CRD-BP mediates stabilization of betaTrCP1 and c-myc mRNA in response to beta-catenin signalling.
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.
Noubissi
Felicite K
FK
Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
Elcheva
Irina
I
Bhatia
Neehar
N
Shakoori
Abbas
A
Ougolkov
Andrei
A
Liu
Jianghuai
J
Minamoto
Toshinari
T
Ross
Jeff
J
Fuchs
Serge Y
SY
Spiegelman
Vladimir S
VS
D000818:Animals; D002460:Cell Line; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics*
D020672:I-kappa B Proteins; C406144:IGF2BP1 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051820:TCF Transcription Factors; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D044843:SKP Cullin F-Box Protein Ligases