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

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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.