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

Abstract

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.

Expression of the RNA-binding protein IMP1 correlates with poor prognosis in ovarian carcinoma

“…Although additional target mRNAs of IMP1 are expected, solid evidence indicates that IMP1 is essential for the regulation of c-myc, bTrCP1 and CD44 mRNA turnover, but also facilitates translational control of the IGF-II and b-actin mRNAs (Nielsen et al, 1999;Lemm and Ross, 2002;Huttelmaier et al, 2005;Noubissi et al, 2006;Vikesaa et al, 2006). While by the regulation of IGF-II and c-myc expression IMP1 is expected to affect cell proliferation, growth and survival, the regulation of CD44 or b-actin expression via IMP1 is suggested to modulate cell adhesion, invadopodia formation and actin dynamics.…”

“…In human cancers, de novo synthesis of IMPs was identified in approximately 80% of colorectal carcinomas, 70% of bone and soft tissue sarcomas, 60% of breast carcinomas and 50% of non-small cell lung carcinomas (Ioannidis et al, 2001(Ioannidis et al, , 2003(Ioannidis et al, , 2004Ross et al, 2001). A pivotal role of IMP1 in colorectal cancer progression was emphasized by recent studies demonstrating that IMP1 mediates stabilization of the bTrCP1 mRNA in response to b-catenin signaling (Noubissi et al, 2006). In primary ovarian carcinoma, only one study reported an overexpression of IMPs based on semiquantitative reverse transcription-PCR (RT-PCR) analyses in carcinoma vs adenoma, but the functional role of IMP1 in ovarian carcinoma-derived cells was not evaluated (Gu et al, 2004).…”

Overexpression of mRNA-binding protein CRD-BP in malignant melanomas

“…We identified the coding region determinantbinding protein (CRD-BP) as a novel transcriptional target of b-catenin, which binds and stabilizes b-TrCP1 mRNA in response to Wnt signaling (Noubissi et al, 2006). Elevated levels of b-TrCP1 result in increased activity of SCF bÀTrCP1 E3 ubiquitin ligase and accelerated degradation of its substrates, including IkBs.…”

IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1)

“…It protects MDR-1 mRNAs from endonucleolytic cleavage by binding to a coding region element (Sparanese and Lee, 2007). Also binds to the coding region of betaTrCP1 mRNA and stabilizes it by disrupting miRNAdependent interaction with AGO2 (Noubissi et al, 2006;Elcheva et al, 2009). Binds and stabilizes GLI1 mRNA causing an elevation of GLI1 expression and transcriptional activity ).…”