title: Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage.
abstract: Replicative senescence in human fibroblasts is absolutely dependent on the function of the phosphoprotein p53 and correlates with activation of p53-dependent transcription. However, no evidence for posttranslational modification of p53 in senescence has been presented, raising the possibility that changes in transcriptional activity result from upregulation of a coactivator. Using a series of antibodies with phosphorylation-sensitive epitopes, we now show that senescence is associated with major changes at putative regulatory sites in the N and C termini of p53 consistent with increased phosphorylation at serine-15, threonine-18, and serine-376 and decreased phosphorylation at serine-392. Ionizing and UV radiation generated overlapping but distinct profiles of response, with increased serine-15 phosphorylation being the only common change. These results support a direct role for p53 in signaling replicative senescence and are consistent with the generation by telomere erosion of a signal which shares some but not all of the features of DNA double-strand breaks.
authors.affiliation: Cancer Research Campaign Laboratories, Department of Pathology, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Webley
authors.forename: J A
authors.initials: JA
authors.lastname: Bond
authors.forename: C J
authors.initials: CJ
authors.lastname: Jones
authors.forename: J P
authors.initials: JP
authors.lastname: Blaydes
authors.forename: A
authors.initials: A
authors.lastname: Craig
authors.forename: T
authors.initials: T
authors.lastname: Hupp
authors.forename: D
authors.initials: D
authors.lastname: Wynford-Thomas
mesh_terms: D002460:Cell Line; D004249:DNA Damage / Q000528:radiation effects; D004261:DNA Replication; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D011499:Protein Processing, Post-Translational; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D016159:Tumor Suppressor Protein p53