Study on the change in FSH-induced signaling pathway involved in granulosa cell survival and death

FSH诱导的颗粒细胞存活和死亡信号通路变化的研究

• 批准号: 11460134
• 负责人: MIYAZAKI Hitoshi
• 金额: $ 8.64万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11460134/
• 关键词: ovary; follicle-stimulating hormone; MAP kinase; ovulation; atretic follicle; cAMP; ホスフォリパーゼC; シグナル伝達; MAPキナーセ゜

Although the vast majority of ovarian follicles undergo a degenerative process termed atresia, the fundamental mechanism of this atretic process is largely unknown. Survival and apoptosis of ovarian granulosa cells (GCs) play a crucial role in determining the number of follicles destined to ovulate. Follicle-stimulating hormone (FSH) is thought to be a critical factor for the survival of GCs and follicular growth. Our laboratory recently found that FSH-induced activation of extracellular-regulated kinase (ERK), which is first identified MAP kinase, is changed in a cAMP-dependent to a cAMP-independent pathway during follicular development. The aim of this study is to examine the pathway of FSH-induced ERK activation in more detail, involving the meaning of the change in the dependency on cAMP.We have obtained the following results.1. Lysophosphatidic acid, a component of the serum, induced the change in the dependency on cAMP.2. Activation of phospholipase C was essential for FSH-elicited ERK activation in both differentiated and undifferentiated GCs prepared from mature and immature follicles, respectively, which is inconsistent with previous reports.3. cAMP was not necessary for the survival of differentiated GCs, rather promoted apoptosis.4. FSH-dependent survival of GCs requires the activities of ERK and p38, another type of MAP kinases. Interestingly, p38 activation is also implicated in apoptosis of GCs induced by oxidative stress.

虽然绝大多数卵巢卵泡经历退行性闭锁过程，但闭锁过程的基本机制在很大程度上是未知的。卵巢颗粒细胞（GCs）的存活和凋亡在决定卵泡排卵数量中起着至关重要的作用。促卵泡激素（FSH）被认为是GCs存活和卵泡生长的关键因素。我们的实验室最近发现，fsh诱导的细胞外调节激酶（ERK）的激活，首先被确定为MAP激酶，在卵泡发育过程中从camp依赖性途径转变为camp非依赖性途径。本研究的目的是更详细地研究fsh诱导的ERK激活途径，包括对cAMP依赖性变化的意义。我们得到了以下结果：血清成分溶血磷脂酸诱导对camp依赖性的改变。在成熟卵泡和未成熟卵泡制备的分化和未分化GCs中，磷脂酶C的激活是fsh诱导的ERK激活所必需的，这与之前的报道不一致。3 . cAMP对分化后的GCs的存活并不是必需的，而是促进了细胞凋亡。GCs依赖fsh存活需要ERK和p38（另一种MAP激酶）的活性。有趣的是，p38激活也与氧化应激诱导的GCs凋亡有关。