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CRD-BP mediates stabilization of βTrCP1 and c-myc mRNA in response to β-catenin signalling


Although constitutive activation of β-catenin/Tcf signalling is implicated in the development of human cancers1, the mechanisms by which the β-catenin/Tcf pathway promotes tumorigenesis are incompletely understood. Messenger RNA turnover has a major function in regulating gene expression and is responsive to developmental and environmental signals. mRNA decay rates are dictated by cis-acting elements within the mRNA and by trans-acting factors, such as RNA-binding proteins (reviewed in refs 2, 3). Here we show that β-catenin stabilizes the mRNA encoding the F-box protein βTrCP1, and identify the RNA-binding protein CRD-BP (coding region determinant-binding protein) as a previously unknown target of β-catenin/Tcf transcription factor. CRD-BP binds to the coding region of βTrCP1 mRNA. Overexpression of CRD-BP stabilizes βTrCP1 mRNA and elevates βTrCP1 levels (both in cells and in vivo), resulting in the activation of the Skp1-Cullin1-F-box protein (SCF)βTrCP E3 ubiquitin ligase and in accelerated turnover of its substrates including IκB and β-catenin. CRD-BP is essential for the induction of both βTrCP1 and c-Myc by β-catenin signalling in colorectal cancer cells. High levels of CRD-BP that are found in primary human colorectal tumours exhibiting active β-catenin/Tcf signalling implicates CRD-BP induction in the upregulation of βTrCP1, in the activation of dimeric transcription factor NF-κB and in the suppression of apoptosis in these cancers.

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Figure 1: β-catenin/Tcf signalling stabilizes βTrCP1 mRNA.
Figure 2: CRD-BP binds to βTrCP1 mRNA, stabilizes it and induces βTrCP1 expression and activities.
Figure 3: β-Catenin/Tcf signalling induces expression of CRD-BP.
Figure 4: CRD-BP is indispensable for the induction of βTrCP1 and c-Myc by β-catenin/Tcf signalling.

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  1. Polakis, P. The oncogenic activation of β-catenin. Curr. Opin. Genet. Dev. 9, 15–21 (1999)

    Article  CAS  Google Scholar 

  2. Guhaniyogi, J. & Brewer, G. Regulation of mRNA stability in mammalian cells. Gene 265, 11–23 (2001)

    Article  CAS  Google Scholar 

  3. Wilusz, C. J., Wormington, M. & Peltz, S. W. The cap-to-tail guide to mRNA turnover. Nature Rev. Mol. Cell Biol. 2, 237–246 (2001)

    Article  CAS  Google Scholar 

  4. Eastman, Q. & Grosschedl, R. Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr. Opin. Cell Biol. 11, 233–240 (1999)

    Article  CAS  Google Scholar 

  5. Spiegelman, V. S. et al. Wnt/β-catenin signaling induces the expression and activity of βTrCP ubiquitin ligase receptor. Mol. Cell 5, 877–882 (2000)

    Article  CAS  Google Scholar 

  6. Nielsen, J. et al. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol. Cell. Biol. 19, 1262–1270 (1999)

    Article  CAS  Google Scholar 

  7. Nielsen, F. C., Nielsen, J. & Christiansen, J. A family of IGF-II mRNA binding proteins (IMP) involved in RNA trafficking. Scand. J. Clin. Lab. Invest. Suppl. 234, 93–99 (2001)

    Article  CAS  Google Scholar 

  8. Runge, S. et al. H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein. J. Biol. Chem. 275, 29562–29569 (2000)

    Article  CAS  Google Scholar 

  9. Atlas, R., Behar, L., Elliott, E. & Ginzburg, I. The insulin-like growth factor mRNA binding-protein IMP-1 and the Ras-regulatory protein G3BP associate with tau mRNA and HuD protein in differentiated P19 neuronal cells. J. Neurochem. 89, 613–626 (2004)

    Article  CAS  Google Scholar 

  10. Bernstein, P. L., Herrick, D. J., Prokipcak, R. D. & Ross, J. Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant. Genes Dev. 6, 642–654 (1992)

    Article  CAS  Google Scholar 

  11. Doyle, G. A. et al. The c-myc coding region determinant-binding protein: a member of a family of KH domain RNA-binding proteins. Nucleic Acids Res. 26, 5036–5044 (1998)

    Article  CAS  Google Scholar 

  12. Prokipcak, R. D., Herrick, D. J. & Ross, J. Purification and properties of a protein that binds to the C-terminal coding region of human c-myc mRNA. J. Biol. Chem. 269, 9261–9269 (1994)

    CAS  PubMed  Google Scholar 

  13. Tessier, C. R., Doyle, G. A., Clark, B. A., Pitot, H. C. & Ross, J. Mammary tumor induction in transgenic mice expressing an RNA-binding protein. Cancer Res. 64, 209–214 (2004)

    Article  CAS  Google Scholar 

  14. Kudo, Y. et al. Role of F-box protein βTrcp1 in mammary gland development and tumorigenesis. Mol. Cell. Biol. 24, 8184–8194 (2004)

