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Chronic spindle assembly checkpoint activation causes myelosuppression and gastrointestinal atrophy.
Karbon, Gerlinde; Schuler, Fabian; Braun, Vincent Z; Eichin, Felix; Haschka, Manuel; Drach, Mathias; Sotillo, Rocio; Geley, Stephan; Spierings, Diana Cj; Tijhuis, Andrea E; Foijer, Floris; Villunger, Andreas.
Afiliação
  • 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.
EMBO Rep ; 25(6): 2743-2772, 2024 Jun.
Article em En | MEDLINE | ID: mdl-38806674
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Apoptose / Proteínas Proto-Oncogênicas c-bcl-2 / Proteínas Reguladoras de Apoptose / Pontos de Checagem da Fase M do Ciclo Celular / Proteínas Mad2 / Proteína 11 Semelhante a Bcl-2 Limite: Animals Idioma: En Revista: EMBO Rep Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Áustria

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Apoptose / Proteínas Proto-Oncogênicas c-bcl-2 / Proteínas Reguladoras de Apoptose / Pontos de Checagem da Fase M do Ciclo Celular / Proteínas Mad2 / Proteína 11 Semelhante a Bcl-2 Limite: Animals Idioma: En Revista: EMBO Rep Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Áustria