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J. Biol. Chem., Vol. 281, Issue 44, 33036-33044, November 3, 2006

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Hdmx Modulates the Outcome of P53 Activation in Human Tumor Cells^*

Mark Wade¹, Ee Tsin Wong², Mengjia Tang¹, Jayne M. Stommel³, and Geoffrey M. Wahl⁴

From the Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037 and the Graduate Program, Division of Biological Sciences, University of California San Diego, La Jolla, California 92037

Tumors that express wild-type P53 provide a target for therapies designed to reactivate P53 function. This is supported by the potent activation of P53 in tumor cells by Nutlin, a cis-imidazoline that inhibits the Hdm2-P53 interaction. The efficacy of Hdm2·P53 antagonists could be compromised if they do not antagonize Hdmx, an Hdm2 homolog that inhibits P53 transactivation. We evaluated the role of Hdmx expression in sensitivity to Nutlin in a range of cancer cell lines. Nutlin reduced Hdmx levels in normal cells and some cancer cell lines, whereas other cancer cells were refractory to such down-regulation. Strikingly, Nutlin did not disrupt Hdmx·P53 complexes, and in cell lines where no Hdmx degradation occurred, Nutlin failed to induce apoptosis. shRNA-mediated reduction of Hdmx sensitized cells to apoptosis, but caspase-3 was neither required nor sufficient for Hdmx degradation or apoptosis. Our data imply that Hdmx is an important determinant of the outcome of P53 activation. Thus, targeting Hdmx may be a therapeutic strategy that complements drugs such as Nutlin.

Received for publication, June 6, 2006 , and in revised form, August 9, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Supported by National Institutes of Health Grant CA61449 (awarded to G. M. W.)

² Recipient of an A*STAR Overseas Scholarship (Singapore).

³ Present address: Dana-Farber Cancer Institute, Mayer 413, 44 Binney St., Boston, MA 02115.

⁴ To whom correspondence should be addressed: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037. E-mail: wahl{at}salk.edu.

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