Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation

Components of the ras signaling pathway contribute to activation of cellular p53. In MCF‐7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co‐expression of p38 stabilized p53 protein. In vitro , p38 ki...

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Bibliographic Details
Published in:The EMBO journal 1999-12, Vol.18 (23), p.6845-6854
Main Authors: Bulavin, Dmitry V., Saito, Shińichi, Hollander, M. Christine, Sakaguchi, Kazuyasu, Anderson, Carl W., Appella, Ettore, Fornace Jr, Albert J.
Format: Article
Language:English
Subjects:
Alanine - metabolism
apoptosis
Apoptosis - radiation effects
Chloramphenicol O-Acetyltransferase - metabolism
DNA Damage
Flow Cytometry
Humans
Irradiation
Mitogen-Activated Protein Kinases - genetics
Mitogen-Activated Protein Kinases - metabolism
Mutagenesis, Site-Directed
p38
p38 Mitogen-Activated Protein Kinases
p38 protein
p53
phosphorylation
Phosphorylation - radiation effects
Plasmids - metabolism
Serine - metabolism
Time Factors
Transcription, Genetic
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Ultraviolet radiation
Ultraviolet Rays
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Summary:Components of the ras signaling pathway contribute to activation of cellular p53. In MCF‐7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co‐expression of p38 stabilized p53 protein. In vitro , p38 kinase phosphorylated p53 at Ser33 and Ser46, a newly identified site. Mutation of these sites decreased p53‐mediated and UV‐induced apoptosis, and the reduction correlated with total abrogation of UV‐induced phosphorylation on Ser37 and a significant decrease in Ser15 phosphorylation in mutant p53 containing alanine at Ser33 and Ser46. Inhibition of p38 activation after UV irradiation decreased phosphorylation of Ser33, Ser37 and Ser15, and also markedly reduced UV‐induced apoptosis in a p53‐dependent manner. These results suggest that p38 kinase plays a prominent role in an integrated regulation of N‐terminal phosphorylation that regulates p53‐mediated apoptosis after UV radiation.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/18.23.6845