Paradoxical implication of BAX/BAK in the persistence of tetraploid cells
Author
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Deng, Jiayin
Author
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Gutiérrez, Lucía
Author
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Stoll, Gautier
Author
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Motino, Omar
Author
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Martins, Isabelle
Author
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Núñez, Lucía
Author
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Bravo San Pedro, José Manuel
Author
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Humeau, Juliette
Author
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Bordenave, Chloe
Author
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Pan, Juncheng
Author
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Fohrer Ting, Helene
Author
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Souquere, Sylvie
Author
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Pierron, Gerard
Author
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Hetz Flores, Claudio Andres
Author
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Villalobos, Carlos
Author
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Kroemer, Guido
Author
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Senovilla, Laura
Admission date
dc.date.accessioned
2022-05-04T15:57:02Z
Available date
dc.date.available
2022-05-04T15:57:02Z
Publication date
dc.date.issued
2021
Cita de ítem
dc.identifier.citation
Cell Death and Disease (2021) 12:1039
es_ES
Identifier
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10.1038/s41419-021-04321-3
Identifier
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https://repositorio.uchile.cl/handle/2250/185255
Abstract
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Pro-apoptotic multi-domain proteins of the BCL2 family such as BAX and BAK are well known for their important role in the
induction of mitochondrial outer membrane permeabilization (MOMP), which is the rate-limiting step of the intrinsic pathway of
apoptosis. Human or mouse cells lacking both BAX and BAK (due to a double knockout, DKO) are notoriously resistant to MOMP
and cell death induction. Here we report the surprising finding that BAX/BAK DKO cells proliferate less than control cells expressing
both BAX and BAK (or either BAX or BAK) when they are driven into tetraploidy by transient exposure to the microtubule inhibitor
nocodazole. Mechanistically, in contrast to their BAX/BAK-sufficient controls, tetraploid DKO cells activate a senescent program, as
indicated by the overexpression of several cyclin-dependent kinase inhibitors and the activation of β-galactosidase. Moreover, DKO
cells manifest alterations in ionomycin-mobilizable endoplasmic reticulum (ER) Ca2+ stores and store-operated Ca2+ entry that are
affected by tetraploidization. DKO cells manifested reduced expression of endogenous sarcoplasmic/endoplasmic reticulum Ca2+
ATPase 2a (Serca2a) and transfection-enforced reintroduction of Serca2a, or reintroduction of an ER-targeted variant of BAK into
DKO cells reestablished the same pattern of Ca2+ fluxes as observed in BAX/BAK-sufficient control cells. Serca2a reexpression and
ER-targeted BAK also abolished the tetraploidy-induced senescence of DKO cells, placing ER Ca2+ fluxes downstream of the
regulation of senescence by BAX/BAK. In conclusion, it appears that BAX/BAK prevent the induction of a tetraploidizationassociated senescence program. Speculatively, this may contribute to the low incidence of cancers in BAX/BAK DKO mice and
explain why human cancers rarely lose the expression of both BAX and BAK.
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Patrocinador
dc.description.sponsorship
Beatriz Galindo senior program of the Spanish Ministry of Universities
Junta de Castilla y Leon CCVC8485
Ligue contre le Cancer (equipe labellisee)
French National Research Agency (ANR)
AMMICa US23/CNRS UMS3655
Association "Ruban Rose"
Region Ile-de-France
Fondation pour la Recherche Medicale
Equipex Onco-Pheno-Screen
European Joint Programme on Rare Diseases (EJPRD)
Gustave Roussy Odyssea
European Commission
Fondation Carrefour
Institut National du Cancer (INCA) France
Inserm (HTE)
Institut Universitaire de France
LabEx Immuno-Oncology ANR-18-IDEX-0001
Leducq Foundation
Cancer Research ASPIRE Award from the Mark Foundation
Programme de cooperation ECO-Sud C17S02
RHU Torino Lumiere
Seerave Foundation
SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
SIRIC Cancer Research and Personalized Medicine (CARPEM)
Spanish Government RTI2018-099298-B-100
Junta de Castilla y Leon CA9751
Programa Estrategico IBGM, Junta de Castilla y Leon, Spain CCVC8485
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Lenguage
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en
es_ES
Publisher
dc.publisher
Springernature
es_ES
Type of license
dc.rights
Attribution-NonCommercial-NoDerivs 3.0 United States