Novel interactions between GnRH receptor and E2F4 transcription factor.

生殖内分泌系统受促性腺激素释放激素(GnRH)的控制，通过其位于脑下垂体前叶的G蛋白偶联受体(GPCR)传递信号。促性腺激素释放激素受体(GnRHR)是治疗一系列内分泌相关疾病和激素依赖性癌症的药物靶点。GnRH激动剂或拮抗剂的持续治疗可通过下调垂体受体而间接阻断促性腺激素的分泌，导致促性腺激素的分泌减少，从而导致类固醇的产生减少。由于大多数使用促性腺激素释放激素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是独立于垂体-性腺轴的，在体外对一些肿瘤细胞系中的细胞生长和DNA合成的抑制是支持的。尽管GnRH类似物得到了广泛的应用，但该受体激活所导致的生长抑制作用的分子基础还不完全清楚。解开受体介导的信号事件背后的蛋白质相互作用将为理解受体在体内的功能提供有价值的信息。我们发现了一种涉及GnRHR和E2F4的新的相互作用，E2F4是一种参与抑制细胞周期进程相关基因转录的转录因子。此外，超过80%的E2F4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-E2F4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。这项建议中确定和研究的相互作用对于治疗生殖肿瘤，如乳腺癌和前列腺癌，以及了解下丘脑-垂体-性腺轴的发育具有重要意义。

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.