Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2.
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 G(1) cell cycle arrest, and inhibits cell proliferation. Interestingly, the knockdown of NS by small interfering RNA also activates p53 and induces G(1) 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.
Dai
Mu-Shui
MS
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
Sun
Xiao-Xin
XX
Lu
Hua
H
D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D049109:Cell Proliferation; D016193:G1 Phase; D019204:GTP-Binding Proteins; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
D002352:Carrier Proteins; C469949:GNL3 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; C029742:ribosomal protein L5; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019204:GTP-Binding Proteins