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）：异常的经典 Wnt 信号传导导致发育异常，而 Wnt 信号传导增加则驱动多种肿瘤的形成，包括儿童髓母细胞瘤和绝大多数人类结直肠癌。这引起了人们对鉴定用于治疗的 Wnt 通路小分子抑制剂的极大兴趣。最近，有人提出通过稳定 Axin 来抑制 Wnt 通路的小分子，例如 IWR-1 和 XAV939，将在治疗中有用。 Axin 是 Wnt 通路的关键负调节因子，因为它作为 β-连环蛋白破坏复合物的支架，在没有配体的情况下使通路保持关闭。我们最近发现，通过突变或 IWR-1 处理来稳定 Axin 会产生相反的作用，在某些干细胞/祖细胞群体的发育过程中促进 Wnt 信号传导。这些发现提出了干细胞中经典 Wnt 通路的回路可能不同的可能性。我们将测试以下假设：稳定的 Axin 可以通过促进 Axin-LRP5/6 膜复合物的形成来激活 Wnt 通路，从而增加游离 β-连环蛋白的水平。我们将定义稳定轴蛋白作用的细胞类型特异性的机制。我们将使用遗传方法来鉴定小鼠中 Axin2 蛋白的稳定激活经典 Wnt 通路的其他细胞，重点关注肠道、大脑、乳房和皮肤中可充当癌症干细胞的 Wnt 依赖性干细胞。绝大多数人类结直肠癌病例与 APC（Wnt 通路的负调节因子）的突变或沉默有关。我们将测试 Axin2 的稳定等位基因是否抑制或增强小鼠 ApcMin 模型中肠息肉的形成。这些研究将为干/祖细胞在对 Wnt 通路抑制剂的敏感性方面与其他细胞的不同之处提供一个范例，这将确定适当的治疗靶点。