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  • The EMBO Journal (1999) 18, 6845 - 6854
  • doi:10.1093/emboj/18.23.6845

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

Dmitry V. Bulavin1, Shin acuteichi Saito2, M. Christine Hollander1, Kazuyasu Sakaguchi2,3, Carl W. Anderson4, Ettore Appella2 and Albert J. Fornace Jr1

  1. Division of Basic Science, Bethesda, MD 20892, USA
  2. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
  3. Present address: Laboratory of Structure-Function Biochemistry, Department of Molecular Science, Kyushu University, Fukuoka 812-8581, Japan
  4. Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA

Correspondence to:

Albert J. Fornace Jr, E-mail: fornace@nih.gov

Received 24 August 1999; Accepted 15 October 1999; Revised 15 October 1999

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.

  • Keywords:

    • apoptosis,
    • DNA damage,
    • p38,
    • p53,
    • phosphorylation