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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121851-05
Application #
8014962
Study Section
Special Emphasis Panel (ZRG1-MONC-U (01))
Program Officer
Strasburger, Jennifer
Project Start
2007-03-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$268,149
Indirect Cost
Name
University of Wisconsin Madison
Department
Dermatology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Goswami, Srikanta; Tarapore, Rohinton S; Poenitzsch Strong, Ashley M et al. (2015) MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor (MITF) mRNA is inhibited by coding region determinant-binding protein (CRD-BP). J Biol Chem 290:384-95
Noubissi, Felicite K; Kim, TaeWon; Kawahara, Tisha N et al. (2014) Role of CRD-BP in the growth of human basal cell carcinoma cells. J Invest Dermatol 134:1718-24
Tarapore, Rohinton S; Siddiqui, Imtiaz A; Adhami, Vaqar M et al. (2013) The dietary terpene lupeol targets colorectal cancer cells with constitutively active Wnt/β-catenin signaling. Mol Nutr Food Res 57:1950-8
Craig, Evisabel A; Weber, Jonathan D; Spiegelman, Vladimir S (2012) Involvement of the mRNA binding protein CRD-BP in the regulation of metastatic melanoma cell proliferation and invasion by hypoxia. J Cell Sci 125:5950-4
Craig, Evisabel A; Spiegelman, Vladimir S (2012) Inhibition of coding region determinant binding protein sensitizes melanoma cells to chemotherapeutic agents. Pigment Cell Melanoma Res 25:83-7
Mongroo, Perry S; Noubissi, Felicite K; Cuatrecasas, Miriam et al. (2011) IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2. Cancer Res 71:2172-82
Bhatia, Neehar; Demmer, Tara A; Sharma, Alok K et al. (2011) Role of β-TrCP ubiquitin ligase receptor in UVB mediated responses in skin. Arch Biochem Biophys 508:178-84
Goswami, Srikanta; Tarapore, Rohinton S; Teslaa, Jessica J et al. (2010) MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor mRNA is inhibited by the coding region determinant-binding protein. J Biol Chem 285:20532-40
Tarapore, Rohinton S; Siddiqui, Imtiaz A; Saleem, Mohammad et al. (2010) Specific targeting of Wnt/β-catenin signaling in human melanoma cells by a dietary triterpene lupeol. Carcinogenesis 31:1844-53
Noubissi, Felicite K; Goswami, Srikanta; Sanek, Nicholas A et al. (2009) Wnt signaling stimulates transcriptional outcome of the Hedgehog pathway by stabilizing GLI1 mRNA. Cancer Res 69:8572-8

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