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.
|Titolo:||Deconstructing PML-induced premature senescence|
PELICCI, PIER GIUSEPPE (Penultimo)
|Parole Chiave:||Animals; Tumor Suppressor Protein p53; Telomerase; Intracellular Signaling Peptides and Proteins; Humans; Fibroblasts; Mice, Knockout; Macromolecular Substances; Transcription Factors; Nuclear Proteins; Phosphorylation; Adaptor Proteins, Signal Transducing; Carrier Proteins; DNA-Binding Proteins; Proto-Oncogene Proteins p21(ras); Protein Processing, Post-Translational; Mice; Recombinant Fusion Proteins; Cell Nucleus; Reactive Oxygen Species; Antigens, Nuclear; Autoantigens; Protein Isoforms; Tumor Suppressor Proteins; Structure-Activity Relationship; SUMO-1 Protein; Acetylation; Neoplasm Proteins; Cell Aging; Organelles|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||1-lug-2002|
|Digital Object Identifier (DOI):||10.1093/emboj/cdf341|
|Appare nelle tipologie:||01 - Articolo su periodico|