Journal Article

DKFZ-2024-01150

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Chronic spindle assembly checkpoint activation causes myelosuppression and gastrointestinal atrophy.

Karbon, G. ; Schuler, F. ; Braun, V. Z. ; Eichin, F. ; Haschka, M. ; Drach, M. ; Sotillo, R.DKFZ* ; Geley, S. ; Spierings, D. C. ; Tijhuis, A. E. ; Foijer, F. ; Villunger, A.

2024
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.1038/s44319-024-00160-3

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.

Keyword(s): Apoptosis ; BH3-only Proteins ; MAD2 ; Mitosis ; Spindle Assembly Checkpoint

Note: 2024 Jun;25(6):2743-2772

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Contributing Institute(s):

1. B220 Molekulare Grundlagen thorakaler Tumoren (B220)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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