Novel interactions between GnRH receptor and E2F4 transcription factor.

GnRH 受体和 E2F4 转录因子之间的新相互作用。

• 批准号: nhmrc : 303256
• 负责人: Karin Eidne
• 金额: $ 30.86万
• 依托单位: The University of Western Australia
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/novel-interactions-gnrh-transcription-factor/99396
• 关键词: Novel; interactions; between; GnRH; receptor

The reproductive endocrine system is under the control of gonadotropin-releasing hormone (GnRH), signalling via its G-protein coupled receptor (GPCR) in the anterior pituitary gland. The GnRH receptor (GnRHR) is the drug target for the treatment of a range of endocrine-related disorders as well as hormone-dependent cancers. Sustained treatment with either GnRH agonists or antagonists can block gonadotropin secretion indirectly, via down-regulation of the pituitary receptor resulting in a reduction of gonadotropin secretion and consequent decline in steroid production. As the majority of tumours treated with GnRH analogues are hormone-dependent, this starves the tumour of the steroid support required for growth. However, the concept of a direct anti-tumour effect of GnRH, independent of the pituitary-gonadal axis, is supported by the in vitro inhibition of both cell growth and DNA synthesis in a number of tumour cell lines. Despite the wide use of GnRH analogues, the molecular basis of the growth inhibitory effects resulting from the activation of this receptor is not fully understood. Unravelling the protein interactions underlying receptor-mediated signalling events will provide valuable information towards understanding of receptor function in vivo. We have identified a novel interaction involving the GnRHR and E2F4, a transcription factor involved in suppression of the transcription of genes involved in cell cycle progression. In addition, over 80% of E2F4 knockout mice are sterile. Owing to the role of the GnRHR in the reproductive pathway we are interested in determining whether the GnRHR-E2F4 interaction has an influence on the development of the hypothalamic-pituitary-gonadal axis, hence affecting reproductive capacity. The interaction identified and studied in this proposal has implications for the treatment of reproductive tumours, such as those of the breast and prostate, and understanding the development of the hypothalamic-pituitary-gonadal axis.

生殖内分泌系统受促性腺激素释放激素（GnRH）控制，通过垂体前叶中的G蛋白偶联受体（GPCR）发出信号。GnRH受体（GnRHR）是治疗一系列内分泌相关疾病以及激素依赖性癌症的药物靶标。GnRH激动剂或拮抗剂持续治疗可通过下调垂体受体间接阻断促性腺激素分泌，导致促性腺激素分泌减少，从而导致类固醇产生下降。由于大多数用GnRH类似物治疗的肿瘤是激素依赖性的，这使肿瘤缺乏生长所需的类固醇支持。然而，GnRH的直接抗肿瘤作用的概念，独立于垂体-性腺轴，支持在体外抑制细胞生长和DNA合成在一些肿瘤细胞系。尽管GnRH类似物被广泛使用，但该受体激活引起的生长抑制作用的分子基础尚未完全了解。解开受体介导的信号事件的蛋白质相互作用将提供有价值的信息，了解受体在体内的功能。我们已经确定了一种新的相互作用，涉及的GnRHR和E2 F4，参与抑制转录的基因参与细胞周期进程的转录因子。此外，超过80%的E2 F4基因敲除小鼠是不育的。由于GnRHR在生殖途径中的作用，我们有兴趣确定GnRHR-E2 F4相互作用是否影响下丘脑-垂体-性腺轴的发育，从而影响生殖能力。本提案中确定和研究的相互作用对治疗生殖肿瘤（如乳腺和前列腺肿瘤）以及了解下丘脑-垂体-性腺轴的发育具有意义。