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Molecular and Cellular Biology, July 2008, p. 4365-4376, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.01662-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Aberrant Expression of Nucleostemin Activates p53 and Induces Cell Cycle Arrest via Inhibition of MDM2{triangledown} ,{dagger}

Mu-Shui Dai,{ddagger} Xiao-Xin Sun,{ddagger} and Hua Lu*

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202

Received 7 September 2007/ Returned for modification 5 October 2007/ Accepted 11 April 2008

The nucleolar protein nucleostemin (NS) is essential for cell proliferation and early embryogenesis. Both depletion and overexpression of NS reduce cell proliferation. However, the mechanisms underlying this regulation are still unclear. Here, we show that NS regulates p53 activity through the inhibition of MDM2. NS binds to the central acidic domain of MDM2 and inhibits MDM2-mediated p53 ubiquitylation and degradation. Consequently, ectopic overexpression of NS activates p53, induces G1 cell cycle arrest, and inhibits cell proliferation. Interestingly, the knockdown of NS by small interfering RNA also activates p53 and induces G1 arrest. These effects require the ribosomal proteins L5 and L11, since the depletion of NS enhanced their interactions with MDM2 and the knockdown of L5 or L11 abrogated the NS depletion-induced p53 activation and cell cycle arrest. These results suggest that a p53-dependent cell cycle checkpoint monitors changes of cellular NS levels via the impediment of MDM2 function.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202. Phone: (317) 278-0920. Fax: (317) 274-4686. E-mail: hualu{at}iupui.edu

{triangledown} Published ahead of print on 21 April 2008.

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

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, July 2008, p. 4365-4376, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.01662-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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