The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest.
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.
Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
Manuel D
MD
Haschka
Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
Claudia
C
Soratroi
Institute for Medical Microbiology and Hygiene, University Medical Center Freiburg, 79106 Freiburg, Germany.
Susanne
S
Kirschnek
Institute for Medical Microbiology and Hygiene, University Medical Center Freiburg, 79106 Freiburg, Germany.
Georg
G
Häcker
Division of Molecular Pathophysiology, Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
Richard
R
Hilbe
Division of Molecular Pathophysiology, Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
Stephan
S
Geley
Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
Andreas
A
Villunger
Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
Luca L
LL
Fava
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins; D008938:Mitosis / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C579095:MCL1 protein, human; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C581062:RTL10 protein, human; D050257:Tubulin Modulators