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StAR expression: Integration of Transcription with regulation via the mRNA 3'UTR

StAR 表达：通过 mRNA 3UTR 进行转录与调控的整合

基本信息

批准号：
8305619
负责人：
COLIN ROBERT JEFCOATE
金额：
$ 30.67万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-22 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305619
关键词：
3&apos Untranslated Regions Acetylation Acetylesterase Acute Address Adrenal Cortex Adrenal Glands Adrenal gland hypofunction Affect Attenuated Binding CREB1 gene Cardiovascular system Cattle Cell Line Cell Separation Cells Characteristics Cholesterol Cholesterol Monooxygenase (Side-Chain-Cleaving)Complex Corticotropin Cyclic AMP Cyclic AMP-Dependent Protein Kinases Dependence Excision Fingers Genes Genetic Transcription Genetic Translation Histone Acetylation Histones Human Hydrocortisone Laboratories Lead Ligands Lipids Mediating Mediation Mediator of activation protein Messenger RNA Metabolic syndrome Modification Mus Mutate Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Export Output Pathway interactions Phorbol Esters Phosphorylation Phosphotransferases Play Post-Transcriptional Regulation Post-Translational Protein Processing Pregnenolone Process Protein Kinase C Proteins RNA Polymerase II Reaction Time Regulation Research Role SF1 Site Specific qualifier value Staging Steroid biosynthesis Steroids Stimulus Stress Testing Time Tissues Transcript Transcriptional Activation Transgenes Translations Trichostatin A U-0126 Work base biological adaptation to stress butyrate response factor 1 chromatin immunoprecipitation dietary control genetic regulatory protein hypothalamic-pituitary-adrenal axis in vivo inhibitor/antagonist leptomycin B mRNA Transcript Degradation novel promoter response transcription factor

项目摘要

Cortisol synthesis in the adrenal cortex plays a central role in stress responses, in dietary control, and in cardiovascular regulation. Aberrations in this control of the hypothalamic pituitary adrenal axis play an important part in the Metabolic Syndrome that is often associated with Type 2 diabetes. ACTH stimulation of cortisol synthesis starts with the conversion of cholesterol to pregnenolone by mitochondrial cytochrome P450 11A1. Activation of this step depends on new synthesis of the steroidogenesis acute regulator (StAR) and its phosphorylation by protein kinase A (PKA). StAR deficiency causes hyperlipidemic adrenal insufficiency. This research focuses on the finding that StAR expression is stimulated in very different ways by PKA and by protein kinase C (PKC). We will show how these processes are clearly distinguished by essential contributions from, respectively, histone de-acetylatases and Erk kinase. We will characterize these processes for different contributions from nuclear factors, including the differentiation regulator, SF-1. This includes time-dependent modifications that cycle up and down during transcription (phosphorylation/de-phosphorylation and acetylation/de- acetylation). Evidence will be developed that PKA can also enhance a late stage in the PKC process, thus producing strong synergy in StAR transcription. Posttranscriptional regulation of StAR provides another point of distinction between PKA and PKC regulation. A novel regulator, the Zn finger protein, TIS11b, targets specific sequences in the extended 3'untranslated region of the 3.5 kb StAR mRNA. TIS11b is rapidly stimulated by PKA, but suppressed by PKC. We will identify specific TIS11b recognition sites at the end of the StAR 3.5 kb mRNA and show that this interaction can enhance StAR protein translation, while increasing mRNA degradation. We will test whether TIS11b is co-transcribed with StAR due to shared transcription factors, including SF-1. We will determine how these mechanisms interplay during ACTH stimulation, including in primary adrenal cell lines and in adrenals in vivo. The promoter and mRNA sequences that specify SF-1 and TIS11b interactions during StAR expression are substantially conserved from mouse to humans. We will test whether these mouse mechanisms are retained in human adrenal H295 cells. Our research shows that TIS11b interaction with StAR and predominance of an extended StAR mRNA are conserved in primary bovine adrenal cells and respond to ACTH. This work will bring together several laboratories to provide a first look at the interplay between PKA, SF-1, and TIS11b (or factors related to each), which is likely to occur in multiple steroidogenic tissues. Cortisol synthesis in the adrenal cortex plays a central role in stress responses, in dietary control, and in cardiovascular regulation. ACTH, which is elevated by stress, stimulates cortisol synthesis through enhanced conversion of cholesterol to pregnenolone. This step depends on new synthesis of the steroidogenesis acute regulator (StAR). The proposed research addresses a novel process, whereby ACTH stimulates not only transcription of StAR, but also a protein called TIS11b, which separately regulates StAR protein translation and mRNA degradation. We make a detailed analysis of regulatory processes that control StAR and TIS11b transcription in order to understand their potential coordination. TIS11b may accelerate the response time to stress, while also aiding in the removal of StAR when the ACTH stimulus is removed. TIS11b regulation is present in other tissues that make steroids (testis). Deficiency in this mRNA regulator may lead to more sluggish responses to ACTH and stress as well as abnormal cortisol output.

