CRD-BP-mediated regulation of Wnt signaling in intestinal tumorigenesis

描述（由申请人提供）：结直肠癌是所有癌症中最致命的一种。结直肠肿瘤发展的主要驱动因素之一是Wnt/β-连环蛋白信号通路。我们之前已经确定CRD-BP作为Wnt信号通路的真正转录靶点，并证明CRD-BP的诱导是导致人结直肠癌细胞中Wnt/β-连环蛋白信号传导的多种多效性效应的原因。我们已经证明：i）通过Wnt/β-连环蛋白信号传导的c-myc上调依赖于CRD-BP; ii）CRD-BP促进Wnt和NF-κB通路之间的串扰; iii）CRD-BP介导响应于Wnt信号传导的GLI 1转录活性的激活，而不依赖于Hh信号传导通路; iv）CRD-BP在转录上受c-myc调节，并且参与c-myc原癌基因的几种功能，包括对翻译、细胞凋亡和细胞凋亡的调节。 大小、细胞周期进程和细胞增殖; v）我们还发现了CRD-BP介导的β TrCP 1 mRNA稳定化的机制。我们假设CRD-BP在肠上皮细胞致癌转化中的Wnt/β-catenin信号转导的调节中起核心作用，包括其在维持、自我更新、分化和转化中的作用。 肠上皮干细胞（IESC）。我们建议研究CRD-BP参与肠道肿瘤发生的机制。根据这些目标，我们的具体目标是：1。分析CRD-BP在大肠癌细胞Wnt信号转导中的作用。2.探讨CRD-BP在肠道肿瘤发生中的作用机制。总体而言，完成拟议的研究将有助于阐明CRD-BP在结直肠癌发生中的作用。它也将描绘CRD-BP在这些肿瘤中的调节和功能的机制。这些研究可能会导致设计能够抑制CRD-BP的药物，用于治疗CRC。

DESCRIPTION (provided by applicant): Colorectal cancer is one of the most lethal of all cancers. One of the major drivers underlying the development of colorectal tumors is the Wnt/ß-catenin signaling pathway. We have previously established CRD-BP as a bona fide transcriptional target of Wnt signaling pathway and demonstrated that induction of CRD-BP is responsible for a variety of pleiotropic effects of Wnt/ß-catenin signaling in human colorectal cancer cells. We have demonstrated that: i) c-myc up-regulation by Wnt/ß-catenin signaling depends on CRD-BP; ii) CRD-BP facilitates cross-talk between Wnt and NF-κB pathways; iii) CRD-BP mediates activation of GLI1 transcriptional activity in response to Wnt signaling independently of Hh signaling pathway; iv) CRD-BP is transcriptionally regulated by c-myc and is involved in several functions of c-myc proto-oncogene, including regulation on translation, cell size, cell cycle progression, and cell proliferation; v) we have also uncovered a mechanism of CRD-BP-mediated stabilization of ßTrCP1 mRNA. We hypothesize that CRD-BP plays a central role in the modulation of Wnt/ß-catenin signaling in the oncogenic transformation of intestinal epithelia, including its role in the maintenance, self-renewal, differentiation, and transformation of intestinal epithelial stem cells (IESCs). We propose to study the mechanisms of CRD-BP involvement in intestinal tumorigenesis. Pursuant to these goals, our specific aims are: 1. To analyze the role of CRD-BP in the regulation of Wnt signaling in CRC cells. 2. To elucidate the mechanisms of CRD-BP function in intestinal tumorigenesis. Overall, the completion of the proposed studies will help elucidate the role of CRD-BP in colorectal carcinogenesis. It will also delineate the mechanisms of regulation and function of CRD-BP in these tumors. These studies may potentially lead to the design of agents capable of inhibiting CRD-BP that might be utilized in the therapy of CRC.