Dissecting the Molecular Mechanisms of Canonical Wnt Signaling

剖析经典 Wnt 信号转导的分子机制

基本信息

  • 批准号:
    8294652
  • 负责人:
  • 金额:
    $ 28.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2014-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): A central characteristic of cancer cells is the ability of the cells to become deregulated in their normal function and subsequently undergo rapid division (tumor growth) and changes in their migratory behavior (tumor metastasis). Several signaling molecules along with components of their signaling pathways have been implicated as causative factors for, one of these being Wnt proteins. There is important evidence for a role of Wnt signaling in cancers as Wnt proteins can transform mammary cells and mutations in components of the Wnt signaling pathway such as 2-Catenin have been shown to play causative roles in cancers in humans. In fact, the first Wnt protein, Wnt-1, was identified as a factor when aberrantly expressed in the mammary gland resulted in breast cancer. We therefore propose that identifying the molecular components and understanding the mechanisms of Wnt signaling remains crucial for our understanding of human cancer formation. Studies have shown that Wnt signaling through the cytoplasmic protein Dishevelled (Dvl) induces the stabilization and nuclear translocation of 2-catenin (2-cat), which then regulates transcriptional induction of Wnt-target genes. However, the regulation of 2-cat nuclear translocation remains poorly defined and also the regulation of 2-cat transcriptional activity is not fully understood. This proposal is directed towards the characterization of a new modulator of Wnt signaling. We have identified this molecule termed DBP, for Dishevelled Binding Molecule, via a yeast-two hybrid screen using Dvl as a bait. In mammalian cells, DBP interacts with key components of the Wnt signaling pathway including Dvl and Casein kinase 1 (CK1), and antagonizes Wnt-stimulated transcriptional induction. Cellular localization studies of DBP demonstrate that this protein is normally present in both the cytoplasmic and nuclear compartments of cells. However, in response to Wnt stimulation, DBP becomes predominantly localized to the nucleus. Furthermore, DBP influences the subcellular localization of 2- cat, a crucial factor required for the transcriptional induction of Wnt-target genes. In vivo analysis of DBP during Xenopus development perturbs embryonic pattern formation and depletion of DBP prevents embryonic head formation. Based on our preliminary studies, we hypothesize that DBP is an essential component required for Wnt signaling. We propose two specific aims in this grant proposal and our studies are directed towards a biochemical, cell biological and in-vivo characterization of DBP to delineate its mode of action along with a recently identified effector for DBP. These studies will utilize mammalian culture cells and the Xenopus embryo as model systems. Towards this end, our studies are directed towards uncovering and understanding the role of these two new components of the Wnt signaling pathway. We propose that analyzing these new components will help to define the molecular nature of Wnt signaling from the plasma membrane to the cell nucleus and ultimately lead to a better understanding of how deregulated Wnt signaling results in cancer formation. PUBLIC HEALTH RELEVANCE: Understanding the development of human cancers remains dependent on identifying key signaling molecules and their signal transduction pathways that contribute to this pathology. One key-signaling molecule that has been demonstrated to play causative roles in human cancer is the Wnt protein. Our studies are focused on understanding two new molecules that we have identified that function in the Wnt signaling pathway, and we propose that these studies can provide important new insights into cancer formation.
描述(由申请人提供):癌细胞的一个核心特征是细胞正常功能失控,随后经历快速分裂(肿瘤生长)和迁移行为改变(肿瘤转移)的能力。一些信号分子及其信号通路的组成部分已被认为是致病因素,其中之一是Wnt蛋白。有重要证据表明Wnt信号在癌症中的作用,因为Wnt蛋白可以转化乳腺细胞,并且Wnt信号通路组分(如2-Catenin)的突变已被证明在人类癌症中起致病作用。事实上,第一个Wnt蛋白Wnt-1在乳腺中异常表达导致乳腺癌时被确定为一个因素。因此,我们认为识别Wnt信号的分子成分和理解Wnt信号的机制对于我们理解人类癌症的形成仍然至关重要。研究表明,Wnt信号通过细胞质蛋白disheveled (Dvl)诱导2-catenin (2-cat)的稳定和核易位,进而调控Wnt靶基因的转录诱导。然而,2-cat核易位的调控仍然不明确,2-cat转录活性的调控也没有完全了解。这一建议是针对表征一个新的Wnt信号调制器。我们已经确定了这种分子称为DBP,即散乱结合分子,通过酵母-二杂交筛选,以Dvl为诱饵。在哺乳动物细胞中,DBP与Wnt信号通路的关键组分相互作用,包括Dvl和酪蛋白激酶1 (CK1),并拮抗Wnt刺激的转录诱导。DBP的细胞定位研究表明,该蛋白通常存在于细胞的细胞质和核室中。然而,在对Wnt刺激的反应中,DBP主要局限于细胞核。此外,DBP影响2- cat的亚细胞定位,这是wnt靶基因转录诱导所需的关键因素。爪蟾发育过程中DBP的体内分析扰乱了胚胎模式的形成,DBP的消耗阻碍了胚胎头的形成。基于我们的初步研究,我们假设DBP是Wnt信号传导所必需的重要成分。我们在这份拨款申请中提出了两个具体目标,我们的研究主要针对DBP的生化、细胞生物学和体内特性,以描述其作用模式以及最近发现的DBP效应物。这些研究将利用哺乳动物培养细胞和爪蟾胚胎作为模型系统。为此,我们的研究旨在揭示和理解Wnt信号通路中这两个新组成部分的作用。我们提出,分析这些新成分将有助于定义从质膜到细胞核的Wnt信号的分子性质,并最终更好地理解Wnt信号的失调如何导致癌症的形成。

