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Molecular and Cellular Biology, September 2006, p. 6819-6831, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.00562-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage{dagger}

Yaron Pereg,1 Suzanne Lam,2 Amina Teunisse,2 Sharon Biton,1 Erik Meulmeester,2 Leonid Mittelman,3 Giacomo Buscemi,4 Koji Okamoto,5 Yoichi Taya,5 Yosef Shiloh,1* and Aart G. Jochemsen2*

Department of Molecular Genetics and Biochemistry,1 Interdepartmental Core Facility, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel,3 Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands,2 Department of Experimental Oncology, Istituto Nazionale Tumori, Milan 20133, Italy,4 Radiobiology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan5

Received 30 March 2006/ Returned for modification 5 May 2006/ Accepted 5 July 2006

The p53 tumor suppressor plays a major role in maintaining genomic stability. Its activation and stabilization in response to double strand breaks (DSBs) in DNA are regulated primarily by the ATM protein kinase. ATM mediates several posttranslational modifications on p53 itself, as well as phosphorylation of p53's essential inhibitors, Hdm2 and Hdmx. Recently we showed that ATM- and Hdm2-dependent ubiquitination and subsequent degradation of Hdmx following DSB induction are mediated by phosphorylation of Hdmx on S403, S367, and S342, with S403 being targeted directly by ATM. Here we show that S367 phosphorylation is mediated by the Chk2 protein kinase, a downstream kinase of ATM. This phosphorylation, which is important for subsequent Hdmx ubiquitination and degradation, creates a binding site for 14-3-3 proteins which controls nuclear accumulation of Hdmx following DSBs. Phosphorylation of S342 also contributed to optimal 14-3-3 interaction and nuclear accumulation of Hdmx, but phosphorylation of S403 did not. Our data indicate that binding of a 14-3-3 dimer and subsequent nuclear accumulation are essential steps toward degradation of p53's inhibitor, Hdmx, in response to DNA damage. These results demonstrate a sophisticated control by ATM of a target protein, Hdmx, which itself is one of several ATM targets in the ATM-p53 axis of the DNA damage response.

* Corresponding author. Mailing address for Yosef Shiloh: Department of Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Phone: 972-3-6409760. Fax: 972-3-6407471. E-mail: yossih{at}post.tau.ac.il. Mailing address for Aart G. Jochemsen: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. Phone: 31-715269220. Fax: 31-715268270. E-mail: a.g.jochemsen{at}lumc.nl.

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

Molecular and Cellular Biology, September 2006, p. 6819-6831, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.00562-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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