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J. Biol. Chem., Vol. 283, Issue 23, 15568-15576, June 6, 2008

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Ribosomal Protein S9 Is a Novel B23/NPM-binding Protein Required for Normal Cell Proliferation^*

Mikael S. Lindström¹ and Yanping Zhang^¶2

From the Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, and the ^¶Department of Pharmacology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7512

B23 (NPM/nucleophosmin) is a multifunctional nucleolar protein and a member of the nucleoplasmin superfamily of acidic histone chaperones. B23 is essential for normal embryonic development and plays an important role in genomic stability, ribosome biogenesis, and anti-apoptotic signaling. Altered protein expression or genomic mutation of B23 is encountered in many different forms of cancer. Although described as multifunctional, a genuine molecular function of B23 is not fully understood. Here we show that B23 is associated with a protein complex consisting of ribosomal proteins and ribosome-associated RNA helicases. A novel, RNA-independent interaction between ribosomal protein S9 (RPS9) and B23 was further investigated. We found that S9 binding requires an intact B23 oligomerization domain. Depletion of S9 by small interfering RNA resulted in decreased protein synthesis and G₁ cell cycle arrest, in association with induction of p53 target genes. We determined that S9 is a short-lived protein in the absence of ribosome biogenesis, and proteasomal inhibition significantly increased S9 protein level. Overexpression of B23 facilitated nucleolar storage of S9, whereas knockdown of B23 led to diminished levels of nucleolar S9. Our results suggest that B23 selectively stores, and protects ribosomal protein S9 in nucleoli and therefore could facilitate ribosome biogenesis.

Received for publication, February 12, 2008 , and in revised form, April 15, 2008.

^* This work was supported, in whole or in part, by a National Institutes of Health grant (to Y. Z.). This work was also supported by grants from the Burroughs Wellcome Fund and the Leukemia Research Foundation (to Y. Z.). 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–S3.

¹ Supported by a senior postdoctoral research fellowship from the Swedish Cancer Foundation (Cancerfonden). Present address: Dept. of Oncology-Pathology, Cancer Center Karolinska, CCK R8:05, Karolinska Institutet, SE-17176 Stockholm, Sweden.

² To whom correspondence should be addressed. Tel.: 919-966-7713; Fax: 919-966-7681; E-mail: ypzhang{at}med.unc.edu.

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