项目成果

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Raymond Habas其他文献

Raymond Habas的其他文献

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{{ truncateString('Raymond Habas', 18)}}的其他基金

Characterization of two proteins that regulate vertebrate
调节脊椎动物的两种蛋白质的表征
  • 批准号:
    10531664
  • 财政年份:
    2022
  • 资助金额:
    $ 28.78万
  • 项目类别:
The role of SRGAP2 in vertebrate gastrulation and neural tube closure
SRGAP2在脊椎动物原肠胚形成和神经管闭合中的作用
  • 批准号:
    8970386
  • 财政年份:
    2015
  • 资助金额:
    $ 28.78万
  • 项目类别:
Understanding The Role of Custos in Canonical Wnt Signaling
了解 Custos 在规范 Wnt 信号传导中的作用
  • 批准号:
    9134182
  • 财政年份:
    2015
  • 资助金额:
    $ 28.78万
  • 项目类别:
Understanding The Role of Custos in Canonical Wnt Signaling
了解 Custos 在规范 Wnt 信号传导中的作用
  • 批准号:
    8944441
  • 财政年份:
    2015
  • 资助金额:
    $ 28.78万
  • 项目类别:
Identifying and characterizing new components for Wnt signaling
识别和表征 Wnt 信号传导的新组件
  • 批准号:
    9041649
  • 财政年份:
    2015
  • 资助金额:
    $ 28.78万
  • 项目类别:
Identifying and characterizing new components for Wnt signaling
识别和表征 Wnt 信号传导的新组件
  • 批准号:
    8868555
  • 财政年份:
    2015
  • 资助金额:
    $ 28.78万
  • 项目类别:
The role of SRGAP2 in vertebrate gastrulation and neural tube closure
SRGAP2在脊椎动物原肠胚形成和神经管闭合中的作用
  • 批准号:
    9128002
  • 财政年份:
    2015
  • 资助金额:
    $ 28.78万
  • 项目类别:
Non-canoical Wnt signaling and cell motility
非典型 Wnt 信号传导和细胞运动
  • 批准号:
    8034898
  • 财政年份:
    2010
  • 资助金额:
    $ 28.78万
  • 项目类别:
Dissecting the Molecular Mechanisms of Canonical Wnt Signaling
剖析经典 Wnt 信号转导的分子机制
  • 批准号:
    8009140
  • 财政年份:
    2010
  • 资助金额:
    $ 28.78万
  • 项目类别:
Dissecting the Molecular Mechanisms of Canonical Wnt Signaling
剖析经典 Wnt 信号转导的分子机制
  • 批准号:
    8499357
  • 财政年份:
    2010
  • 资助金额:
    $ 28.78万
  • 项目类别:
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