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GSK3-SCFFBXW7 targets JunB for degradation in G2 to preserve chromatid cohesion before anaphase

Oncogene volume 32, pages 2189–2199 (2013)Cite this article

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Abstract

JunB, an activator protein-1 (AP-1) transcription factor component, acts either as a tumor suppressor or as an oncogene depending on the cell context. In particular, JunB is strongly upregulated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) where it enhances cell proliferation. Although its overexpression is linked to lymphomagenesis, the mechanisms whereby JunB promotes neoplastic growth are still largely obscure. Here, we show that JunB undergoes coordinated phosphorylation-dependent ubiquitylation during the G2 phase of the cell cycle. We characterized a critical consensus phospho-degron that controls JunB turnover and identified GSK3 and SCFFBXW7 as, respectively, the kinase and the E3 ubiquitin ligase responsible for its degradation in G2. Pharmacological or genetic inactivation of the GSK3-FBXW7-JunB axis induced accumulation of JunB in G2/M and entailed transcriptional repression of the DNA helicase DDX11, leading to premature sister chromatid separation. This abnormal phenotype due to dysregulation of the GSK3β/JunB/DDX11 pathway is phenocopied in ALK-positive ALCL. Thus, our results reveal a novel mechanism by which mitosis progression and chromatid cohesion are regulated through GSK3/SCFFBXW7-mediated proteolysis of JunB, and suggest that JunB proteolysis in G2 is an essential step in maintaining genetic fidelity during mitosis.

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Acknowledgements

We thank Sandra Gallach and Pablo Mateos for their excellent technical support and A Ferrando, TM Thomson, G Bossis and O Coux for fruitful discussions and critical reading of the manuscript. This research was supported by grants from the Fondo de Investigaciones Sanitarias (PI08/1127) and from Valencia’s Regional Ministry of Health (AP007/11) to RF, from the Spanish Ministry of Science and Innovation (SAF2009-08334) to JFM. RF is supported by the Institute of Health Carlos III and by the Regional Ministry of Health. MP was supported by the program ‘Equipe Labellisée’ of the French Ligue against Cancer. We are grateful to B Vogelstein for providing DLD1 and DLD1FBXW7−/− cells, M Pagano for Flag-tagged SKP2, CDH1 and CDC20 constructs, O Sangfield for Flag-tagged FBXW7α and FBXW7γ constructs, C Bonne-Andrea for Flag-tagged FBXW7α(R465A), PK Vogt (Scripps Research Institute) for activated AKT and E Noguchi for DDX11.

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Authors and Affiliations

  1. Cytomics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain

    B Pérez-Benavente & R Farràs

  2. Unidad de Investigación, Instituto Estudios Ciencias de la Salud de Castilla y Leon-(IECSCYL)-Hospital Universitario de Salamanca, Centro de Investigación del Cáncer Universidad de Salamanca-CSIC, Salamanca, Spain

    J L García

  3. Proteomics Unit, CIC bioGUNE, Bizkaia, Spain

    M S Rodríguez

  4. Structural Biochemistry Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain

    A Pineda-Lucena

  5. Institut de Génétique Moléculaire de Montpellier UMR 5535 CNRS, Université Montpellier 2, Université Montpellier 1, Montpellier Cedex 2, France

    M Piechaczyk

  6. Cellular and Molecular Biology Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain

    J Font de Mora

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  1. B Pérez-Benavente
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Pérez-Benavente, B., García, J., Rodríguez, M. et al. GSK3-SCFFBXW7 targets JunB for degradation in G2 to preserve chromatid cohesion before anaphase. Oncogene 32, 2189–2199 (2013). https://doi.org/10.1038/onc.2012.235

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