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Molecular and Cellular Biology, February 2005, p. 1258-1271, Vol. 25, No. 4
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.4.1258-1271.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Nucleophosmin (B23) Targets ARF to Nucleoli and Inhibits Its Function

Chandrashekhar Korgaonkar,1 Jussara Hagen,1,{dagger} Van Tompkins,1 April A. Frazier,1 Chantal Allamargot,1 Frederick W. Quelle,1,2 and Dawn E. Quelle1,3*

Department of Pharmacology,1 Immunology Graduate Program,2 Molecular Biology Graduate Program, University of Iowa College of Medicine, Iowa City, Iowa3

Received 4 June 2004/ Returned for modification 6 July 2004/ Accepted 15 November 2004

The ARF tumor suppressor is a nucleolar protein that activates p53-dependent checkpoints by binding Mdm2, a p53 antagonist. Despite persuasive evidence that ARF can bind and inactivate Mdm2 in the nucleoplasm, the prevailing view is that ARF exerts its growth-inhibitory activities from within the nucleolus. We suggest ARF primarily functions outside the nucleolus and provide evidence that it is sequestered and held inactive in that compartment by a nucleolar phosphoprotein, nucleophosmin (NPM). Most cellular ARF is bound to NPM regardless of whether cells are proliferating or growth arrested, indicating that ARF-NPM association does not correlate with growth suppression. Notably, ARF binds NPM through the same domains that mediate nucleolar localization and Mdm2 binding, suggesting that NPM could control ARF localization and compete with Mdm2 for ARF association. Indeed, NPM knockdown markedly enhanced ARF-Mdm2 association and diminished ARF nucleolar localization. Those events correlated with greater ARF-mediated growth suppression and p53 activation. Conversely, NPM overexpression antagonized ARF function while increasing its nucleolar localization. These data suggest that NPM inhibits ARF's p53-dependent activity by targeting it to nucleoli and impairing ARF-Mdm2 association.

* Corresponding author. Mailing address: Department of Pharmacology, The University of Iowa, College of Medicine, Iowa City, IA 52242. Phone: (319) 353-5749. Fax: (319) 335-8930. E-mail: dawn-quelle{at}uiowa.edu.

{dagger} C.K. and J.H. contributed equally to this work.

{ddagger} Present address: Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202.

Molecular and Cellular Biology, February 2005, p. 1258-1271, Vol. 25, No. 4
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.4.1258-1271.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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