Molecular Mechanisms of Hormone Regulated Gene Expression in the Pituitary

垂体激素调节基因表达的分子机制

• 批准号: 8054228
• 负责人: JOHN H. NILSON
• 金额: $ 38.9万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054228
• 关键词: 3' Untranslated Regions; Address; Affect; Alleles; Binding; Biological; Cell Line; Colon Carcinoma; Complex; Consensus; Cues; Cyclic AMP-Dependent Protein Kinases; DNA-Binding Proteins; Data; Dependency; Disease; Docking; Elements; Endocrine System Diseases; Ensure; Exhibits; Family; Fertility; Future; G-Protein-Coupled Receptors; Gametogenesis; Gene Expression; Gene Expression Profile; Gene Family; Gene Transfer Techniques; Generic Drugs; Genes; Genetic Transcription; Glycoproteins; Gonadotrope Cell; Hematologic Neoplasms; Homeostasis; Hormones; Hypothalamic Hormones; Hypothalamic structure; Immediate-Early Genes; In Vitro; Infertility; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; N-terminal; Orphan; Pathway interactions; Phosphorylation; Phosphotransferases; Pituitary Gland; Pituitary Gonadotropins; Play; Post-Translational Protein Processing; Promoter Regions; Protein Kinase; Proteins; RNA-Binding Proteins; Regulation; Role; Route; SF1; Signal Pathway; Signal Transduction; Site; Steroid biosynthesis; System; Technology; Testing; Therapeutic Agents; Transgenic Mice; Transgenic Organisms; Translations; WNT Signaling Pathway; cancer cell; extracellular; gonad function; hypothalamic pituitary gonadal axis; in vivo; jun Oncogene; malignant endocrine gland neoplasm; member; new therapeutic target; novel; overexpression; promoter; receptor; receptor binding; recombinase; reproductive; reproductive function; sensor

DESCRIPTION (provided by applicant): This application investigates three new and discrete aspects of the GnRH transcriptional network. Aim 1 should reveal to what extent post-transcriptional and post-translational mechanisms interface with GnRH regulated transcription of Egr1. While these mechanisms have been studied for IEGs in other systems, their role in gonadotropes remains unknown. We are convinced that the combination of post-transcriptional and post-translational contributions will provide a powerful one, two punch that ensures Egr1 mRNA and EGR1 protein reach maximally effective concentrations after transcriptional stimulation by GnRH. Aim 2 draws upon steadily emerging evidence, including our own, indicating that 2-catenin may be viewed as a new member of the GnRH signaling pathway that plays an instrumental role in regulating hormone stimulated expression of Jun mRNA and possibly Atf3 and Egr1 mRNA. Almost nothing is known about the signaling pathways GnRH uses to regulate transcription of Jun. Our approach addresses the role of 2-catenin as well as major pathway components such as PKC, PKA, and PI3K. Thus, Aim 2 is comprehensive and addresses a timely and important topic. The studies in Aim 3 address another novel feature of 2-catenin, namely its role as a required co-activator for SF1, certainly in acting permissively to allow Lhb to respond to transcriptional cues that flow from GnRH through Egr1. We suspect that the role of 2-catenin is broader and will extend to the other three signature genes that depend on SF1 for their expression. While Aims 1 and 2 are heavy on molecular detail and reliant on a gonadotrope cell line, Aim 3 uses transgenic technology to determine whether the requirement for 2-catenin and SF1 occurs in vivo and within the setting of a functional HPG axis. Most importantly, the transgenic approaches described in Aim 3 provide an exciting future direction that will be used to determine whether post-transcriptional and post-translational modifications uncovered for Egr1 have a significant impact when studied in vivo and in the context of a functional HPG axis. In short, we have charted an exciting new course that will deepen our mechanistic understanding of how GnRH controls gonadotrope homeostasis when signaling through a complex transcriptional network. Project Narrative: Normal reproductive function requires precise hypothalamic-gonadal control of the pituitary gonadotropins, LH and FSH. Too much or too little of either hormone disrupts gonadal function causing a spectrum of diseases ranging from infertility to endocrine cancer. This application focuses on GnRH, the hypothalamic hormone that signals through a cascade of protein kinases to regulate transcription, translation and ultimately secretion of LH and FSH from gonadotropes. Within this context, we consider how a tiered network of primary, secondary, and tertiary genes respond to the GnRH signal as well as contributions from components that act independently of GnRH. Completing these aims will deepen our understanding of the mechanistic coordination of gonadotrope gene expression required for maintaining reproductive homeostasis within the hypothalamic-pituitary-gonadal axis. Such an understanding is required for identifying new therapeutic targets and agents that can be used to either promote fertility or treat infertility and other endocrine disorders including hormone-dependent cancer.

描述（由申请人提供）：本申请研究了GNRH转录网络的三个新的离散方面。 AIM 1应揭示与GNRH调节的EGR1转录的转录后和翻译后机制在多大程度上。尽管这些机制已在其他系统中的IEG中进行了研究，但它们在促性腺体中的作用仍然未知。我们坚信，转录后和翻译后贡献的结合将提供有力的两次打孔，以确保Egr1 mRNA和EGR1蛋白在GNRH转录刺激后达到最大有效的浓度。 AIM 2利用了包括我们自己的稳定新兴证据，表明2-catenin可能被视为GNRH信号传导途径的新成员，该途径在调节激素刺激JUN mRNA的激素表达方面起着工具作用，可能是ATF3和EGR1 mRNA。 GNRH用来调节Jun的转录的信号通路几乎一无所知。我们的方法探讨了2-catenin以及主要途径成分（例如PKC，PKA和PI3K）的作用。因此，AIM 2是全面的，并解决了一个及时，重要的话题。 AIM 3中的研究介绍了2-catenin的另一个新型特征，即作为SF1所需的共激活因子的作用，当然可以允许起作用以允许LHB响应从GNRH到EGR1的转录提示。我们怀疑2-catenin的作用更广泛，并将扩展到依赖SF1表达的其他三个签名基因。虽然目标1和2在分子细节上很重，并且依赖于促性腺细胞系，但AIM 3使用转基因技术来确定对2-catenin和SF1的需求是否发生在体内和功能性HPG轴的环境中。最重要的是，AIM 3中描述的转基因方法提供了令人兴奋的未来方向，该方向将用于确定针对EGR1发现的转录后和翻译后修饰是否会在体内进行研究并在功能性HPG轴的背景下产生重大影响。 。简而言之，我们绘制了一个令人兴奋的新课程，该课程将加深我们对GNRH如何控制促性腺稳态的机械理解，当时通过复杂的转录网络发出信号。 项目叙述：正常的生殖功能需要精确的垂体性促性腺激素，LH和FSH的下丘脑基达控制。两种激素的过多或太少会破坏性腺功能，导致各种疾病范围从不孕症到内分泌癌。该应用集中在GnRH上，GNRH是通过蛋白激酶级联反应的下丘脑激素，以调节促性腺激素的LH和FSH的转录，翻译和最终分泌。在这种情况下，我们考虑了基本，次级和第三级基因的分层网络如何响应GNRH信号以及独立于GNRH的组件的贡献。完成这些目标将加深我们对在下丘脑 - 垂体 - 间轴轴内维持生殖稳态所需的性腺基因表达的机械配位的理解。需要这种理解来识别可用于促进生育能力或治疗不育和其他内分泌疾病在内的新治疗靶标和药物，包括激素依赖性癌症。