Letter | Published:

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

Naturevolume 441pages898901 (2006) | Download Citation

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Abstract

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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Acknowledgements

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.).

Author information

Author notes

    • Andrei Ougolkov

    Present address: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota, 55905, USA

Affiliations

  1. Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706, USA

    • Felicite K. Noubissi
    • , Irina Elcheva
    • , Neehar Bhatia
    •  & Vladimir S. Spiegelman
  2. Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, 920-0934, Japan

    • Abbas Shakoori
    • , Andrei Ougolkov
    •  & Toshinari Minamoto
  3. Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    • Jianghuai Liu
    •  & Serge Y. Fuchs
  4. McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53706, USA

    • Jeff Ross

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Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Corresponding author

Correspondence to Vladimir S. Spiegelman.

Supplementary information

  1. 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)

  2. 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)

  3. 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)

  4. Supplementary Methods

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

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https://doi.org/10.1038/nature04839

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