دورية أكاديمية
أعرض في EDS

Chronic spindle assembly checkpoint activation causes myelosuppression and gastrointestinal atrophy.

التفاصيل البيبلوغرافية
العنوان: Chronic spindle assembly checkpoint activation causes myelosuppression and gastrointestinal atrophy.
المؤلفون: Karbon G; Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Schuler F; Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Braun VZ; Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Eichin F; Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Haschka M; Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Drach M; Dermatology, General Hospital, University Hospital Vienna, Vienna, Austria., Sotillo R; German Cancer Research Center (DKFZ), Division of Molecular Thoracic Oncology, Heidelberg, Germany., Geley S; Institute for Pathophysiology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Spierings DC; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands., Tijhuis AE; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands., Foijer F; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands., Villunger A; Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria. andreas.villunger@i-med.ac.at.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria. andreas.villunger@i-med.ac.at.
المصدر: EMBO reports [EMBO Rep] 2024 Jun; Vol. 25 (6), pp. 2743-2772. Date of Electronic Publication: 2024 May 28.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 100963049 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1469-3178 (Electronic) Linking ISSN: 1469221X NLM ISO Abbreviation: EMBO Rep Subsets: MEDLINE
أسماء مطبوعة: Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Oxford, UK : Published for EMBO by Oxford University Press, 2000-
مواضيع طبية MeSH: Bcl-2-Like Protein 11*/metabolism , Bcl-2-Like Protein 11*/genetics , Mad2 Proteins*/metabolism , Mad2 Proteins*/genetics , Apoptosis Regulatory Proteins*/metabolism , Apoptosis Regulatory Proteins*/genetics , M Phase Cell Cycle Checkpoints* , Proto-Oncogene Proteins c-bcl-2*/metabolism , Proto-Oncogene Proteins c-bcl-2*/genetics , Apoptosis*, Animals ; Mice ; Atrophy ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins/genetics ; Mitosis ; BH3 Interacting Domain Death Agonist Protein/metabolism ; BH3 Interacting Domain Death Agonist Protein/genetics ; Cdc20 Proteins/metabolism ; Cdc20 Proteins/genetics ; Bone Marrow/pathology ; Bone Marrow/metabolism ; Membrane Proteins/metabolism ; Membrane Proteins/genetics ; Tumor Suppressor Proteins
مستخلص: Interference with microtubule dynamics in mitosis activates the spindle assembly checkpoint (SAC) to prevent chromosome segregation errors. The SAC induces mitotic arrest by inhibiting the anaphase-promoting complex (APC) via the mitotic checkpoint complex (MCC). The MCC component MAD2 neutralizes the critical APC cofactor, CDC20, preventing exit from mitosis. Extended mitotic arrest can promote mitochondrial apoptosis and caspase activation. However, the impact of mitotic cell death on tissue homeostasis in vivo is ill-defined. By conditional MAD2 overexpression, we observe that chronic SAC activation triggers bone marrow aplasia and intestinal atrophy in mice. While myelosuppression can be compensated for, gastrointestinal atrophy is detrimental. Remarkably, deletion of pro-apoptotic Bim/Bcl2l11 prevents gastrointestinal syndrome, while neither loss of Noxa/Pmaip or co-deletion of Bid and Puma/Bbc3 has such a protective effect, identifying BIM as rate-limiting apoptosis effector in mitotic cell death of the gastrointestinal epithelium. In contrast, only overexpression of anti-apoptotic BCL2, but none of the BH3-only protein deficiencies mentioned above, can mitigate myelosuppression. Our findings highlight tissue and cell-type-specific survival dependencies in response to SAC perturbation in vivo.
(© 2024. The Author(s).)
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معلومات مُعتمدة: /87171 EC | ERC | HORIZON EUROPE European Research Council (ERC); I 3271 Austrian Science Fund (FWF); I 6642 Austrian Science Fund (FWF); P 36658 Austrian Science Fund (FWF); TRR353 Deutsche Forschungsgemeinschaft (DFG); DOC-fellowship Austrian Academy of Sciences
فهرسة مساهمة: Keywords: Apoptosis; BH3-only Proteins; MAD2; Mitosis; Spindle Assembly Checkpoint
المشرفين على المادة: 0 (Bcl-2-Like Protein 11)
0 (Mad2 Proteins)
0 (Apoptosis Regulatory Proteins)
0 (Bcl2l11 protein, mouse)
0 (Proto-Oncogene Proteins c-bcl-2)
0 (Pmaip1 protein, mouse)
0 (PUMA protein, mouse)
0 (Proto-Oncogene Proteins)
0 (Mad2l1 protein, mouse)
0 (BH3 Interacting Domain Death Agonist Protein)
0 (Cdc20 Proteins)
0 (Membrane Proteins)
0 (Tumor Suppressor Proteins)
تواريخ الأحداث: Date Created: 20240528 Date Completed: 20240612 Latest Revision: 20240615
رمز التحديث: 20240615
مُعرف محوري في PubMed: PMC11169569
DOI: 10.1038/s44319-024-00160-3
PMID: 38806674
قاعدة البيانات: MEDLINE
الوصف
تدمد:1469-3178
DOI:10.1038/s44319-024-00160-3