action as evidenced by the lack of these P4-dependent effects in PGRMC1-depleted cells. In addition, mice in which PGRMC1 is conditionally depleted in granulosa cells show diminished follicle development. While the mechanism through which P4 activation of PGRMC1 affects granulosa cell function is not well defined, it appears that PGRMC1 controls granulosa cell function in part by regulating gene expression in T cell specific transcription factor/lymphoid enhancer factor (Tcf/Lef)-dependent manner. Clinically, altered PGRMC1 expression has been correlated with premature ovarian failure/insufficiency, polycystic ovarian syndrome and infertility. These collective studies provide strong evidence that PGRMC1 functions as a receptor for P4 in granulosa cells and that altered expression results in compromised reproductive capacity. Ongoing studies seek to define the components of the signal transduction cascade through which P4-activation of PGRMC1 results in the regulation of granulosa cell function.