Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice
| العنوان: | Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice |
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| المؤلفون: | María Maroto, María Salazar-Roa, Marcos Malumbres, David Partida, Guillermo de Cárcer, Marianna Trakala, Paulina Wachowicz |
| المساهمون: | Fundación La Caixa, Ministerio de Economia y Competitividad (MINECO), Comunidad de Madrid, Worldwide Cancer Research (WCR), European Union (EU), Consolider-Ingenio Programme, Ministerio de Economía y Competitividad (España), Comunidad de Madrid (España), Worldwide Cancer Research, Unión Europea |
| المصدر: | Repisalud Instituto de Salud Carlos III (ISCIII) |
| بيانات النشر: | American Society of Hematology, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Immunology, Fluorescent Antibody Technique, POLYPLOIDIZATION, Cell Cycle Proteins, PHASE-2 TRIAL, Protein Serine-Threonine Kinases, Biology, Bioinformatics, Biochemistry, PLK1, Spindle pole body, Mice, Megakaryocyte, Proto-Oncogene Proteins, medicine, VOLASERTIB BI 6727, CELL-CYCLE, Animals, Mitosis, MEGAKARYOCYTE ENDOMITOSIS, IN-VIVO, Mice, Knockout, AURORA-B, Cell Differentiation, POLO-LIKE KINASES, INHIBITOR VOLASERTIB, Cell Biology, Hematology, Cell cycle, Flow Cytometry, Protein-Serine-Threonine Kinases, Thrombocytopenia, Cell biology, Spindle checkpoint, medicine.anatomical_structure, Centrosome, MITOSIS, M Phase Cell Cycle Checkpoints, Endomitotic cell cycle, Megakaryocytes |
| الوصف: | Polyploidization in megakaryocytes is achieved by endomitosis, a specialized cell cycle in which DNA replication is followed by aberrant mitosis. Typical mitotic regulators such as Aurora kinases or Cdk1 are dispensable for megakaryocyte maturation, and inhibition of mitotic kinases may in fact promote megakaryocyte maturation. However, we show here that Polo-like kinase 1 (Plk1) is required for endomitosis, and ablation of the Plk1 gene in megakaryocytes results in defective polyploidization accompanied by mitotic arrest and cell death. Lack of Plk1 results in defective centrosome maturation and aberrant spindle pole formation, thus impairing the formation of multiple poles typically found in megakaryocytes. In these conditions, megakaryocytes arrest for a long time in mitosis and frequently die. Mitotic arrest in wild-type megakaryocytes treated with Plk1 inhibitors or Plk1-null cells is triggered by the spindle assembly checkpoint (SAC), and can be rescued in the presence of SAC inhibitors. These data suggest that, despite the dispensability of proper chromosome segregation in megakaryocytes, an endomitotic SAC is activated in these cells upon Plk1 inhibition. SAC activation results in defective maturation of megakaryocytes and cell death, thus raising a note of caution in the use of Plk1 inhibitors in therapeutic strategies based on polyploidization regulators. This work was supported by a fellowship from the Foundation La Caixa (M.T.), and the Cell Division and Cancer group of the CNIO was funded by the Ministry of Economy and Competitiveness (SAF2012-38215), Consolider-Ingenio 2010 Programme (SAF2014-57791-REDC), Red Tematica CellSYS (BFU2014-52125-REDT), Comunidad de Madrid (OncoCycle Programme, S2010/BMD-2470), Worldwide Cancer Research (WCR #15-0278), and the MitoSys project (HEALTH-F5-2010-241548, European Union Seventh Framework Programme). Sí |
| تدمد: | 1528-0020 0006-4971 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::558ebef83a0c23c67396b456765a853eTest https://doi.org/10.1182/blood-2015-03-634402Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....558ebef83a0c23c67396b456765a853e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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