Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage.
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.
Webley
K
K
Cancer Research Campaign Laboratories, Department of Pathology, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom.
Bond
J A
JA
Jones
C J
CJ
Blaydes
J P
JP
Craig
A
A
Hupp
T
T
Wynford-Thomas
D
D
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
D016159:Tumor Suppressor Protein p53