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Molecular and Cellular Biology, April 2000, p. 2803-2808, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Posttranslational Modifications of p53 in Replicative Senescence Overlapping but Distinct from Those Induced by DNA Damage

Katherine Webley,1 Jane A. Bond,1 Christopher J. Jones,1 Jeremy P. Blaydes,2 Ashley Craig,2 Ted Hupp,2 and David Wynford-Thomas1,*

Cancer Research Campaign Laboratories, Department of Pathology, University of Wales College of Medicine, Cardiff CF14 4XN,1 and Department of Molecular & Cellular Pathology, Ninewells Hospital Medical School, University of Dundee, Dundee DD1 9SY,2 United Kingdom

Received 16 September 1999/Returned for modification 4 November 1999/Accepted 19 January 2000

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.

* Corresponding author. Mailing address: Cancer Research Campaign Laboratories, Department of Pathology, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom. Phone: 44 (029) 2074 2700. Fax: 44 (029) 2074 2704. E-mail: KingTD{at}Cardiff.ac.uk.

Molecular and Cellular Biology, April 2000, p. 2803-2808, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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