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Molecular and Cellular Biology, October 2005, p. 8874-8886, Vol. 25, No. 20
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.20.8874-8886.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Nucleophosmin Is Required for DNA Integrity and p19Arf Protein Stability{dagger}

Emanuela Colombo,1 Paola Bonetti,1 Eros Lazzerini Denchi,1,2,{ddagger} Paola Martinelli,1 Raffaella Zamponi,1 Jean-Christophe Marine,3 Kristian Helin,1 Brunangelo Falini,4 and Pier Giuseppe Pelicci1,2,5*

Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy,1 IFOM Institute, Via Adamello 16, 20139 Milan, Italy,2 Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium,3 Institute of Hematology and Internal Medicine, University of Perugia, 06100 Perugia, Italy,4 Department of Medicine, Surgery and Dentistry, University of Milan, Milan, Italy5

Received 24 June 2005/ Returned for modification 2 July 2005/ Accepted 21 July 2005

Nucleophosmin (NPM) is a nucleolar phosphoprotein that binds the tumor suppressors p53 and p19Arf and is thought to be indispensable for ribogenesis, cell proliferation, and survival after DNA damage. The NPM gene is the most frequent target of genetic alterations in leukemias and lymphomas, though its role in tumorigenesis is unknown. We report here the first characterization of a mouse NPM knockout strain. Lack of NPM expression results in accumulation of DNA damage, activation of p53, widespread apoptosis, and mid-stage embryonic lethality. Fibroblasts explanted from null embryos fail to grow and rapidly acquire a senescent phenotype. Transfer of the NPM mutation into a p53-null background rescued apoptosis in vivo and fibroblast proliferation in vitro. Cells null for both p53 and NPM grow faster than control cells and are more susceptible to transformation by activated oncogenes, such as mutated Ras or overexpressed Myc. In the absence of NPM, Arf protein is excluded from nucleoli and is markedly less stable. Our data demonstrate that NPM regulates DNA integrity and, through Arf, inhibits cell proliferation and are consistent with a putative tumor-suppressive function of NPM.

* Corresponding author. Mailing address: European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Phone: 39-02-57489838. Fax: 39-02-57489851. E-mail: piergiuseppe.pelicci{at}ifom-ieo-campus.it.

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

{ddagger} Present address: The Rockefeller University, 1230 York Avenue, New York, N.Y.

Molecular and Cellular Biology, October 2005, p. 8874-8886, Vol. 25, No. 20
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.20.8874-8886.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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