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

Although constitutive activation of beta-catenin/Tcf signalling is implicated in the development of human cancers(1), 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 beta TrCP1, 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 bTrCP1 mRNA. Overexpression of CRD-BP stabilizes bTrCP1 mRNA and elevates beta TrCP1 levels ( both in cells and in vivo), resulting in the activation of the Skp1-Cullin1-F-box protein (SCF) beta TrCP E3 ubiquitin ligase and in accelerated turnover of its substrates including I kappa B and beta-catenin. CRD-BP is essential for the induction of both beta TrCP1 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 beta TrCP1, in the activation of dimeric transcription factor NF-kappa B and in the suppression of apoptosis in these cancers.