Deconstructing PML-induced premature senescence.
In this study, we investigated the subcellular and molecular mechanisms underlying promyelocytic leukemia (PML)-induced premature senescence. We demonstrate that intact PML nuclear bodies are not required for the induction of senescence. We have determined further that of seven known PML isoforms, only PML IV is capable of causing premature senescence, providing the first evidence for functional differences among these isoforms. Of interest is the fact that in contrast to PML(+/+) fibroblasts, PML(-/-) cells are resistant to PML IV-induced senescence. This suggests that although PML IV is necessary for this process to occur, it is not sufficient and requires other components for activity. Finally, we provide evidence that PML IV-induced senescence involves stabilization and activation of p53 through phosphorylation at Ser46 and acetylation at Lys382, and that it occurs independently of telomerase and differs from that elicited by oncogenic Ras. Taken together, our data assign a specific pro-senescent activity to an individual PML isoform that involves p53 activation and is independent from PML nuclear bodies.
Bischof
Oliver
O
Unité de Recombinaison et Expression Génétique, INSERM U 163, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
Kirsh
Olivier
O
Pearson
Mark
M
Itahana
Koji
K
Pelicci
Pier Giuseppe
PG
Dejean
Anne
A
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D034961:Antigens, Nuclear; D001324:Autoantigens / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology; D002467:Cell Nucleus / Q000648:ultrastructure; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology; D015388:Organelles / Q000502:physiology; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins / Q000502:physiology; D025842:SUMO-1 Protein / Q000502:physiology; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D034961:Antigens, Nuclear; D001324:Autoantigens; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D004268:DNA-Binding Proteins; C491473:Daxx protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C066642:SP100 protein, human; C070576:PML protein, human; D019098:Telomerase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)