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FBXO31 protects against genomic instability by capping FOXM1 levels at the G2/M transition

Oncogene volume 36, pages 1012–1022 (2017)Cite this article

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Abstract

F-box proteins in conjunction with Skp1, Cul1 and Rbx1 generate SCF complexes that are responsible for the ubiquitination of proteins, leading to their activation or degradation. Here we show that the F-box protein FBXO31 is required for normal mitotic progression and genome stability due to its role in regulating FOXM1 levels during the G2/M transition. FBXO31-depleted cells undergo a transient delay in mitosis due to an activated spindle checkpoint concomitant with an increase in lagging chromosomes and anaphase bridges. FBXO31 regulates mitosis in part by controlling the levels of FOXM1, a transcription factor and master regulator of mitosis. FBXO31 specifically interacts with FOXM1 during the G2/M transition, resulting in FOXM1 ubiquitination and degradation. FBXO31 depletion results in increased expression of FOXM1 transcriptional targets and mimics the FOXM1 overexpression. In contrast, co-depletion of FBXO31 and FOXM1 restores the genomic instability phenotype but not the delay in mitosis, indicating that FBXO31 probably has additional mitotic substrates. Thus, FBXO31 is the first described negative regulator of FOXM1 during the G2/M transition.

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Acknowledgements

This work is funded by the NHMRC (Program Grant), the Cancer Council of Queensland and the Cancer Council of South Australia. Murugan Kalimutho is supported by project grant from the Cancer Council Queensland. Pegah Johansson is a Swedish Research Council (Vetenskapsrådet) post-doctoral fellow. We thank Professor Michele Pagano for the Skp1, Cul1 and Rbx1 antibodies, and the FLAG–Skp2, FLAG–FBW9, FLAG–HA–FBXO10, FLAG–HA–FBXO24 and FLAG–β-Trcp1 constructs; Dr Sabine Elowe for BUBR1 pS676 antibody; and Stephen Miles for tissue culture assistance.

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Author notes

  1. M Kalimutho and P Johansson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell and Molecular Biology, Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    J M Jeffery, M Kalimutho, D G Cardenas & K K Khanna

  2. Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

    P Johansson

  3. Department of Paediatrics, School of Medicine and the Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia

    R Kumar

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  1. J M Jeffery
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Correspondence to R Kumar or K K Khanna.

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Jeffery, J., Kalimutho, M., Johansson, P. et al. FBXO31 protects against genomic instability by capping FOXM1 levels at the G2/M transition. Oncogene 36, 1012–1022 (2017). https://doi.org/10.1038/onc.2016.268

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