Inhibition of HDM2 and activation of p53 by ribosomal protein L23.
The importance of coordinating cell growth with proliferation has been recognized for a long time. The molecular basis of this relationship, however, is poorly understood. Here we show that the ribosomal protein L23 interacts with HDM2. The interaction involves the central acidic domain of HDM2 and an N-terminal domain of L23. L23 and L11, another HDM2-interacting ribosomal protein, can simultaneously yet distinctly interact with HDM2 together to form a ternary complex. We show that, when overexpressed, L23 inhibits HDM2-induced p53 polyubiquitination and degradation and causes a p53-dependent cell cycle arrest. On the other hand, knocking down L23 causes nucleolar stress and triggers translocation of B23 from the nucleolus to the nucleoplasm, leading to stabilization and activation of p53. Our data suggest that cells may maintain a steady-state level of L23 during normal growth; alternating the levels of L23 in response to changing growth conditions could impinge on the HDM2-p53 pathway by interrupting the integrity of the nucleolus.
Jin
Aiwen
A
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, USA.
Itahana
Koji
K
O'Keefe
Kevin
K
Zhang
Yanping
Y
D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D003609:Dactinomycin / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D046911:Macromolecular Substances; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D046911:Macromolecular Substances; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C027624:ribosomal protein L11; C032493:ribosomal protein L17; D003609:Dactinomycin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2