Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli

抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体复合物的抑制

基本信息

  • 批准号:
    10217057
  • 负责人:
  • 金额:
    $ 65.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-15 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary Inhibition of Wnt Receptor Activation by the Tumor Suppressor Adenomatous Polyposis Coli The long-term objective of this study is to investigate how the tumor suppressor Adenomatous polyposis coli (APC) inhibits the Wnt signal transduction pathway by regulating the Wnt receptor complex (signalosome) and to demonstrate how this can be exploited to target APC mutant colorectal cancers (CRCs). Wnt signaling is essential for intestinal stem cell maintenance, whereas aberrant activation of this pathway, which occurs most frequently through mutational inactivation of APC, triggers the development of the vast majority of CRCs. In the classical model for Wnt signaling, the sole role of APC is to destabilize the key transcriptional activator in the Wnt pathway, beta-catenin. However, our recently published findings reveal an additional and entirely new function – APC prevents the internalization and consequent activation of the signalosome, a novel role that is evolutionarily conserved. We have shown that: 1) inducible loss of APC is rapidly followed by ligand-independent signalosome activation; 2) depletion or antibody-mediated inhibition of LRP6 (a signalosome component) inhibits the stabilization of beta-catenin, the transcriptional activation of Wnt target genes, and the proliferation of APC mutant cells; and 3) in APC mutant cells, endocytosis of Wnt receptors is required for the aberrant activation of Wnt signaling. The goal of this project is to use in vitro, ex vivo, and in vivo approaches to gain a better understanding of how APC inhibits signalosome activation under physiological conditions and to determine how aberrant activation of the signalosome underlies the consequences of APC inactivation in tumors. The three specific aims are to: 1) elucidate the mechanism by which APC loss promotes signalosome assembly in CRC cells; 2) identify the APC mutant CRC cells most susceptible to LRP6 inactivation; and 3) test the efficacy of LRP6 inactivation on CRC tumorigenicity in vivo. Because the molecular mechanisms by which APC prevents the aberrant activation of Wnt signaling are important for our understanding of colorectal carcinogenesis, the knowledge gained from this study will aid in the development of new therapeutic strategies for the treatment of CRC and other Wnt-driven cancers.
项目总结

项目成果

期刊论文数量(0)
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Yasmath Ahmed其他文献

Yasmath Ahmed的其他文献

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{{ truncateString('Yasmath Ahmed', 18)}}的其他基金

A Cereblon signaling network in Wnt-driven cancers
Wnt 驱动的癌症中的 Cereblon 信号网络
  • 批准号:
    10670555
  • 财政年份:
    2023
  • 资助金额:
    $ 65.05万
  • 项目类别:
Super-resolution spinning disk confocal microscope for Dartmouth Life Sciences
用于达特茅斯生命科学的超分辨率转盘共焦显微镜
  • 批准号:
    10427997
  • 财政年份:
    2022
  • 资助金额:
    $ 65.05万
  • 项目类别:
Genetic and Molecular Dissection of Wnt Pathway Activation
Wnt 通路激活的遗传和分子剖析
  • 批准号:
    10163216
  • 财政年份:
    2020
  • 资助金额:
    $ 65.05万
  • 项目类别:
Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli
抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体复合物的抑制
  • 批准号:
    10063347
  • 财政年份:
    2020
  • 资助金额:
    $ 65.05万
  • 项目类别:
Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli
抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体复合物的抑制
  • 批准号:
    10653134
  • 财政年份:
    2020
  • 资助金额:
    $ 65.05万
  • 项目类别:
Genetic and Molecular Dissection of Wnt Pathway Activation
Wnt 通路激活的遗传和分子剖析
  • 批准号:
    10417184
  • 财政年份:
    2020
  • 资助金额:
    $ 65.05万
  • 项目类别:
Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli
抑癌基因腺瘤性息肉病大肠杆菌对 Wnt 受体复合物的抑制
  • 批准号:
    10424450
  • 财政年份:
    2020
  • 资助金额:
    $ 65.05万
  • 项目类别:
Role of ADP-ribosylation in Wnt Pathway Activation
ADP-核糖基化在 Wnt 通路激活中的作用
  • 批准号:
    9892659
  • 财政年份:
    2017
  • 资助金额:
    $ 65.05万
  • 项目类别:
Role of ADP-ribosylation in Wnt Pathway Activation
ADP-核糖基化在 Wnt 通路激活中的作用
  • 批准号:
    9383497
  • 财政年份:
    2017
  • 资助金额:
    $ 65.05万
  • 项目类别:
APC Tumor Suppressor in Cell Differentiation and Death
APC 肿瘤抑制因子在细胞分化和死亡中的作用
  • 批准号:
    9383490
  • 财政年份:
    2017
  • 资助金额:
    $ 65.05万
  • 项目类别:

相似海外基金

APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    7620114
  • 财政年份:
    2006
  • 资助金额:
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APC mutation and breast cancer: Prevention by curcumin
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    $ 65.05万
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APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    7247167
  • 财政年份:
    2006
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    $ 65.05万
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  • 批准号:
    7132974
  • 财政年份:
    2006
  • 资助金额:
    $ 65.05万
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APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    8260721
  • 财政年份:
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  • 资助金额:
    $ 65.05万
  • 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    7813928
  • 财政年份:
    2006
  • 资助金额:
    $ 65.05万
  • 项目类别:
APC mutation and the initiation of colorectal cancer
APC突变与结直肠癌的发生
  • 批准号:
    nhmrc : 400251
  • 财政年份:
    2006
  • 资助金额:
    $ 65.05万
  • 项目类别:
    NHMRC Project Grants
Development of novel screening method by detection of APC mutation from colorectal cancer cells in stool
开发粪便中结直肠癌细胞APC突变检测新筛查方法
  • 批准号:
    17591404
  • 财政年份:
    2005
  • 资助金额:
    $ 65.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER
饮食与结肠癌 APC 突变的相互作用
  • 批准号:
    2748805
  • 财政年份:
    1995
  • 资助金额:
    $ 65.05万
  • 项目类别:
DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER
饮食与结肠癌 APC 突变的相互作用
  • 批准号:
    2111759
  • 财政年份:
    1995
  • 资助金额:
    $ 65.05万
  • 项目类别:
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