肾上腺皮质中的皮质醇合成在应激反应、饮食控制和免疫调节中起着重要作用。心血管调节下丘脑-垂体-肾上腺轴的这种控制中的畸变在 2型糖尿病是一种常见的代谢综合征。ACTH刺激皮质醇合成始于胆固醇通过线粒体细胞色素P450 11 A1转化为双烯醇酮。这一步骤的激活取决于类固醇生成急性调节因子（星星）及其受体的新合成。通过蛋白激酶A（PKA）磷酸化。星星缺乏会导致高脂血症性肾上腺功能不全。这项研究的重点是发现星星表达的刺激方式非常不同的PKA和蛋白激酶C（PKC）。我们将展示这些过程是如何通过基本贡献来明确区分的分别来自组蛋白去乙酰化酶和Erk激酶。我们将描述这些过程的不同来自核因子的贡献，包括分化调节因子SF-1。这包括时间依赖性在转录过程中上下循环的修饰（磷酸化/去磷酸化和乙酰化/去乙酰化），乙酰化）。将有证据表明PKA也可以增强PKC过程的晚期阶段，从而在星星转录中产生强烈的协同作用。邮政星星的转录调节提供了PKA和PKC调节之间的另一个区别点。一一种新的调节剂，锌指蛋白，TIS 11b，靶向在延伸的3 '非翻译区的特定序列， 3.5kb星星mRNA。TIS 11b被PKA快速激活，但被PKC抑制。我们将确定具体 TIS 11b识别位点位于星星3.5 kb mRNA的末端，表明这种相互作用可以增强星星蛋白质翻译，同时增加mRNA降解。我们将测试TIS 11b是否与星星共转录这是由于共有的转录因子，包括SF-1。我们将确定这些机制如何相互作用，在促肾上腺皮质激素刺激，包括在原代肾上腺细胞系以及体内的肾上腺。启动子和mRNA序列，指定SF-1和TIS 11b的相互作用，星星表达从小鼠到人类基本上是保守的。我们将测试这些老鼠机制保留在人肾上腺H295细胞中。我们的研究表明，TIS 11b与星星的相互作用，延伸星星mRNA的优势在原代牛肾上腺细胞中是保守的，并对ACTH有反应。这项工作将汇集几个实验室，以提供PKA，SF-1， TIS 11b（或与每个相关的因子），可能发生在多种类固醇生成组织中。肾上腺皮质中的皮质醇合成在应激反应中起着重要作用，饮食控制和心血管调节。促肾上腺皮质激素会因压力而升高，刺激皮质醇合成，通过增强胆固醇转化为去甲烯醇酮这一步取决于新的合成类固醇生成急性监管机构（星星）。这项研究提出了一个新的过程，不仅刺激星星的转录，还刺激一种名为TIS 11b的蛋白质，分别调节星星蛋白翻译和mRNA降解。我们做一个详细分析控制星星和TIS 11b转录的调控过程，以了解其潜在的协调性。TIS 11b可能会加速反应时间的压力，同时也有助于在去除星星时，促肾上腺皮质激素刺激是删除. TIS 11b调节存在于产生类固醇的其他组织（睾丸）中。这种mRNA调节因子的缺乏可能导致对ACTH的反应更加迟缓，压力以及异常的皮质醇分泌。