1. Paradoxical implication of BAX/BAK in the persistence of tetraploid cells
- Author
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Deng, Jiayin, Gutiérrez, Lucía, Stoll, Gautier, Motiño, Omar, Martins, Isabelle, Núñez, Lucía, Bravo-San Pedro, José, Humeau, Juliette, Bordenave, Chloé, Pan, Juncheng, Fohrer-Ting, Hélène, Souquere, Sylvie, Pierron, Gerard, Hetz, Claudio, Villalobos, Carlos, Kroemer, Guido, Senovilla, Laura, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Gustave Roussy (IGR), Universidad de Valladolid [Valladolid] (UVa), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Universidad de Chile = University of Chile [Santiago] (UCHILE), Buck Institute for Research on Aging, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and Gestionnaire, Hal Sorbonne Université
- Subjects
Mice, Knockout ,Cell death ,QH573-671 ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Fibroblasts ,Endoplasmic Reticulum ,Senescence ,Microtubules ,Article ,Cell Line ,Clone Cells ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,Mice, Inbred C57BL ,Tetraploidy ,Cell growth ,bcl-2 Homologous Antagonist-Killer Protein ,Animals ,Humans ,Calcium ,Calcium Signaling ,biological phenomena, cell phenomena, and immunity ,Cytology ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Cellular Senescence ,bcl-2-Associated X Protein - Abstract
International audience; 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) Ca 2+ stores and store-operated Ca 2+ entry that are affected by tetraploidization. DKO cells manifested reduced expression of endogenous sarcoplasmic/endoplasmic reticulum Ca 2+ 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 Ca 2+ 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 Ca 2+ 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.
- Published
- 2021