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The NOXA–MCL1–BIM axis defines lifespan on extended mitotic arrest

Author

Listed:
  • Manuel D. Haschka

    (Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria)

  • Claudia Soratroi

    (Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria)

  • Susanne Kirschnek

    (Institute for Medical Microbiology and Hygiene, University Medical Center Freiburg)

  • Georg Häcker

    (Institute for Medical Microbiology and Hygiene, University Medical Center Freiburg)

  • Richard Hilbe

    (Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria)

  • Stephan Geley

    (Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria)

  • Andreas Villunger

    (Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria)

  • Luca L. Fava

    (Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria)

Abstract

Cell death on extended mitotic arrest is considered arguably most critical for the efficacy of microtubule-targeting agents (MTAs) in anticancer therapy. While the molecular machinery controlling mitotic arrest on MTA treatment, the spindle assembly checkpoint (SAC), appears well defined, the molecular components executing cell death, as well as factors connecting both networks remain poorly understood. Here we conduct a mini screen exploring systematically the contribution of individual BCL2 family proteins at single cell resolution to death on extended mitotic arrest, and demonstrate that the mitotic phosphorylation of BCL2 and BCLX represent a priming event for apoptosis that is ultimately triggered by NOXA-dependent MCL1 degradation, enabling BIM-dependent cell death. Our findings provide a comprehensive model for the initiation of apoptosis in cells stalled in mitosis and provide a molecular basis for the increased efficacy of combinatorial treatment of cancer cells using MTAs and BH3 mimetics.

Suggested Citation

  • Manuel D. Haschka & Claudia Soratroi & Susanne Kirschnek & Georg Häcker & Richard Hilbe & Stephan Geley & Andreas Villunger & Luca L. Fava, 2015. "The NOXA–MCL1–BIM axis defines lifespan on extended mitotic arrest," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7891
    DOI: 10.1038/ncomms7891
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