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

描述（由申请人提供）：异常的典型Wnt信号导致发育异常，Wnt信号的增加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。这引起了人们对识别用于治疗Wnt通路的小分子抑制剂的极大兴趣。最近，有研究表明，通过稳定轴蛋白抑制Wnt通路的小分子，如IWR-1和XAV939，将在治疗中发挥作用。轴蛋白是Wnt通路的一个关键负调控因子，因为它是Wnt通路的一个支架。-连环蛋白破坏复合物，在没有配体的情况下阻止通路。我们最近发现，在某些干细胞/祖细胞群体的发育过程中，通过突变或IWR-1处理来稳定轴蛋白具有与促进Wnt信号传导相反的作用。这些发现提出了干细胞中典型Wnt通路通路不同的可能性。我们将验证这一假设，即稳定的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-catenin的水平。我们将定义稳定的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体内其他细胞，其中Axin2蛋白的稳定性激活了典型的Wnt通路，重点关注肠、脑、乳腺和皮肤中可能作为癌症干细胞的Wnt依赖性干细胞。绝大多数人类结直肠癌病例与APC突变或沉默有关，APC是Wnt通路的负调节因子。我们将在小鼠ApcMin模型中测试Axin2稳定等位基因是否抑制或促进肠息肉的形成。这些研究将为干细胞/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提供一个范例，这将确定合适的治疗靶点。

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.