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Molecular and Cellular Biology, December 2008, p. 7050-7065, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.01548-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Nucleophosmin Serves as a Rate-Limiting Nuclear Export Chaperone for the Mammalian Ribosome{triangledown}

Leonard B. Maggi Jr.,1,2 Michael Kuchenruether,1,2 David Y. A. Dadey,1,2 Rachel M. Schwope,1 Silvia Grisendi,3,4 R. Reid Townsend,5 Pier Paolo Pandolfi,3,4 and Jason D. Weber1,2*

Department of Internal Medicine, Division of Molecular Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110,1 Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110,2 Cancer Biology and Genetics Program, Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021,3 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Harvard Medical School, Boston, Massachusetts 02115,4 Department of Medicine, Division of Metabolism and Proteomics Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 631105

Received 23 August 2007/ Returned for modification 22 October 2007/ Accepted 8 September 2008

Nucleophosmin (NPM) (B23) is an essential protein in mouse development and cell growth; however, it has been assigned numerous roles in very diverse cellular processes. Here, we present a unified mechanism for NPM's role in cell growth; NPM directs the nuclear export of both 40S and 60S ribosomal subunits. NPM interacts with rRNA and large and small ribosomal subunit proteins and also colocalizes with large and small ribosomal subunit proteins in the nucleolus, nucleus, and cytoplasm. The transduction of NPM shuttling-defective mutants or the loss of Npm1 inhibited the nuclear export of both the 40S and 60S ribosomal subunits, reduced the available pool of cytoplasmic polysomes, and diminished overall protein synthesis without affecting rRNA processing or ribosome assembly. While the inhibition of NPM shuttling can block cellular proliferation, the dramatic effects on ribosome export occur prior to cell cycle inhibition. Modest increases in NPM expression amplified the export of newly synthesized rRNAs, resulting in increased rates of protein synthesis and indicating that NPM is rate limiting in this pathway. These results support the idea that NPM-regulated ribosome export is a fundamental process in cell growth.

* Corresponding author. Mailing address: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Campus Box 8069, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: (314) 747-3896. Fax: (314) 747-2797. E-mail: jweber{at}im.wustl.edu

{triangledown} Published ahead of print on 22 September 2008.

Molecular and Cellular Biology, December 2008, p. 7050-7065, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.01548-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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