Inhibition of MDM2-mediated p53 Ubiquitination and Degradation by Ribosomal Protein L5

The oncoprotein MDM2 associates with ribosomal proteins L5, L11, and L23. Both L11 and L23 have been shown to activate p53 by inhibiting MDM2-mediated p53 suppression. Here we have shown that L5 also activates p53. Overexpression of L5 stabilized ectopic p53 in H1299 cells and endogenous p53 in U2OS cells. Consequently, L5 enhanced p53 transcriptional activity and induced p53-dependent G1 cell cycle arrest. Furthermore, like L11 and L23, L5 also remarkably inhibited MDM2-mediated p53 ubiquitination. The interaction of L5 with MDM2 was also enhanced by treatment with a low dose of actinomycin D. Actinomycin D-induced p53 was inhibited by small interference RNA against L5. By reciprocal co-immunoprecipitation, we further showed that there were at least two MDM2-ribosomal protein complexes in cells: MDM2-L5-L11-L23 and p53-MDM2-L5-L11-L23. We propose that the MDM2-L5-L11-L23 complex functions to inhibit MDM2-mediated p53 ubiquitination and thus activates p53. The oncoprotein MDM2 associates with ribosomal proteins L5, L11, and L23. Both L11 and L23 have been shown to activate p53 by inhibiting MDM2-mediated p53 suppression. Here we have shown that L5 also activates p53. Overexpression of L5 stabilized ectopic p53 in H1299 cells and endogenous p53 in U2OS cells. Consequently, L5 enhanced p53 transcriptional activity and induced p53-dependent G1 cell cycle arrest. Furthermore, like L11 and L23, L5 also remarkably inhibited MDM2-mediated p53 ubiquitination. The interaction of L5 with MDM2 was also enhanced by treatment with a low dose of actinomycin D. Actinomycin D-induced p53 was inhibited by small interference RNA against L5. By reciprocal co-immunoprecipitation, we further showed that there were at least two MDM2-ribosomal protein complexes in cells: MDM2-L5-L11-L23 and p53-MDM2-L5-L11-L23. We propose that the MDM2-L5-L11-L23 complex functions to inhibit MDM2-mediated p53 ubiquitination and thus activates p53. Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. Vol. 279 (2004) 44475–44482Journal of Biological ChemistryVol. 279Issue 50PreviewPage 44479: In the right column, lines 13–16, the word “not” was omitted from the sentence. The correct sentence should read: “Of note, the slight decrease of p53 in L5 siRNA-treated cells was specific to p53; it was not caused by global translational inhibition after reduction of L5 by its siRNA.” Full-Text PDF Open Access The oncoprotein MDM2 is a crucial feedback regulator of the tumor suppressor protein p53 (1Piette J. Neel H. Marechal V. Oncogene. 1997; 15: 1001-1010Crossref PubMed Scopus (241) Google Scholar). Under physiological conditions, p53 is short-lived mainly because of MDM2-mediated ubiquitination and degradation. Under pathological conditions, the half-life of p53 is prolonged because multiple cellular pathways are activated to prevent MDM2-mediated p53 ubiquitination and degradation, consequently leading to p53 activation (2Brooks C.L. Gu W. Curr. Opin. Cell Biol. 2003; 15: 164-171Crossref PubMed Scopus (641) Google Scholar). In addition to induction of many p53-responsive genes, including those involved in cell cycle and apoptotic regulation, activated p53 also induces transcription of MDM2, which in turn suppresses p53 function. Hence, tight regulation of this MDM2-p53 feedback pathway is critically important for a cell to respond to various stresses. An example of such stress is ribosomal biogenesis stress. In response to the ribosomal biogenesis stress caused by either a low dose (5 nm) of actinomycin D (Act D) 1The abbreviations used are: Act D: actinomycin D; siRNA: small interference RNA; GST, glutathione S-transferase; GFP, green fluorescence protein; E2, ubiquitin carrier protein; E3, ubiquitin-protein isopeptide ligase. or overexpression of the mutant Bop1, a nucleolar protein critical for rRNA processing and ribosome assembly, p53 is activated and induces cell growth arrest at the G1 phase (3Ashcroft M. Kubbutat M.H. Vousden K.H. Mol. Cell. Biol. 1999; 19: 1751-1758Crossref PubMed Scopus (379) Google Scholar, 4Pestov D.G. Strezoska Z. Lau L.F. Mol. Cell. Biol. 2001; 21: 4246-4255Crossref PubMed Scopus (293) Google Scholar, 5Strezoska Z. Pestov D.G. Lau L.F. J. Biol. Chem. 2002; 277: 29617-29625Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Ironically, this activation does not appear to require posttranslational modifications of p53, such as phosphorylation (6Ashcroft M. Taya Y. Vousden K.H. Mol. Cell. Biol. 2000; 20: 3224-3233Crossref PubMed Scopus (324) Google Scholar). Instead, recent studies by several groups, including ours, suggest that association of the ribosomal proteins L11 and L23 with MDM2 might be responsible for p53 activation after Act D treatment (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, 8Lohrum M.A. Ludwig R.L. Kubbutat M.H. Hanlon M. Vousden K.H. Cancer Cells. 