Physiological role and transmembranesignaling of gonadotropin-releasing hormonein granulosa cells : expression of Gn-RH and its receptor in the ovary

颗粒细胞促性腺激素释放激素的生理作用和跨膜信号传导：卵巢中 Gn-RH 及其受体的表达

• 批准号: 04670996
• 负责人: IMAI Atsushi
• 金额: $ 1.34万
• 依托单位: Gifu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670996/
• 关键词: Ovary; Ovarian carcinoma; Gn-RH; Gn-RH receptor; Gonadotropin; Molecular biology; Endometrial carcinoma; Hormone-therapy; 受容・応答機構; 分子生物学; 受容体占有; イノシトールリン脂質; 卵巣機能; オートクリン調節; 遺伝子発現; メッセンジャーRNA

In granulosa cells, Gn-RH stimulated [^<32>P] phosphate incorporation into phosphatidylinositol (PtdIns) , which could be terminated by displacement of previously boundGn-RH from its receptor by antide and restarted by reoccupyingthe receptors with G1n-RH.Antide could rapidly prevent Gn-RH-stimulated PtdIns phosphorylation whenever it was added to incubations. An identical effect of antide was observed also in the anti-FSH action of Gn-RH.The aromatase activity initiated by FSH was quenched by Gn-RH and restarted at a time when Gn-RH was removed from its receptor by antide. These two responses associated with the occupancy of Gn-RH receptor provide the evidence in favor of a tight coupling of stimulated PtdIns turnover to suppression of aromatase activation. Taken together these data of requirement of continued occupancy of receptor for Gn-RH to exert its action, Gn-RH or Gn-RH-like hormonein ovaries, in addition to from pituitary, could participate in the control of steroidogenesis in … More the ovary in an autocrine or a paracrine manner.In human ovarian carcinomas surgically removed and human ovarian carcinoma cell lines, Gn-RH was shown to be present in extracts of ovarian mucinouscystadenocarcinoma sample (0.8<plus-minus>0.12pg/mgprotein) and ovarian adenocarcinoma cell line SK-OV-3 (0.92<plus-minus>0.17 pg/mgprotein) , but not in the normal ovary and placenta. Two of two extract samples from individual cases evoked dose-dependent phosphoinositide breakdown in rat granulosa cells similar to that caused by authentic Gn-RH.Gn-RH mRNA was detected in two of two mucinouscystadenocarcinoma specimens, one of one serouscystadenocarcinoma, and SK-OV-3cells, but not in the dysgerminoma, mucinouscystadenoma, and normal ovary and placenta. High affinity binding sites with nonomolar range of Kd and Gn-RHR mRNA were detected in a high proportion (over 90%) of the specimens from endometria (6 of 6) and endometrial carcinomas (16 of 17) , myometria (6 of 6) and myomas (4 of 5) , epithelial carcinoma (21 of 23) and stromal tumors (3 of 3) of the ovary. There was no substantial Gn-RHR in cervical carcinomas or germ cell-drived tumors of the ovary. Cloned cell lines gave identical results to those obtained in their respective mother tumWe detected Gn-RHR in a wide range of the carcinomas and tissues originating from the endometrium and ovary, but not in the uterine cervix or germ cell-derived tumors. The expression of Gn-RH receptor raises the possibility that Gn-RH may play a direct regulatory role in the growth of these carcinomas, and provides a possible point of attack for therapeutic approaches using Gn-RH analogs in these malignancies. The demonstration of Gn-RH and its mRNA raises the possibility that Gn-RH may play an autocrine regulatory role in the growth of ovarian carcinoma. Less

