Sox transcription factors: Regulatory mechanisms and impact on steroidogenesis

Sox 转录因子：调节机制及其对类固醇生成的影响

• 批准号: 386557-2012
• 负责人: Martin, Luc
• 金额: $ 2.4万
• 依托单位: Université de Moncton
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=595952
• 关键词: Sox; transcription; factors; Regulatory; mechanisms

Members of the Sox family of transcription factors, Sry and Sox9, are known to play important roles in sex determination and differentiation in mammals. More than 20 members of this family have been characterized, of which several are expressed in the testis. To ensure their specificity of action, Sox proteins rely on recruitment of partners and post-translational modifications. However, their role in transcriptional regulation of steroidogenesis has never been investigated. Interestingly, putative binding sites for Sox members are present in the promoters of several steroidogenic genes. Thus, Sox family members might play a crucial role in transcriptional regulation of steroidogenesis in Leydig cells. These cells supply testosterone important to maintain fertility in male and to avoid andropause related symptoms associated to aging. Steroidogenesis can be regulated at different levels such as gonads (for steroidogenic genes), pituitary (by regulating LH and FSH productions) and hypothalamus (by regulating GnRH production). Therefore, the main goal of my research program is to define the role of Sox members in functional regulation of the Hypothalamic-Pituitary-Gonadal axis, important for sex steroids production. The current proposal aims to identify which Sox members are expressed in rodent male gonads, which genes they regulate and what mechanisms regulate their activities. Overall, different approaches of molecular and cell biology will be used to better understand the role of Sox transcription factors in Leydig cells' function. As in other tissues, Sox members might be functionally redundant in steroidogenic cells, explaining the lack of steroidogenic phenotypes in Sox-deficient mice models. Results from this proposal will have a great significance for basic physiology and endocrinology of gonadal steroidogenesis in vertebrates and might be relevant for novel male contraception. In addition, our results will contribute to a better understanding of prostate cancer development and progression.

Sox转录因子家族成员Sry和Sox9在哺乳动物性别决定和分化中发挥重要作用。这个家族的20多个成员已经被描述为特征，其中一些在睾丸中表达。为了确保其作用的特异性，SOX蛋白依赖于伙伴的招募和翻译后的修饰。然而，它们在类固醇合成的转录调控中的作用从未被研究过。有趣的是，SOX成员的假定结合位点存在于几个类固醇合成基因的启动子中。因此，SOX家族成员可能在间质细胞类固醇合成的转录调控中发挥重要作用。这些细胞提供对维持男性生育能力和避免与衰老相关的雄停滞症状至关重要的睾丸素。类固醇的生成可以在不同的水平上进行调节，如性腺(类固醇生成基因)、垂体(通过调节促黄体生成素和卵泡刺激素的产生)和下丘脑(通过调节促性腺激素释放激素的产生)。因此，我的研究计划的主要目标是确定SOX成员在下丘脑-垂体-性腺轴的功能调节中的作用，这对性类固醇的产生很重要。目前的提案旨在确定哪些SOX成员在啮齿类雄性性腺中表达，它们调节哪些基因，以及什么机制调节它们的活动。总体而言，将使用不同的分子和细胞生物学方法来更好地了解Sox转录因子在间质细胞功能中的作用。就像在其他组织中一样，SOX成员在类固醇生成细胞中可能在功能上是多余的，这解释了为什么在SOX缺乏的小鼠模型中缺乏类固醇生成表型。这一研究结果将对脊椎动物性腺类固醇合成的基本生理学和内分泌学研究具有重要意义，并可能为新的男性避孕措施提供参考。此外，我们的结果将有助于更好地了解前列腺癌的发展和进展。