2003; 3: 577-587Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google Scholar). L11 and L23 can bind to MDM2 directly, and this binding is enhanced in response to Act D treatment. RNA interference against L23 can block Act D-induced p53 activation, demonstrating that L23 is required for p53 activation in response to ribosomal biogenesis stress (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar). Another ribosomal protein, L5, has also been shown to bind to MDM2 in vitro and in cells (10Marechal V. Elenbaas B. Piette J. Nicolas J.C. Levine A.J. Mol. Cell. Biol. 1994; 14: 7414-7420Crossref PubMed Scopus (294) Google Scholar, 11Elenbaas B. Dobbelstein M. Roth J. Shenk T. Levine A.J. Mol. Med. 1996; 2: 439-451Crossref PubMed Google Scholar). However, it is still puzzling whether L5, like L11 and L23, can activate p53 by inhibiting MDM2-mediated p53 ubiquitination. It is also unclear whether these three ribosomal proteins can form a single complex with MDM2 to inhibit its ubiquitin ligase activity toward p53 in cells. To address these issues, we have performed a series of cellular experiments. Our studies demonstrate that L5 can also activate p53 and induce p53-dependent G1 arrest in response to Act D-induced ribosomal biogenesis stress. Additionally, a set of reciprocal immunoprecipitation experiments reveals that L5, L11, and L23 appear to bind to MDM2 simultaneously, forming one quadruple complex in cells. The steady state level of the complex is reduced in the of p53, that the ribosomal proteins with p53 for that the three ribosomal proteins inhibit MDM2 by forming a complex with Cell and and cells were in with as (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, Y. H. Zeng S.X. M.S. Lu H. J. 2003; PubMed Scopus Google Scholar). To L5 the L5 was by from cell and The was in and The was by the and in and and were (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, Y. Zeng S.X. M.S. Lu H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The L5 was by and in and of the L5 protein was in and used as to and were (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google Scholar). and were and and have been (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, Y. Zeng S.X. M.S. Lu H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). and or cells were with as in the the were and in of cell were used for as (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, S.X. M.S. Lu H. J. 2002; 21: PubMed Scopus Google Scholar). was as in the and (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, S.X. M.S. Lu H. J. 2002; 21: PubMed Scopus Google Scholar). were with with and and with proteins were by as in the and and were (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, S.X. M.S. Lu H. J. 2002; 21: PubMed Scopus Google Scholar). L5, L11, L23, and MDM2 proteins were in a column, and by interaction were as Y. Zeng S.X. M.S. Lu H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). L5, L11, or L23 proteins were with of or GST, for at The were in in and in proteins were a and by or and or cells were with the and a by two of the from the MDM2 D. Levine A.J. 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The for p53 were and In cells were with ubiquitin p53 and L5 as in after cells were and two one for and the for ubiquitination The in ubiquitination was as (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, Y. H. Zeng S.X. M.S. Lu H. J. 2003; PubMed Scopus Google Scholar). proteins were by with p53 of against L5 by with Act of endogenous L5 was performed as (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, M. J. Gu W. