Tissue-specific Roles of Axin in Canonical Wnt Signaling and Tumorigenesis

轴蛋白在经典 Wnt 信号传导和肿瘤发生中的组织特异性作用

基本信息

批准号：
8448637
负责人：
Kathryn V Anderson
金额：
$ 18.7万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448637
关键词：
Adult Alleles Animals Axin protein Biochemical Bone Density Brain Breast Cells Cerebellum Characteristics Child Childhood Childhood Medulloblastomas Colorectal Colorectal Cancer Complex Defect Development Disease Embryo Foundations Gene Targeting Genetic Hematopoietic Human Institutes Intestinal Polyps Intestines Kidney Large Intestine Carcinoma Lead Ligands Malignant Childhood Neoplasm Malignant Neoplasms Membrane Modeling Mus Mutation Paraxial Mesoderm Pathway interactions Play Population Primitive Streaks Proteins Role Scaffolding Protein Signal Pathway Signal Transduction Skin Somatic Cell Specificity Stem cells Tankyrase Testing Therapeutic Intervention Tissues anticancer research base body system bone cancer stem cell cell type developmental disease improved in vivo inhibitor/antagonist innovation interest loss of function medulloblastoma novel prevent progenitor research study scaffold sex small molecule stem stem cell population tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Abnormal canonical Wnt signaling causes developmental abnormalities and increased Wnt signaling drives the formation of a variety of tumors, including the childhood medulloblastoma and the vast majority of human colorectal carcinomas. This has generated considerable interest in the identification of small molecule inhibitors of the Wnt pathway for therapy. Recently, it has been suggested that small molecules that inhibit the Wnt pathway through stabilization of Axin, such as IWR-1 and XAV939, would be useful in therapy. Axin is a key negative regulator of the Wnt pathway because of its role as a scaffold of the ?-catenin destruction complex, which keeps the pathway off in the absence of ligand. We recently discovered that stabilization of Axin through either mutation or by treatment with IWR-1 has the opposite effect of promoting Wnt signaling in certain stem/progenitor populations during development. These findings raise the possibility that the circuitry of the canonical Wnt pathway is different in stem cells. We will test the hypothesis that stabilized Axin can activate the Wnt pathway by favoring the formation of an Axin-LRP5/6 membrane complex that increases the level of free ?-catenin. We will define the mechanisms responsible for the cell type specificity of the effects of stabilized Axin protein. We will use a genetic approach to identify other cells in the mouse where stabilization of Axin2 protein activates the canonical Wnt pathway, focusing on the Wnt-dependent stem cells in the intestine, brain, breast and skin that could act as cancer stem cells. The vast majority of cases of human colorectal carcinoma are associated with mutation or silencing of APC, a negative regulator of the Wnt pathway. We will test whether the stabilized allele of Axin2 suppresses or enhances intestinal polyp formation in the mouse ApcMin model. The studies will provide a paradigm for how stem/progenitor cells differ from other cells in their sensitivity to Wnt pathway inhibitors, which will define appropriae targets for therapy.

描述（由申请人提供）：异常的典型WNT信号传导会引起发育异常，并增加WNT信号传导驱动了各种肿瘤的形成，包括儿童髓母细胞瘤和绝大多数人结肠直肠癌。这对鉴定Wnt途径的小分子抑制剂的鉴定引起了极大的兴趣。最近，有人提出，通过稳定AXIN（例如IWR-1和XAV939）抑制Wnt途径的小分子将在治疗中有用。 Axin是Wnt途径的关键负调节剂，因为它是 - 卡丁蛋白破坏复合物的脚手架的作用，在没有配体的情况下，它可以使该途径保持不变。我们最近发现，通过突变或用IWR-1处理稳定AXIN的作用是在发育过程中促进某些茎/祖细胞种群中Wnt信号传导的相反作用。这些发现增加了干细胞中规范WNT途径的电路不同的可能性。我们将检验以下假设：稳定的轴可以通过有利于形成的轴Lrp5/6膜复合物的形成来激活Wnt途径，从而增加了游离？-catenin的水平。我们将定义负责稳定轴蛋白作用细胞类型特异性的机制。我们将使用一种遗传方法来鉴定小鼠中的其他细胞，其中AXIN2蛋白的稳定化激活了规范的Wnt途径，重点是肠道，脑，乳腺和皮肤中的Wnt依赖性干细胞，可以用作癌症干细胞。绝大多数人结直肠癌病例与APC的突变或沉默是WNT途径的负调节剂的突变或沉默。我们将测试AXIN2的稳定等位基因抑制或增强小鼠APCMIN模型中的肠息肉形成。这些研究将为茎/祖细胞与其他细胞的不同对Wnt途径抑制剂的敏感性提供范式，这将定义适当的治疗靶标。