Nuclear AXIN2 and Colorectal Cancer

项目总结 结直肠癌(CRC)是第三种最常见的癌症，也是第三大致癌原因。 在美国发生了相关死亡事件。发现Wnt/β-连环蛋白信号通路各组成部分发生突变 在90%的自发发生的癌中。这些突变导致β-连环蛋白转录产物的积累 核内共激活因子与Wnt/β-catenin靶基因的非调控表达，包括轴突抑制 两个(AXIN2)。AXIN2的主要作用被描述为一种细胞质蛋白，它服务于 通过靶向蛋白酶体降解的β-连环蛋白来减轻Wnt信号。然而，在CRC中，我们发现 AXIN2定位于胞质和胞核。我们发现AXIN2直接抑制 β-连环蛋白与T细胞因子形成三元复合体表达c-myc原癌基因 MYC附近的WNT反应DNA调控元件(WRE)的转录因子。因此，我们 假设核AXIN2调节Wnt/β-catenin靶基因表达促进肿瘤发生。在……里面 目的1，我们将确定核AXIN2和β调控的Wnt/AXIN2-Catenin靶基因的纲要。 机械地评估AXIN2如何调节它们的表达。在目标2中，我们将评估核能是否 AXIN2调节已建立的人结直肠癌细胞系的致癌潜能。这项工作将进一步阐明 致癌基因Wnt/β-catenin信号如何控制基因表达并可能导致新基因的发现 以及具有潜在治疗意义的途径。

PROJECT SUMMARY Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer- related deaths in the United States. Mutations in components of the Wnt/β-catenin signaling pathway are found in 90% of spontaneously arising CRCs. These mutations lead to accumulation of the β-catenin transcriptional co-activator in the nucleus and deregulated expression of Wnt/β-catenin target genes, including Axis inhibition two (AXIN2). The predominant role of AXIN2 has been described as a cytoplasmic protein that serves to mitigate Wnt signaling by targeting β-catenin for proteasomal degradation. However, in CRCs, we find that AXIN2 localizes both to cytoplasmic and nuclear compartments. We have found that AXIN2 directly represses expression of the c-MYC proto-oncogene by forming a ternary complex with β-catenin and T-cell factor (TCF) transcription factors at Wnt responsive DNA regulatory elements (WREs) in proximity to MYC. We therefore hypothesize that nuclear AXIN2 regulates Wnt/β-catenin target gene expression to promote tumorigenesis. In Aim 1, we will define the compendium of Wnt/β-catenin target genes regulated by nuclear AXIN2 and mechanistically assess how AXIN2 regulates their expression. In Aim 2, we will evaluate whether nuclear AXIN2 regulates the oncogenic potential of established human CRC cell lines. This work will further elucidate how oncogenic Wnt/β-catenin signaling controls gene expression and may lead to discovery of novel genes and pathways of potential therapeutic relevance.