在颗粒细胞中，Gn-RH刺激磷脂酰肌醇(PtdIns)的磷酸参入，这种作用可被Anide从其受体上置换Gn-RH而终止，并可通过G1n-RH重新占据受体而重新启动。Anide可迅速阻止Gn-RH刺激的PtdIns的磷酸化。在Gn-RH的抗FSH作用中也观察到同样的作用。Gn-RH使FSH启动的芳香酶活性被Gn-RH猝灭，当Gn-RH从其受体上移除时，芳香酶活性重新启动。这两种反应与Gn-RH受体的占位有关，为促进PtdIn的周转与抑制芳香酶活性的紧密耦合提供了证据。综上所述，卵巢Gn-RH或Gn-RH样激素除来自垂体外，还可能参与…激素合成的调控。在手术切除的人卵巢癌和人卵巢癌细胞系中，Gn-RH存在于卵巢粘液囊腺癌和卵巢癌细胞株的提取液中(0.8和0.12pg/mg蛋白)和卵巢癌细胞系SK-OV-3细胞(0.92和0.17pg/mg蛋白)，而在正常卵巢和胎盘中不存在。Gn-RH在两例粘液囊腺癌和SK-OV-3细胞中均有表达，而在无性细胞瘤、粘液囊腺瘤、正常卵巢和胎盘中未检测到Gn-RH基因。在子宫内膜(6/6)、子宫内膜癌(16/17)、子宫肌层(6/6)、子宫肌瘤(4/5)、卵巢上皮癌(21/23)和间质瘤(3/3)组织中，KD和Gn-RHR高亲和力结合位点的表达比例较高(>90%)。在子宫颈癌和生殖细胞驱动的卵巢肿瘤中未见实质性的Gn-RHR。克隆的细胞系给出了与它们各自的母体肿瘤相同的结果。我们在广泛的癌症和起源于子宫内膜和卵巢的组织中检测到Gn-RHR，但在子宫颈或生殖细胞来源的肿瘤中没有检测到Gn-RHR。Gn-RH受体的表达增加了Gn-RH可能在这些肿瘤的生长中发挥直接调节作用的可能性，并为使用Gn-RH类似物治疗这些恶性肿瘤提供了一个可能的攻击点。Gn-RH及其mRNA的表达增加了Gn-RH在卵巢癌生长中发挥自分泌调节作用的可能性。较少

项目成果

Imai,A.et al: "Tight coupling of gonadotroπn-releasing hormone receptor to stiμlated phosphoinositide mηbolism and anti-gonadotroπc action in graνlosa cells." Obstet.Gynecol.Invest.33. 36-41 (1992)

Imai，A.等人：“促性腺激素释放激素受体与graνlosa细胞中刺激的磷酸肌醇代谢和抗促性腺激素作用的紧密偶联。”Obstet.Gynecol.Invest.36-41。

Imai,A.et al: "Gonadotropin-releasing hormone stimulates phospholipase C but not protein phosphorylation/dephosphorylation in plasma" Int.J.Gynecol.Cancer. 3. 311-317 (1993)

Imai,A.et al：“促性腺激素释放激素刺激磷脂酶 C，但不会刺激血浆中的蛋白质磷酸化/去磷酸化”Int.J.Gynecol.Cancer。

Imai,A.et al: "Is extrapituitary action of gonadotropin-releasing hormone(Gn-RH)biologically significant?" Ann.Clin.Biochem.29. 477-480 (1992)

Imai,A.et al：“促性腺激素释放激素 (Gn-RH) 的垂体外作用具有生物学意义吗？”

Imai,A.et al.: "Expression of gonadotropin-releasing hormone receptor in human epithelial ovarian carcinoma." Ann.Clin.Biochem.31. 550-555 (1994)

Imai,A.et al.：“促性腺激素释放激素受体在人上皮性卵巢癌中的表达”。

Imai A.et al: "Gonadotropin-releasing hormone receptor in gynecologic tumors:frequent expression in adenocarcinoma histologic types" Cancer. 74. 2555-2561 (1994)

Imai A.et al：“妇科肿瘤中的促性腺激素释放激素受体：在腺癌组织学类型中频繁表达”癌症。