Requirement of GSK-3 for PUMA induction upon loss of pro-survival PI3K signaling.
Fiche publication
Date publication
mai 2018
Journal
Cell death & disease
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CHARVET Céline
Tous les auteurs :
Schubert F, Rapp J, Brauns-Schubert P, Schlicher L, Stock K, Wissler M, Weiß M, Charvet C, Borner C, Maurer U
Lien Pubmed
Résumé
Growth factor withdrawal induces rapid apoptosis via mitochondrial outer membrane permeabilization. We had previously observed that cell death of IL-3-dependent Ba/F3 cells, induced by removal of the growth factor, required the activity of the kinase GSK-3. Employing CRISPR/Cas9-mediated gene knockout, we aimed to identify pro-apoptotic GSK-3 regulated factors in this process. Knockout of either Puma or Bim demonstrated that the induction of Puma, but not Bim, was crucial for apoptosis induced by IL-3 deprivation. Thus, we aimed at identifying the GSK-3-dependent PUMA regulator. Loss of FOXO3A reduced the induction of Puma, while additional loss of p53 completely repressed induction upon growth factor withdrawal. A constitutively active mutant of FOXO3A, which cannot be controlled by AKT directly, still required active GSK-3 for the full transcriptional induction of Puma and cell death upon IL-3 withdrawal. Thus, the suppression of GSK-3 is the key function of PI3K signaling in order to prevent the induction of Puma by FOXO3A and p53 and thereby apoptosis upon growth factor withdrawal.
Référence
Cell Death Dis. 2018 05 1;9(5):470