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J. Biol. Chem., Vol. 279, Issue 40, 41275-41279, October 1, 2004

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Hypoxia-induced Nucleophosmin Protects Cell Death through Inhibition of p53^*

June Li, Xiaoling Zhang, Daniel P. Sejas, Grover C. Bagby, and Qishen Pang¶

From the Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and the Oregon Cancer Institute, Division of Hematology and Oncology, Oregon Health Sciences University, Portland, Oregon 97201

Nucleophosmin (NPM) is a multifunctional protein that is overexpressed in actively proliferating cells and cancer cells. Here we report that this proliferation-promoting protein is strongly induced in response to hypoxia in human normal and cancer cells. Up-regulation of NPM is hypoxia-inducible factor-1 (HIF-1)-dependent. The NPM promoter encodes a functional HIF-1-responsive element that can be activated by hypoxia or forced expression of HIF-1. Suppression of NPM expression by small interfering RNA targeting NPM increases hypoxia-induced apoptosis, whereas overexpression of NPM protects against hypoxic cell death of wild-type but not p53-null cells. Moreover, NPM inhibits hypoxia-induced p53 phosphorylation at Ser-15 and interacts with p53 in hypoxic cells. Thus, this study not only demonstrates hypoxia regulation of a proliferation-promoting protein but also suggests that hypoxia-driven cancer progression may require increased expression of NPM to suppress p53 activation and maintain cell survival.

Received for publication, June 24, 2004 , and in revised form, July 23, 2004.

^* This work was supported by an American Cancer Society (Ohio Division) support grant, a Fanconi Anemia Research Fund grant, a Trustee grant from the Cincinnati Children's Hospital Medical Center, and National Institutes of Health Grant R01 CA109641 (to Q. P.). 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.

^¶ To whom correspondence and reprint requests should be addressed: Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229. Tel.: 513-636-1152; Fax: 513-636-3768; E-mail: qishen.pang{at}cchmc.org.

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