Paradoxical implication of BAX/BAK in the persistence of tetraploid cells

Abstract 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 bo...

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Autores principales:	Jiayin Deng, Lucía G. Gutiérrez, Gautier Stoll, Omar Motiño, Isabelle Martins, Lucía Núñez, José Manuel Bravo-San Pedro, Juliette Humeau, Chloé Bordenave, Juncheng Pan, Hélène Fohrer-Ting, Sylvie Souquere, Gerard Pierron, Claudio Hetz, Carlos Villalobos, Guido Kroemer, Laura Senovilla
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/b8e22883032443a5aba0575cbed66635
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spelling	oai:doaj.org-article:b8e22883032443a5aba0575cbed666352021-11-07T12:05:11ZParadoxical implication of BAX/BAK in the persistence of tetraploid cells10.1038/s41419-021-04321-32041-4889https://doaj.org/article/b8e22883032443a5aba0575cbed666352021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04321-3https://doaj.org/toc/2041-4889Abstract 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 tetraploidization-associated 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.Jiayin DengLucía G. GutiérrezGautier StollOmar MotiñoIsabelle MartinsLucía NúñezJosé Manuel Bravo-San PedroJuliette HumeauChloé BordenaveJuncheng PanHélène Fohrer-TingSylvie SouquereGerard PierronClaudio HetzCarlos VillalobosGuido KroemerLaura SenovillaNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 11, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Jiayin Deng Lucía G. Gutiérrez Gautier Stoll Omar Motiño Isabelle Martins Lucía Núñez José Manuel Bravo-San Pedro Juliette Humeau Chloé Bordenave Juncheng Pan Hélène Fohrer-Ting Sylvie Souquere Gerard Pierron Claudio Hetz Carlos Villalobos Guido Kroemer Laura Senovilla Paradoxical implication of BAX/BAK in the persistence of tetraploid cells
description	Abstract 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 tetraploidization-associated 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.
format	article
author	Jiayin Deng Lucía G. Gutiérrez Gautier Stoll Omar Motiño Isabelle Martins Lucía Núñez José Manuel Bravo-San Pedro Juliette Humeau Chloé Bordenave Juncheng Pan Hélène Fohrer-Ting Sylvie Souquere Gerard Pierron Claudio Hetz Carlos Villalobos Guido Kroemer Laura Senovilla
author_facet	Jiayin Deng Lucía G. Gutiérrez Gautier Stoll Omar Motiño Isabelle Martins Lucía Núñez José Manuel Bravo-San Pedro Juliette Humeau Chloé Bordenave Juncheng Pan Hélène Fohrer-Ting Sylvie Souquere Gerard Pierron Claudio Hetz Carlos Villalobos Guido Kroemer Laura Senovilla
author_sort	Jiayin Deng
title	Paradoxical implication of BAX/BAK in the persistence of tetraploid cells
title_short	Paradoxical implication of BAX/BAK in the persistence of tetraploid cells
title_full	Paradoxical implication of BAX/BAK in the persistence of tetraploid cells
title_fullStr	Paradoxical implication of BAX/BAK in the persistence of tetraploid cells
title_full_unstemmed	Paradoxical implication of BAX/BAK in the persistence of tetraploid cells
title_sort	paradoxical implication of bax/bak in the persistence of tetraploid cells
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/b8e22883032443a5aba0575cbed66635
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Paradoxical implication of BAX/BAK in the persistence of tetraploid cells

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