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Molecular and Cellular Biology, November 2005, p. 9608-9620, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9608-9620.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

DNA Damage-Induced Phosphorylation of MdmX at Serine 367 Activates p53 by Targeting MdmX for Mdm2-Dependent Degradation{dagger}

Koji Okamoto,1* Kenji Kashima,1 Yaron Pereg,2 Michiko Ishida,1 Satomi Yamazaki,1 Ayumi Nota,1 Amina Teunisse,3 Domenico Migliorini,4 Issay Kitabayashi,5 Jean-Christophe Marine,6 Carol Prives,4 Yosef Shiloh,2 Aart G. Jochemsen,3 and Yoichi Taya1

Radiobiology Division, National Cancer Center Research Institute, Tokyo 104-0045, and CREST and SORST, Japan Science and Technology Agency, Tokyo, Japan,1 David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel,2 Department of Molecular and Cell Biology, Leiden University Medical Center, 2300 RA Leiden, The Netherlands,3 Department of Biological Sciences, Columbia University, New York, New York 10027,4 Molecular Oncology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan,5 Laboratory of Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, B-9052 Ghent, Belgium6

Received 17 February 2005/ Returned for modification 15 April 2005/ Accepted 14 August 2005

Understanding how p53 activity is regulated is crucial in elucidating mechanisms of cellular defense against cancer. Genetic data indicate that Mdmx as well as Mdm2 plays a major role in maintaining p53 activity at low levels in nonstressed cells. However, biochemical mechanisms of how Mdmx regulates p53 activity are not well understood. Through identification of Mdmx-binding proteins, we found that 14-3-3 proteins are associated with Mdmx. Mdmx harbors a consensus sequence for binding of 14-3-3. Serine 367 (S367) is located within the putative binding sequence for 14-3-3, and its substitution with alanine (S367A) abolishes binding of Mdmx to 14-3-3. Transfection assays indicated that the S367A mutation, in cooperation with Mdm2, enhances the ability of Mdmx to repress the transcriptional activity of p53. The S367A mutant is more resistant to Mdm2-dependent ubiquitination and degradation than wild-type Mdmx, and Mdmx phosphorylated at S367 is preferentially degraded by Mdm2. Several types of DNA damage markedly enhance S367 phosphorylation, coinciding with increased binding of Mdmx to 14-3-3 and accelerated Mdmx degradation. Furthermore, promotion of growth of normal human fibroblasts after introduction of Mdmx is enhanced by the S367 mutation. We propose that Mdmx phosphorylation at S367 plays an important role in p53 activation after DNA damage by triggering Mdm2-dependent degradation of Mdmx.

* Corresponding author. Mailing address: National Cancer Center Research Institute, Radiobiology Division, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81 3 3542 2511, ext. 4805. Fax: 81 3 5565 0727. E-mail: kojokamo{at}gan2.res.ncc.go.jp.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org.

Molecular and Cellular Biology, November 2005, p. 9608-9620, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9608-9620.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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