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

描述（由申请人提供）：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“2005年癌症事实与数据”，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肿瘤发生的生物学机制认识不足，尤其是对不同信号转导通路在结直肠肿瘤发生发展中的作用认识不足。虽然组成激活？-连环蛋白信号通路与人类癌症的发展有关，catenin/Tcf通路促进肿瘤发生的机制尚不完全清楚。我们的初步结果显示？-连环蛋白稳定？TrCP 1（SCF的底物识别组分？TrCP 1泛素连接酶）。我们将CRD-BP确定为？- catenin/Tcf转录因子。CRD-BP结合的编码区？TrCP 1 mRNA，并使其稳定。升高？TrCP 1水平导致SCF激活？TrCP 1泛素连接酶和加速营业额的底物，包括I？B。CRD-BP是必不可少的诱导？TrCP 1由？结直肠癌细胞中的连环蛋白信号传导。我们发现高水平的CRD- BP在原发性人类结直肠肿瘤中表现出活性？连环蛋白信号传导。我们假设CRD-BP的诱导是由？catenin信号转导的结果上调？TrCP 1、NF-？B与结直肠癌细胞凋亡的抑制。本研究拟探讨CRD-BP在结直肠肿瘤发生中的作用，Wnt信号通路对CRD-BP的调控，以及Wnt信号通路对CRD-BP的调控机制。TrCP 1 mRNA稳定化。根据这些目标，具体的目标是：（1）确定CRD-BP在结直肠癌发展中的作用。(2)为了阐明Wnt/β对CRD-BP的调节机制，catenin/Tcf信号转导。(3)以确定的机制？通过CRD-BP稳定TrCP 1 mRNA。总的来说，完成拟议的研究将确定CRD-BP在活化的？连环蛋白信号传导。它还将揭示的机制（S）？通过CRD-BP稳定TrCP 1 mRNA。公共卫生相关性：自？TrCP 1介导I？B对IKK诱导刺激（细胞因子、放射、化疗等）的反应，的机制？TrCP 1调节由？-连环蛋白信号传导可能潜在地导致能够抑制？TrCP 1功能和有效的癌症预防和治疗。

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.