Regulation of Estrogen Signaling by Tuberin and Rheb

马铃薯蛋白和 Rheb 对雌激素信号的调节

• 批准号: 7091714
• 负责人: Elizabeth P Henske
• 金额: $ 42.75万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091714
• 关键词: G protein; apoptosis; athymic mouse; biological signal transduction; disease /disorder model; estradiol; estrogen receptors; estrogens; gene mutation; genetic transcription; guanosinetriphosphatases; hormone regulation /control mechanism; human tissue; lymphangioleiomyomatosis; mTOR protein; metastasis; orphan disease /drug; protein localization; protein protein interaction; serine threonine protein kinase; tissue /cell culture; tuberous sclerosis; tumor suppressor proteins; women' s health; xenotransplantation

DESCRIPTION (provided by applicant): This proposal is focused on the mechanisms through which the tuberous sclerosis complex (TSC) proteins, tuberin and hamartin, repress estrogen-mediated signals. Tuberin (TSC2) is known to interact with estrogen receptor (ER) alpha, and has been previously shown to inhibit ER-driven transcription. We have uncovered an additional, novel pathway linking tuberin and Rheb with 17-beta-estradiol (E2)-mediated signaling. Rheb was recently identified as the target of tuberin's highly conserved GTPase activating domain. Rheb activates the mammalian target of rapamycin (mTOR). In preliminary studies, we found that MCF-7 cells exposed to E2 rapidly convert Rheb to its inactive GDP-bound state. E2 exposure also rapidly activates S6 Kinase (S6K), a key target of mTOR. Activation of S6K by E2 is inhibited by tuberin expression. These data indicate that tuberin and Rheb transduce signals from E2 to mTOR. Our central hypothesis is that tuberin inhibits both rapid ("non-genomic") and transcriptional E2- dependent signaling pathways. To address this hypothesis, we propose the following specific aims: 1) To determine whether tuberin inhibits estradiol's activation of mTOR and S6K; 2) To determine the mechanism of tuberin's repression of ER-driven transcription; 3) To determine whether estradiol promotes the survival and metastasis of cells lacking tuberin, using both in vitro and in vivo models. This project will define the central estrogen signaling pathways that are regulated by tuberin and Rheb. These pathways may underlie the striking female predominance of lymphangiomyomatosis (LAM). Tuberin and Rheb are expressed in most normal tissues, and the clinical manifestations of TSC impact many organ systems, including the CNS. Estrogen-mediated signals are critical to many normal developmental and metabolic events and estrogen is linked to high prevalence human diseases. We strongly believe, therefore, that the results of this project will have broad medical and biological significance. Lay summary. Estrogen triggers many different cellular events. This project is focused on a protein, tuberin, which appears to inhibit estrogen's actions in the cytoplasm and in the nucleus. The results of this project will elucidate the cause of a female-predominant disease, lymphangiomyomatosis (LAM), and may also contribute to our understanding of other estrogen-linked diseases.

描述（由申请人提供）：该提案集中在结核性硬化症复合物（TSC）蛋白（TUBERIN和HAMARTIN）抑制雌激素介导的信号的机制上。已知Tuberin（TSC2）与雌激素受体（ER）α相互作用，并以前已证明可以抑制ER驱动的转录。我们发现了另外的新型途径，将Tuberin和Rheb与17β-雌二醇（E2）介导的信号传导联系起来。最近将Rheb确定为Tuberin高度保守的GTPase激活结构域的靶标。 Rheb激活雷帕霉素（MTOR）的哺乳动物靶标。在初步研究中，我们发现暴露于E2的MCF-7细胞迅速将RHEB转化为无活跃的GDP结合状态。 E2暴露还迅速激活S6激酶（S6K），这是MTOR的关键目标。 E2对S6K的激活被Tuberin表达抑制。这些数据表明Tuberin和Rheb从E2转移到MTOR。我们的中心假设是Tuberin抑制了快速（“非基因组”）和转录E2依赖性信号传导途径。为了解决这一假设，我们提出了以下特定目的：1）确定Tuberin是否抑制雌二醇的MTOR和S6K激活； 2）确定Tuberin抑制ER驱动转录的机制； 3）确定雌二醇是否促进了使用体外和体内模型的细胞的生存和转移。该项目将定义由Tuberin和Rheb调节的中央雌激素信号通路。这些途径可能是淋巴管瘤病（LAM）的惊人女性占主导地位的基础。 Tuberin和Rheb在大多数正常组织中表达，TSC的临床表现影响许多器官系统，包括CNS。雌激素介导的信号对于许多正常发育和代谢事件至关重要，雌激素与高患病率有关。因此，我们坚信该项目的结果将具有广泛的医学和生物学意义。摘要摘要。雌激素触发许多不同的细胞事件。该项目的重点是蛋白质Tuberin，该蛋白似乎抑制了雌激素在细胞质和细胞核中的作用。该项目的结果将阐明女性促疾病，淋巴管瘤病（LAM）的原因，也可能有助于我们对其他雌激素连接疾病的理解。