The Role of CRD-BP-regulated mRNA Stability in Colorectal Cancers

描述(申请人提供)：结直肠癌是所有癌症中最致命的癌症之一。根据美国癌症协会“癌症事实与数字2005”，10%的癌症死亡与结直肠癌有关。结直肠癌治疗效果不佳的主要原因是我们对结直肠癌发生的生物学机制认识不足，尤其是不同信号转导通路在结直肠癌发生发展中的作用。尽管β-连环蛋白信号通路的结构性激活参与了人类癌症的发生发展，但其促进肿瘤发生的机制尚不完全清楚。我们的初步结果表明，β-连环蛋白稳定了TrCP1(SCF？TrCP1泛素连接酶的底物识别成分)的mRNA。我们发现CRD-BP是β-连环蛋白/Tcf转录因子的新靶点。CRD-BP与TrCP1mRNA的编码区结合，并使其稳定。？TrCP1水平升高导致SCF？TrCP1泛素连接酶激活，并加速其底物包括I？B的周转。CRD-BP是通过？-catenin信号在结直肠癌细胞中诱导？TrCP1的必不可少的。我们发现在原发人类大肠肿瘤中CRD-BP的表达水平很高，表现出活跃的？-连环蛋白信号。我们推测，在结直肠癌中，β-catenin信号诱导CRD-BP导致TrCP1上调，核因子-β活化，抑制细胞凋亡。我们建议研究CRD-BP在大肠肿瘤发生中的作用，Wnt信号通路对CRD-BP的调控，以及TrCP1mRNA稳定的机制。根据这些目标，具体目标是：(1)确定CRD-BP在结直肠癌发生中的作用。(2)阐明Wnt/β-catenin/Tcf信号对CRD-BP的调控机制(S)。(3)探讨CRD-BP稳定TrCP1mRNA的机制。总体而言，拟议研究的完成将确定CRD-BP在激活的？-catenin信号诱导的结直肠癌发生中的作用。这也将揭示CRD-BP稳定TrCP1mRNA的机制(S)。公共卫生相关性：由于？TrCP1在IKK诱导的刺激(细胞因子、辐射、化疗药物等)的作用下介导I？B的泛素化和降解，？-连环蛋白信号调节？TrCP1的机制可能会导致设计出能够抑制？TrCP1功能并有效预防和治疗癌症的药物。

DESCRIPTION (provided by applicant): Colorectal cancer is one of the most lethal of all of the cancers. According to American Cancer Society "Cancer Facts & Figures 2005" 10% of cancer deaths are associated with colorectal cancer. The major reason for lack of satisfactory management of colorectal cancer is our poor understanding of the biology of colorectal tumorigenesis, especially the role of different signal transduction pathways in the development of colorectal tumors. Although constitutive activation of ?-catenin signaling pathway is implicated in the development of human cancers, the mechanisms by which the ?-catenin/Tcf pathway promotes tumorigenesis are incompletely understood. Our preliminary results show that ?-catenin stabilizes mRNA of ?TrCP1 (substrate-recognizing component of SCF?TrCP1 ubiquitin ligase). We identified CRD-BP as a novel target of ?-catenin/Tcf transcription factor. CRD-BP binds to the coding region of ?TrCP1 mRNA, and stabilizes it. Elevated ?TrCP1 levels result in activation of the SCF?TrCP1 ubiquitin ligase and in accelerated turnover of its substrates including I?B. CRD-BP is essential for induction of ?TrCP1 by ?-catenin signaling in colorectal cancer cells. We found high levels of CRD- BP in primary human colorectal tumors exhibiting active ?-catenin signaling. We hypothesize that induction of CRD-BP by ?-catenin signaling results in up-regulation of ?TrCP1, activation of NF-?B and suppression of apoptosis in colorectal cancers. We propose to study the role of CRD-BP in colorectal tumorigenesis, the regulation of CRD-BP by Wnt signaling pathway, and the mechanisms of ?TrCP1 mRNA stabilization. Pursuant to these goals, the specific aims are: (1) To determine the role of CRD-BP in colorectal cancer development. (2) To delineate the mechanism(s) of CRD-BP regulation by Wnt/?-catenin/Tcf signaling. (3) To determine the mechanism of ?TrCP1 mRNA stabilization by CRD-BP. Overall, the completion of the proposed studies will define the role of CRD-BP in colorectal carcinogenesis induced by activated ?-catenin signaling. It will also uncover the mechanism(s) of ?TrCP1 mRNA stabilization by CRD-BP. Public Health Relevance: Since ?TrCP1 mediates ubiquitination and degradation of I?B in response to IKK-inducing stimuli (cytokines, radiation, chemotherapeutics, etc.), the mechanisms of ?TrCP1 regulation by ?-catenin signaling may potentially lead to design of the agents capable of inhibiting ?TrCP1 function and effective for cancer prevention and therapy.