CRD-BP mediates stabilization of betaTrCP1 and c-myc mRNA in response to beta-catenin signalling

Nature. 2006 Jun 15;441(7095):898-901. doi: 10.1038/nature04839.


Although constitutive activation of beta-catenin/Tcf signalling is implicated in the development of human cancers, the mechanisms by which the beta-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 beta-catenin stabilizes the mRNA encoding the F-box protein betaTrCP1, and identify the RNA-binding protein CRD-BP (coding region determinant-binding protein) as a previously unknown target of beta-catenin/Tcf transcription factor. CRD-BP binds to the coding region of betaTrCP1 mRNA. Overexpression of CRD-BP stabilizes betaTrCP1 mRNA and elevates betaTrCP1 levels (both in cells and in vivo), resulting in the activation of the Skp1-Cullin1-F-box protein (SCF)(betaTrCP) E3 ubiquitin ligase and in accelerated turnover of its substrates including IkappaB and beta-catenin. CRD-BP is essential for the induction of both betaTrCP1 and c-Myc by beta-catenin signalling in colorectal cancer cells. High levels of CRD-BP that are found in primary human colorectal tumours exhibiting active beta-catenin/Tcf signalling implicates CRD-BP induction in the upregulation of betaTrCP1, in the activation of dimeric transcription factor NF-kappaB and in the suppression of apoptosis in these cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Genes, myc / genetics*
  • Humans
  • I-kappa B Proteins / metabolism
  • Mice
  • NF-kappa B / metabolism
  • RNA Stability*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Signal Transduction*
  • TCF Transcription Factors / metabolism
  • beta Catenin / metabolism*
  • beta-Transducin Repeat-Containing Proteins / genetics*


  • I-kappa B Proteins
  • IGF2BP1 protein, human
  • NF-kappa B
  • RNA, Messenger
  • RNA-Binding Proteins
  • TCF Transcription Factors
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins
  • SKP Cullin F-Box Protein Ligases