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@ARTICLE{Karbon:290533,
author = {G. Karbon and F. Schuler and V. Z. Braun and F. Eichin and
M. Haschka and M. Drach and R. Sotillo$^*$ and S. Geley and
D. C. Spierings and A. E. Tijhuis and F. Foijer and A.
Villunger},
title = {{C}hronic spindle assembly checkpoint activation causes
myelosuppression and gastrointestinal atrophy.},
journal = {EMBO reports},
volume = {25},
number = {6},
issn = {1469-221X},
address = {Hoboken, NJ [u.a.]},
publisher = {Wiley},
reportid = {DKFZ-2024-01150},
pages = {2743-2772},
year = {2024},
note = {2024 Jun;25(6):2743-2772},
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.},
keywords = {Apoptosis (Other) / BH3-only Proteins (Other) / MAD2
(Other) / Mitosis (Other) / Spindle Assembly Checkpoint
(Other)},
cin = {B220},
ddc = {570},
cid = {I:(DE-He78)B220-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38806674},
doi = {10.1038/s44319-024-00160-3},
url = {https://inrepo02.dkfz.de/record/290533},
}