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: 7798212
• 负责人: JOHN H. NILSON
• 金额: $ 38.41万
• 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/7798212
• 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; Hematopoietic; 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; 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GnRH转录网络的三个新的和离散的方面。目的1应揭示在何种程度上转录后和翻译后机制接口与GnRH调节Egr 1的转录。虽然这些机制已经在其他系统中研究了IEG，但它们在促性腺激素中的作用仍然未知。我们相信，转录后和翻译后的贡献相结合，将提供一个强大的一，两个冲床，确保Egr 1 mRNA和EGFR 1蛋白达到最大有效浓度后，由GnRH的转录刺激。目的2利用不断出现的证据，包括我们自己的，表明2-连环蛋白可能被视为GnRH信号通路的新成员，在调节激素刺激的Jun mRNA和可能的Atf 3和Egr 1 mRNA的表达中起着重要作用。几乎没有什么是已知的信号通路GnRH用于调节转录的Jun。我们的方法地址的作用，2-catenin以及主要的通路成分，如PKC，PKA，PI 3 K。因此，目标2是全面的，涉及一个及时和重要的主题。目标3中的研究解决了2-连环蛋白的另一个新特征，即它作为SF 1所需的共激活剂的作用，当然是允许Lhb对从GnRH通过Egr 1流动的转录线索做出反应。我们怀疑2-catenin的作用更广泛，并将扩展到其他三个依赖SF 1表达的标记基因。虽然目标1和2是重分子细节和依赖于促性腺细胞系，目标3使用转基因技术，以确定是否需要2-连环蛋白和SF 1发生在体内和功能性HPG轴的设置。最重要的是，目标3中描述的转基因方法提供了一个令人兴奋的未来方向，将用于确定Egr 1的转录后和翻译后修饰是否在体内研究和功能性HPG轴的背景下具有显着的影响。简而言之，我们已经绘制了一个令人兴奋的新课程，这将加深我们对GnRH如何通过复杂的转录网络进行信号传导时控制促性腺激素稳态的机械理解。 项目叙述：正常的生殖功能需要下丘脑-性腺对垂体促性腺激素LH和FSH的精确控制。任何一种激素过多或过少都会破坏性腺功能，导致一系列疾病，从不孕症到内分泌癌。该应用程序的重点是GnRH，下丘脑激素，通过蛋白激酶级联信号调节转录，翻译和最终从促性腺激素分泌LH和FSH。在这种情况下，我们考虑一级，二级和三级基因的分层网络如何响应GnRH信号以及来自独立于GnRH的成分的贡献。完成这些目标将加深我们对下丘脑-垂体-性腺轴内维持生殖稳态所需的促性腺激素基因表达的机制协调的理解。这种理解是确定新的治疗靶点和药物，可用于促进生育或治疗不孕症和其他内分泌疾病，包括乳腺癌依赖性癌症所必需的。