Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2

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

^* To whom correspondence should be addressed. Email: hualu{at}iupui.edu.

	Abstract

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 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, knockdown of NS by siRNA also activates p53 and induces G1 arrest. These effects require the ribosomal proteins L5 and L11, since depletion of NS enhanced their interaction with MDM2 and knockdown 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.