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The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin

Abstract

Ubiquitin-conjugation targets numerous cellular regulators for proteasome-mediated degradation. Thus, the identification of ubiquitin ligases and their physiological substrates is crucially important, especially for those cases in which aberrant levels of regulatory proteins (e.g., β-catenin, p27) result from a deregulated ubiquitination pathway. In yeast, the proteolysis of several G1 regulators is controlled by ubiquitin ligases (or SCFs) formed by three subunits: Skp1, Cul A (Cdc53), and one of many F-box proteins. Specific F-box proteins (Fbps) recruit different substrates to the SCF. Although many Fbps have been identified in mammals, their specific substrates and the existence of multiple SCFs have not yet been reported. We have found that one human Fbp, β-Trcp (β-Transducin repeat containing protein), does indeed form a novel SCF with human Skp1 and Cul1. Consistent with recent reports indicating that Xenopus and Drosophila β-Trcp homologs act as negative regulators of the Wnt/β-catenin signaling pathway, we report here that human β-Trcp interacts with β-catenin in vivo. Furthermore, β-catenin is specifically stabilized in vivo by the expression of a dominant negative β-Trcp. These results indicate that the Cul1/Skp1/β-Trcp complex forms a ubiquitin ligase that mediates the degradation of β-catenin.

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Acknowledgements

We thank M Garabedian, E Kipreos, D Morgan, Y Xiong for reagents; J Bloom, AC Carrano, C Cenciarelli, S Guadagno (Zymed Inc.), A Hershko and MT Petrucci for their contribution to this work; and J Bloom and L Yamasaki for critically reading the manuscript. EL is supported by the Molecular Oncology Program (NIH 5T32-CA09161); MP is in part supported by a HFSPO grant RG0229/98-M and NIH grants RO1-CA76584 and RO1-GM57587.

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Latres, E., Chiaur, D. & Pagano, M. The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin. Oncogene 18, 849–854 (1999). https://doi.org/10.1038/sj.onc.1202653

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Keywords

  • ubiquitin
  • F-box
  • SCF
  • β-catenin
  • cancer

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