Steroidogenic factor-1 as a therapeutic target for of severe ovarian failure

类固醇生成因子 1 作为严重卵巢功能衰竭的治疗靶点

• 批准号: 13470348
• 负责人: SHOZU Makio
• 金额: $ 5.5万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470348/
• 关键词: aromatase; granulosa cells; steroidogenic factor-1; IL-β; estrogen; ovulation; 子宮内膜症; IL=1β

Aromatization of androgens, catalyzed by aromatase P450, is essential for estrogen biosynthesis, hetero for folliculogenesis. Here we investigated the transcriptional regulation of aromatase in granulosa cells and identify both steroidogenic factor-1 and LRH-1 as important regulatory factors binding to the nuclear half site of proximal promoter PII of aromatase. Both transcriptional factors were expressed in granulosa cell of healthy growing follicles and luteal cells. COV432, a cell lines established from a human granulosa cell, express exclusively LRH-1 and granulosa cells in growing follicle expressed much LRH-1 than SF-l. Granulosa luteal cells expressed much LRH-1, while theca luteal cells almost exclusively expressed SF-1. Co-expression of SF-1 or LRH-1 stimulated the expression of promoter vectors containing various lengths of PII sequences. We also investigated mechanism of IL-lb- and GnRH agonsit- induced induction of aromatase in endometriosis-derived stromal cells. IL-lb increased aromatase expression through COX2-dependent and COX2-independent mechanisms. GnRH agonists transiently stimulated aromatase expression through the activation of PKC. IGF-1 and BMP also stimulated aromatase expression in the presence of FSH.

由芳香化酶P450催化的雄激素芳香化是雌激素生物合成所必需的，而卵泡形成则是不同的。本文研究了芳香化酶在颗粒细胞中的转录调控，发现甾体生成因子-1和LRH-1是结合芳香化酶近端启动子PII核半位点的重要调控因子。两种转录因子均在健康卵泡颗粒细胞和黄体细胞中表达。COV432是由人颗粒细胞建立的细胞系，只表达LRH-1，生长毛囊中的颗粒细胞表达的LRH-1高于sf -1。黄体颗粒细胞大量表达LRH-1，而黄体膜细胞几乎只表达SF-1。SF-1或LRH-1的共表达刺激了包含不同长度PII序列的启动子载体的表达。我们还研究了IL-lb和GnRH激动素诱导的子宫内膜异位症基质细胞中芳香化酶的诱导机制。IL-lb通过依赖和不依赖cox - 2的机制增加芳香化酶的表达。GnRH激动剂通过激活PKC瞬间刺激芳香化酶表达。在FSH存在的情况下，IGF-1和BMP也会刺激芳香化酶的表达。

项目成果

Over-expression of aromatase P-450 in leiomyoma tissues is driven through the promoter 1.4 of aromatase P-450.

芳香酶 P-450 在平滑肌瘤组织中的过度表达是通过芳香酶 P-450 的启动子 1.4 驱动的。

• 发表时间: 2002
• 期刊: J Clin Endocrinol Metab 87
• 作者: Shozu;M.;Sumitani;H.;Segawa;T.;Yang;H.-J.;Murakami;K.;Kasai;T.;Inoue;M.
• 通讯作者: M.

Shozu M, Murakami K, Inoue M: "Expression of aromatase in leiomyomas of the uterus"Semin Reprod Med.. (In press).

Shozu M、Murakami K、Inoue M：“子宫平滑肌瘤中芳香酶的表达”Semin Reprod Med..（正在出版）。

Shozu M, Murakami K, Segawa T, Kasai T, Ishikawa H, Shinohara K, Okada M, Inoue M: "Decreased expression of early growth response-1 and its role in uterine leiomyoma growth"Cancer Res.. (In press).

Shozu M、Murakami K、Sekawa T、Kasai T、Ishikawa H、Shinohara K、Okada M、Inoue M：“早期生长反应 1 的表达减少及其在子宫肌瘤生长中的作用”癌症研究（正在出版）。

Successful Treatment of Symptomatic Uterine Leiomyoma with a Non-Steroidal Aromatase Inhibitor in a Perimenopausal Woman

使用非甾体芳香酶抑制剂成功治疗围绝经期妇女的症状性子宫平滑肌瘤

• 发表时间: 2003
• 期刊: Fertil Steril 79
• 作者: Shozu;M.;Murakami;K.;Segawa;T.;Kasai;T.;Inoue;M.
• 通讯作者: M.

Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene

• DOI: 10.1056/nejmoa021559
• 发表时间: 2003-05-08
• 期刊: NEW ENGLAND JOURNAL OF MEDICINE
• 影响因子: 158.5
• 作者: Shozu, M;Sebastian, S;Bulun, SE
• 通讯作者: Bulun, SE