title: Granzyme B-activated p53 interacts with Bcl-2 to promote cytotoxic lymphocyte-mediated apoptosis.
abstract: Granzyme B (GzmB) plays a major role in CTLs and NK cell-mediated elimination of virus-infected cells and tumors. Human GzmB preferentially induces target cell apoptosis by cleaving the proapoptotic Bcl-2 family member Bid, which, together with Bax, induces mitochondrial outer membrane permeabilization. We previously showed that GzmB also induces a rapid accumulation of the tumor-suppressor protein p53 within target cells, which seems to be involved in GzmB-induced apoptosis. In this article, we show that GzmB-activated p53 accumulates on target cell mitochondria and interacts with Bcl-2. This interaction prevents Bcl-2 inhibitory effect on both Bax and GzmB-truncated Bid, and promotes GzmB-induced mitochondrial outer membrane permeabilization. Consequently, blocking p53-Bcl-2 interaction decreases GzmB-induced Bax activation, cytochrome c release from mitochondria, and subsequent effector caspases activation leading to a decreased sensitivity of target cells to both GzmB and CTL/NK-mediated cell death. Together, our results define p53 as a new important player in the GzmB apoptotic signaling pathway and in CTL/NK-induced apoptosis.
authors.affiliation: U753 INSERM, 94805 Villejuif, France; Gustave Roussy Cancer Campus, 94805 Villejuif, France; University Paris Sud, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France; and.
authors.forename: Thouraya
authors.initials: T
authors.lastname: Ben Safta
authors.affiliation: U753 INSERM, 94805 Villejuif, France; Gustave Roussy Cancer Campus, 94805 Villejuif, France; University Paris Sud, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France; and.
authors.forename: Linda
authors.initials: L
authors.lastname: Ziani
authors.affiliation: U753 INSERM, 94805 Villejuif, France; Gustave Roussy Cancer Campus, 94805 Villejuif, France; University Paris Sud, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France; and.
authors.forename: Loetitia
authors.initials: L
authors.lastname: Favre
authors.affiliation: U753 INSERM, 94805 Villejuif, France; Gustave Roussy Cancer Campus, 94805 Villejuif, France; University Paris Sud, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France; and.
authors.forename: Lucille
authors.initials: L
authors.lastname: Lamendour
authors.affiliation: U753 INSERM, 94805 Villejuif, France; Gustave Roussy Cancer Campus, 94805 Villejuif, France; University Paris Sud, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France; and.
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Gros
authors.affiliation: U753 INSERM, 94805 Villejuif, France; Gustave Roussy Cancer Campus, 94805 Villejuif, France; University Paris Sud, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France; and.
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Martinvalet
authors.affiliation: U753 INSERM, 94805 Villejuif, France; Gustave Roussy Cancer Campus, 94805 Villejuif, France; University Paris Sud, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France; and.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.affiliation: U753 INSERM, 94805 Villejuif, France; Gustave Roussy Cancer Campus, 94805 Villejuif, France; University Paris Sud, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France; and jerome.thiery@gustaveroussy.fr.
authors.forename: Jerome
authors.initials: J
authors.lastname: Thiery
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D052160:Benzothiazoles / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D061986:MCF-7 Cells; D008928:Mitochondria / Q000276:immunology; D051336:Mitochondrial Membranes / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D052160:Benzothiazoles; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D014050:Toluene; D045304:Cytochromes c; C121565:pifithrin; C509213:GZMB protein, human; D053804:Granzymes; D053148:Caspase 3