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  • Original Paper
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Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation

Oncogene volume 24, pages 7955–7963 (2005)Cite this article

Abstract

The Caudal-related homeodomain transcription factor Cdx2 plays a key role in intestinal cell fate determination. Reduction of Cdx2 expression is a feature of many human colon carcinomas and inactivation of one cdx2 allele facilitates the development of invasive adenocarcinoma in the murine colon. Here, we investigated the post-translational regulation of Cdx2. We showed that various forms of Cdx2 coexist in the intestine and colon cancer cell lines, some of them being phosphorylated forms. We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. Using site-specific mutagenesis, we identified serine 281 as a new key residue for Cdx2 phosphorylation. Intriguingly, serine 281 belongs to a conserved motif of four evenly spaced serines (the 4S motif) similar to the one controlling β-catenin degradation by the proteasome pathway. A nonphosphorylated mutant Cdx2 lacking the 4S motif (4S>A) exhibited reduced polyubiquitination upon proteasome inhibition and increased stability compared to wild-type Cdx2. In addition, we found that this mutant was less efficient to suppress colony formation than wild-type Cdx2. Thus, our data highlight a novel post-translational mechanism controlling Cdx2 degradation via phosphorylation and polyubiquitination, which may be of importance for intestinal development and cancer.

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Acknowledgements

We thank Pr JD Licht (Mount Sinai School of Medicine, NY, USA), as well as our colleagues Drs G Mellitzer and E Pencreac’h, for critical reading of the manuscript. We acknowledge M Yahya (IUT Louis Pasteur, Strasbourg, France) for excellent technical assistance. We thank Drs M Rousset (INSERM U.505, Paris, France), D Bohmann (University of Rochester, NY, USA), S van den Heuvel (Harvard Medical School, MA, USA), R Davies (University of Massachusetts Medical School, MA, USA), J Pouyssegur (CNRS-UMR 6543, Nice, France), SC Lin (Xiamen University, Fujian, China) and the IGBMC (Strasbourg, France) for the generous gift of plasmids and cell lines. This work was supported at U.682 by INSERM, Association pour la Recherche sur le Cancer (ARC, #3286) and Ligue Contre le Cancer (Comités Départementaux du Bas-Rhin et du Haut-Rhin, France). IG is a fellow of the ARC. CG is supported by ARC (#3288), Ligue Contre le Cancer (Comité Départemental du Bas-Rhin, France), CNRS, INSERM and Région Alsace.

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  1. Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Authors and Affiliations

  1. INSERM Unit 682, Development and Physiopathology of the Intestine and Pancreas, 3, avenue Molière, Strasbourg, 67200, France

    Isabelle Gross, Benoit Lhermitte, Claire Domon-Dell, Isabelle Duluc, Elisabeth Martin, Michele Kedinger & Jean-Noël Freund

  2. INSERM Unit 692, Molecular Signaling and Neurodegeneration, Strasbourg, France

    Christian Gaiddon

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  1. Isabelle Gross
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Gross, I., Lhermitte, B., Domon-Dell, C. et al. Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation. Oncogene 24, 7955–7963 (2005). https://doi.org/10.1038/sj.onc.1208945

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