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

Felicite K. Noubissi, Irina Elcheva, Neehar Bhatia, Abbas Shakoori, Andrei Ougolkov, Jianghuai Liu, Toshinari Minamoto, Jeff Ross, Serge Y. Fuchs, Vladimir Spiegelman

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

Although constitutive activation of β-catenin/Tcf signalling is implicated in the development of human cancers, 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.

Original languageEnglish (US)
Pages (from-to)898-901
Number of pages4
JournalNature
Volume441
Issue number7095
DOIs
StatePublished - Jun 15 2006

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Catenins
Carrier Proteins
Messenger RNA
F-Box Proteins
RNA-Binding Proteins
Colorectal Neoplasms
Transcription Factors
Ubiquitin-Protein Ligases
Trans-Activators
RNA Stability
Human Development
Open Reading Frames
Neoplasms
Carcinogenesis
Up-Regulation
Apoptosis
Gene Expression

All Science Journal Classification (ASJC) codes

  • General

Cite this

Noubissi, Felicite K. ; Elcheva, Irina ; Bhatia, Neehar ; Shakoori, Abbas ; Ougolkov, Andrei ; Liu, Jianghuai ; Minamoto, Toshinari ; Ross, Jeff ; Fuchs, Serge Y. ; Spiegelman, Vladimir. / CRD-BP mediates stabilization of βTrCP1 and c-myc mRNA in response to β-catenin signalling. In: Nature. 2006 ; Vol. 441, No. 7095. pp. 898-901.
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abstract = "Although constitutive activation of β-catenin/Tcf signalling is implicated in the development of human cancers, 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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Noubissi, FK, Elcheva, I, Bhatia, N, Shakoori, A, Ougolkov, A, Liu, J, Minamoto, T, Ross, J, Fuchs, SY & Spiegelman, V 2006, 'CRD-BP mediates stabilization of βTrCP1 and c-myc mRNA in response to β-catenin signalling', Nature, vol. 441, no. 7095, pp. 898-901. https://doi.org/10.1038/nature04839

CRD-BP mediates stabilization of βTrCP1 and c-myc mRNA in response to β-catenin signalling. / Noubissi, Felicite K.; Elcheva, Irina; Bhatia, Neehar; Shakoori, Abbas; Ougolkov, Andrei; Liu, Jianghuai; Minamoto, Toshinari; Ross, Jeff; Fuchs, Serge Y.; Spiegelman, Vladimir.

In: Nature, Vol. 441, No. 7095, 15.06.2006, p. 898-901.

Research output: Contribution to journalArticle

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AU - Noubissi, Felicite K.

AU - Elcheva, Irina

AU - Bhatia, Neehar

AU - Shakoori, Abbas

AU - Ougolkov, Andrei

AU - Liu, Jianghuai

AU - Minamoto, Toshinari

AU - Ross, Jeff

AU - Fuchs, Serge Y.

AU - Spiegelman, Vladimir

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N2 - Although constitutive activation of β-catenin/Tcf signalling is implicated in the development of human cancers, 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.

AB - Although constitutive activation of β-catenin/Tcf signalling is implicated in the development of human cancers, 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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