Reversal of senescence in mouse fibroblasts through lentiviral suppression of p53.
Senescence is generally defined as an irreversible state of G(1) cell cycle arrest in which cells are refractory to growth factor stimulation. In mouse embryo fibroblasts (MEFs), induction of senescence requires the presence of p19(ARF) and p53, as genetic ablation of either of these genes allows escape from senescence and leads to immortalization. We have developed a lentiviral vector that directs the synthesis of a p53-specific short hairpin transcript, which mediates stable suppression of p53 expression through RNA interference. We show that suppression of p53 expression in senescent MEFs leads to rapid cell cycle re-entry, is associated with loss of expression of senescence-associated genes, and leads to immortalization. These data indicate that senescence in MEFs is reversible and demonstrate that both initiation and maintenance of senescence is p53-dependent.
Dirac
Annette M G
AM
Division of Molecular Carcinogenesis, and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Bernards
René
R
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D016922:Cellular Senescence / Q000502:physiology*; D005333:Fetus / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D009690:Nucleic Acid Conformation; D034622:RNA Interference / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53