    Article  CAS  Google Scholar 

  15. Fuchs, S. Y., Spiegelman, V. S. & Kumar, K. G. The many faces of β-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer. Oncogene 23, 2028–2036 (2004)

    Article  CAS  Google Scholar 

  16. Roose, J. et al. Synergy between tumor suppressor APC and the β-catenin-Tcf4 target Tcf1. Science 285, 1923–1926 (1999)

    Article  CAS  Google Scholar 

  17. Morin, P. J. β-Catenin signaling and cancer. BioEssays 21, 1021–1030 (1999)

    Article  CAS  Google Scholar 

  18. Ougolkov, A. et al. Associations among β-TrCP, an E3 ubiquitin ligase receptor, β-catenin, and NF-κB in colorectal cancer. J. Natl Cancer Inst. 96, 1161–1170 (2004)

    Article  CAS  Google Scholar 

  19. Lin, A. & Karin, M. NF-κB in cancer: a marked target. Semin. Cancer Biol. 13, 107–114 (2003)

    Article  CAS  Google Scholar 

  20. Ross, J., Lemm, I. & Berberet, B. Overexpression of an mRNA-binding protein in human colorectal cancer. Oncogene 20, 6544–6550 (2001)

    Article  CAS  Google Scholar 

  21. He, T. C. et al. Identification of c-MYC as a target of the APC pathway. Science 281, 1509–1512 (1998)

    Article  CAS  ADS  Google Scholar 

  22. Hansen, T. V. et al. Dwarfism and impaired gut development in insulin-like growth factor II mRNA-binding protein 1-deficient mice. Mol. Cell. Biol. 24, 4448–4464 (2004)

    Article  CAS  Google Scholar 

  23. Leeds, P. et al. Developmental regulation of CRD-BP, an RNA-binding protein that stabilizes c-myc mRNA in vitro. Oncogene 14, 1279–1286 (1997)

    Article  CAS  Google Scholar 

  24. Ioannidis, P. et al. CRD-BP: a c-Myc mRNA stabilizing protein with an oncofetal pattern of expression. Anticancer Res. 23, 2179–2183 (2003)

    CAS  PubMed  Google Scholar 

  25. Ioannidis, P. et al. Expression of the RNA-binding protein CRD-BP in brain and non-small cell lung tumors. Cancer Lett. 209, 245–250 (2004)

    Article  CAS  Google Scholar 

  26. Ioannidis, P. et al. C-MYC and IGF-II mRNA-binding protein (CRD-BP/IMP-1) in benign and malignant mesenchymal tumors. Int. J. Cancer 94, 480–484 (2001)

    Article  CAS  Google Scholar 

  27. Ioannidis, P. et al. 8q24 Copy number gains and expression of the c-myc mRNA stabilizing protein CRD-BP in primary breast carcinomas. Int. J. Cancer 104, 54–59 (2003)

    Article  CAS  Google Scholar 

  28. Ross, J. Messenger RNA turnover in cell-free extracts from higher eukaryotes. Methods Mol. Biol. 118, 459–476 (1999)

    CAS  PubMed  Google Scholar 

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We thank K. Spiegelman for help with the manuscript preparation. This work was supported by an American Cancer Society Award (to V.S.S.). The work was supported in part by a University of Pennsylvania Cancer Center Pilot Grant and an NCI grant (to S.Y.F.), by NIH grants (to J.R.) and by the Japanese Ministry of Education, Science, Sports, Technology and Culture, by the Ministry of Health, Labor and Welfare, and by the Japan Society for the Promotion of Science (to T.M.).

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Correspondence to Vladimir S. Spiegelman.

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Supplementary information

Supplementary Figure 1

This figure provides details on interaction of CRD–BP with the mRNA of β-TrCP1. It also shows that overexpression of CRD-BP in cells led to accumulation of its steady state levels. (PDF 239 kb)

Supplementary Figure 2

This figure shows that CRD-BP expression does not affect IκB phosphorylation. It also contains detailed characterization of CRD–BP shRNA used in this study, and shows that knockdown of endogenous CRD–BP by specific shRNA prevents β-catenin/Tcf-dependent stabilization of endogenous β-TrCP1 mRNA. (PDF 371 kb)

Supplementary Figure 3

This figure demonstrates the transient nature of Wnt3A-induced β-catenin-DNA interaction that can be significantly prolonged by CRD-BP knockdown. It also shows that knock down of CRD–BP noticeably decreased βTrCP1 expression, and leads to the inhibition of NF-κB activity, induction of apoptosis, and suppression of colony formation in colorectal cancer cells . (PDF 374 kb)

Supplementary Methods

This section provides detailed methods used in this manuscript. (PDF 164 kb)

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Noubissi, F., Elcheva, I., Bhatia, N. et al. CRD-BP mediates stabilization of βTrCP1 and c-myc mRNA in response to β-catenin signalling. Nature 441, 898–901 (2006).

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