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Molecular and Cellular Biology, October 2004, p. 8884-8894, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.8884-8894.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Increased Sensitivity to UV Radiation in Mice with a p53 Point Mutation at Ser389

Wendy Bruins,1 Edwin Zwart,1 Laura D. Attardi,2 Tomoo Iwakuma,3 Esther M. Hoogervorst,1 Rudolf B. Beems,1 Barbara Miranda,4 Conny T. M. van Oostrom,1 Jolanda van den Berg,1 Gerard J. van den Aardweg,5 Guillermina Lozano,3 Harry van Steeg,1 Tyler Jacks,4 and Annemieke de Vries1*

Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and Environment (RIVM), Bilthoven,1 Josephine Nefkens Institute, Erasmus University Rotterdam, Rotterdam, The Netherlands,5 Department of Radiation Oncology, Stanford University Medical Center, Stanford, California,2 Cancer Genetics, Department of Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas,3 Center for Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts4

Received 27 May 2004/ Returned for modification 23 June 2004/ Accepted 8 July 2004

Phosphorylation is important for p53 protein stabilization and activation after DNA damage. Serine 389 of p53 is specifically phosphorylated after UV irradiation, whereas gamma radiation activates p53 through a different pathway. To study the in vivo significance of p53 phosphorylation at serine 389, we generated a physiological mouse model in which p53 phosphorylation at serine 389 is abolished by alanine substitution. Homozygous mutant p53.S389A mice are viable and have an apparently normal phenotype. However, cells isolated from these mice are partly compromised in transcriptional activation of p53 target genes and apoptosis after UV irradiation, whereas gamma radiation-induced responses are not affected. Moreover, p53.S389A mice show increased sensitivity to UV-induced skin tumor development, signifying the importance of serine 389 phosphorylation for the tumor-suppressive function of p53.

* Corresponding author. Mailing address: National Institute of Public Health and the Environment, Laboratory of Toxicology, Pathology and Genetics, P.O. Box 1, 3721 MA Bilthoven, The Netherlands. Phone: 31 30 274 3483. Fax: 31 30 274 4446. E-mail: Annemieke.de.Vries{at}rivm.nl.

Molecular and Cellular Biology, October 2004, p. 8884-8894, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.8884-8894.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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