title: Absence of tumor suppressor tumor protein 53-induced nuclear protein 1 (TP53INP1) sensitizes mouse thymocytes and embryonic fibroblasts to redox-driven apoptosis.
abstract: The p53-transcriptional target TP53INP1 is a potent stress-response protein promoting p53 activity. We previously showed that ectopic overexpression of TP53INP1 facilitates cell cycle arrest as well as cell death. Here we report a study investigating cell death in mice deficient for TP53INP1. Surprisingly, we found enhanced stress-induced apoptosis in TP53INP1-deficient cells. This observation is underpinned in different cell types in vivo (thymocytes) and in vitro (thymocytes and MEFs), following different types of injury inducing either p53-dependent or -independent cell death. Nevertheless, absence of TP53INP1 is unable to overcome impaired cell death of p53-deficient thymocytes. Stress-induced ROS production is enhanced in the absence of TP53INP1, and antioxidant NAC complementation abolishes increased sensitivity to apoptosis of TP53INP1-deficient cells. Furthermore, antioxidant defenses are defective in TP53INP1-deficient mice in correlation with ROS dysregulation. Finally, we show that autophagy is reduced in TP53INP1-deficient cells both at the basal level and upon stress. Altogether, these data show that impaired ROS regulation in TP53INP1-deficient cells is responsible for their sensitivity to induced apoptosis. In addition, they suggest that this sensitivity could rely on a defect of autophagy. Therefore, these data emphasize the role of TP53INP1 in protection against cell injury.
authors.affiliation: INSERM U624 Stress cellulaire, Case 915 Parc Scientifique de Luminy, Marseille Cedex 9, France.
authors.forename: Prudence
authors.initials: P
authors.lastname: N'guessan
authors.forename: Laurent
authors.initials: L
authors.lastname: Pouyet
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Gosset
authors.forename: Sonia
authors.initials: S
authors.lastname: Hamlaoui
authors.forename: Marion
authors.initials: M
authors.lastname: Seillier
authors.forename: Carla E
authors.initials: CE
authors.lastname: Cano
authors.forename: Mylène
authors.initials: M
authors.lastname: Seux
authors.forename: Pierre
authors.initials: P
authors.lastname: Stocker
authors.forename: Marcel
authors.initials: M
authors.lastname: Culcasi
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.forename: Nelson J
authors.initials: NJ
authors.lastname: Dusetti
authors.forename: Sylvia
authors.initials: S
authors.lastname: Pietri
authors.forename: Alice
authors.initials: A
authors.lastname: Carrier
mesh_terms: D015086:2,6-Dichloroindophenol / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology*
chemical_list: D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; C518507:tumor protein 53-induced nuclear protein 1, mouse; D015086:2,6-Dichloroindophenol; D005978:Glutathione