The Molecular Regulation of Gli2 in Hedgehog Signaling

Hedgehog 信号转导中 Gli2 的分子调控

基本信息

批准号：
8299077
负责人：
BAOLIN WANG
金额：
$ 33.13万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8299077
关键词：
Activator Appliances Biological Biological Assay C-terminal Cancer Etiology Cell Differentiation process Cell Proliferation Cells Congenital Abnormality Cultured Cells Cyclic AMP-Dependent Protein Kinases Data Defect Development Drosophila genus Embryo Embryonic Development Embryonic Structures Enzymes Erinaceidae Family Gene Targeting Genes Gli2 protein Health Human Knock-in Mouse Length Malignant Neoplasms Mediating Modification Molecular Mus Mutate Nature Organogenesis Pathway interactions Pattern Phosphorylation Play Post-Translational Protein Processing Prevention Process Production Promoter Regions Property Proteins Recruitment Activity Regulation Reporter Role Signaling Protein Site Specific qualifier value Spinal Cord Testing Therapeutic Agents Transcription Coactivator Transcriptional Activation Ubiquitin Zinc Fingers base cell fate specification cell type design genetic analysis hedgehog signal transduction human HDAC5 protein in vivo insight morphogens multicatalytic endopeptidase complex mutant null mutation overexpression prevent smoothened signaling pathway transcription factor

项目摘要

DESCRIPTION (provided by applicant): The Hedgehog (Hh) family of secreted signaling proteins plays important roles in organogenesis and patterning of the embryo. Loss of the Hh signaling results in severe developmental defects, whereas aberrant activation of the Hh pathway is associated with several common types of human cancer. A thorough understanding of the molecular mechanism of Hh signal transduction is crucial for prevention and remedy of the abnormalities related to the Hh pathway. In mice, Hh signaling is primarily mediated by the Gli2 and Gli3 transcription factors. Gli2 is generally considered to be a transcriptional activator, while Gli3 acts largely as a repressor, though it also has a weak activator function. The distinct functions of Gli2 and Gli3 is primarily attributed to their intrinsic molecular properties, and is also due to the fact that in the absence of Hh signaling, the majority of the full-length Gli3 protein undergoes the proteasome-mediated processing to a C-terminally truncated repressor, while only a small fraction of Gli2 is processed. The processing of both proteins is induced by the phosphorylation of the first four of the six protein kinase A (PKA) sites at their C-termini. Hh signaling inhibits Gli2 and Gli3 processing and generates the full-length Gli2 and Gli3 proteins. However, full- length Gli2 itself is not sufficient to activate Hh target genes and thus has to be converted into an activator; this conversion is also dependent on Hh signaling. To date, the mechanism of production and molecular nature of the Gli2 activator are unknown. Our preliminary studies indicate that post-translational modification plays a critical role in the regulation of Gli2 transcriptional activity. We thus hypothesize that Hh signaling activates full-length Gli2 protein by regulating its post-translational modification. We will test this hypothesis by perusing two specific aims. Aim 1. To understand the biological significance and mechanism of PKA phosphorylation- mediated suppression of Gli2 activity; Aim 2. To understand the role of SUMO modification in the regulation of Gli2 activity and the molecular mechanism underlying it. The completion of the proposed study will significantly advance our understanding of the molecular mechanisms by which Hh signaling regulates Gli2 transcriptional activity. It may also give us insight into the molecular mechanisms of the human birth defects and cancer associated with abnormal Hh signaling. PUBLIC HEALTH RELEVANCE: The Hedgehog (Hh) family of secreted signaling proteins plays fundamental roles in cell fate specification and cell proliferation and differentiation. Loss of Hh signaling results in a wide range of birth defects, whereas aberrant activation of the Hh pathway causes several types of human cancer. Understanding the molecular mechanism of Hh signaling may provide insights into the design of therapeutic agents to modulate Hh pathway activity and therefore prevent or treat birth defects and cancers caused by misregulation of the Hh signaling activity.

描述（由申请人提供）：分泌信号蛋白的刺猬（HH）家族在胚胎的器官发生和模式中起重要作用。 HH信号传导的丧失导致严重的发育缺陷，而HH途径的异常激活与几种常见的人类癌症相关。对HH信号转导的分子机制的透彻理解对于预防与HH途径相关的异常情况至关重要。在小鼠中，HH信号主要由GLI2和GLI3转录因子介导。 GLI2通常被认为是转录激活剂，而GLI3主要充当阻遏物，尽管它也具有较弱的激活剂函数。 Gli2和Gli3的独特功能主要归因于它们的固有分子特性，也是由于这样一个事实，即在没有HH信号传导的情况下，大多数全长GLI3蛋白都经历了蛋白酶体介导的处理，而蛋白酶体介导的处理与C-末端截短的抑制器，而Gli2则仅处理Gli2的小额fraction。两种蛋白质的加工是通过其C-末端的六种蛋白激酶A（PKA）位点的磷酸化诱导的。 HH信号传导抑制GLI2和GLI3处理，并生成全长GLI2和GLI3蛋白。但是，全长GLI2本身不足以激活HH靶基因，因此必须转换为激活剂。该转换还取决于HH信号传导。迄今为止，Gli2激活剂的生产机理和分子性质尚不清楚。我们的初步研究表明，翻译后修饰在调节GLI2转录活性中起关键作用。因此，我们假设HH信号通过调节其翻译后修饰来激活全长Gli2蛋白。我们将通过仔细研究两个具体目标来检验这一假设。目的1。了解PKA磷酸化介导的GLI2活性抑制的生物学意义和机制；目的2。了解Sumo修饰在GLI2活性调节中的作用和其基础机制的作用。拟议研究的完成将显着提高我们对HH信号调节GLI2转录活性的分子机制的理解。它也可能使我们深入了解与异常HH信号相关的人类先天缺陷和癌症的分子机制。公共卫生相关性：分泌信号蛋白的刺猬（HH）家族在细胞命运规格以及细胞增殖和分化中起着基本作用。 HH信号传导的丧失导致广泛的先天缺陷，而HH途径的异常激活会导致几种类型的人类癌症。了解HH信号传导的分子机制可能会为治疗剂设计以调节HH途径活性的设计提供见解，从而预防或治疗由于HH信号传导活性的不正调而导致的出生缺陷和癌症。