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The with a to L5 or the RNA as a were were U2OS cells the The cells were either with or Act D for were after for To the global protein after L5 U2OS cells were with either L5 or RNA as The cells were and of protein were a by the cells were in a for by with of for The cells were and of proteins were a The was in for and to L5 with MDM2 in and in MDM2 complex that ribosomal proteins L5, L11, and L23 from of a cell by (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar). with (10Marechal V. Elenbaas B. Piette J. Nicolas J.C. Levine A.J. Mol. Cell. Biol. 1994; 14: 7414-7420Crossref PubMed Scopus (294) Google we also that L5 to and were in cells with against or not the it has not been whether endogenous L5 and MDM2 proteins bind to we to this The a at the for L5, in cells as as the also endogenous L5 by not in which a level of endogenous MDM2 L5, like L11 and L23 (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google with MDM2 in vitro as shown in glutathione association To the binding in we and of from cells. was in the and the as shown by and and by (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar). of were with shown in was by in Furthermore, we with MDM2 or its mutant cells. Cell were with shown in and MDM2 were with the It is that the level of this mutant was that of MDM2 because of its degradation in the Y. H. Zeng S.X. M.S. Lu H. J. 2003; PubMed Scopus Google Scholar). the mutant of MDM2 is in the Y. H. Zeng S.X. M.S. Lu H. J. 2003; PubMed Scopus Google and L5 is in the and the not these that L5 can bind to MDM2 in the and the of L5 p53 and G1 Cell (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google and M.A. Ludwig R.L. Kubbutat M.H. Hanlon M. Vousden K.H. Cancer Cells. 2003; 3: 577-587Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google have shown that overexpression of either L11 or L23 induces p53 transcriptional To whether L5 has a we U2OS cells that endogenous p53. overexpression of also induced p53 in a the of the p53 and MDM2 were also Overexpression of a p53 and induction The induction of p53 by L5 at the level as the level of p53 was not induction at the transcriptional level that overexpression of L5 p53 transcriptional To further this p53 transcriptional we a by a ectopic of L5 transcription in a in U2OS not in cells. that the enhanced activity is To whether induction of p53 and by L5 to cell growth we L5 or U2OS and cells. were to cell after treatment with the J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). cells were for cell cycle in that of U2OS cells were in the G1 of U2OS cells were in the G1 phase and The G1 arrest induced by L5 was p53 because was in cells that and p53 and protein as as the level of were induced by not GFP, in U2OS cells. these demonstrate that ectopic of L5 induces p53 transcriptional activity and p53-dependent G1 arrest. Overexpression of L5 MDM2-mediated p53 whether p53 induction by L5 is caused by inhibition of MDM2-mediated p53 ubiquitination and degradation, we MDM2, p53, and L5 cell H1299 cells. cells were after and after treatment with the for ubiquitination and shown in and by Ludwig R.L. Vousden K.H. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. A. M. 1997; PubMed Scopus Google Scholar, H. H. 1997; PubMed Scopus Google MDM2 p53 By of L5 and remarkably inhibited p53 ubiquitination in a inhibition was not by as the of the proteins were of L5 also MDM2-mediated p53 degradation in the of with that L5 can p53 by MDM2-mediated p53 ubiquitination and degradation. Actinomycin D L5 and p53, by L5 recent (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google that L23 be involved in p53 activation induced by a low dose (5 nm) of Act D. of Act D has been shown to inhibit RNA and thus to to of ribosomal biogenesis and p53 activation (6Ashcroft M. Taya Y. Vousden K.H. Mol. Cell. Biol. 2000; 20: 3224-3233Crossref PubMed Scopus (324) Google we to whether L5, like L11 M.A. Ludwig R.L. Kubbutat M.H. Hanlon M. Vousden K.H. Cancer Cells. 2003; 3: 577-587Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google and L23 (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google also a in this ribosomal biogenesis To this against L5 was U2OS cells to treatment with of Act D. shown in to the of L23 (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google against L5 also inhibited Act D-induced p53 to of and activation by the reduced MDM2 and of and that L5 might also be important regulator of the Act However, in the of L23, in which L23 reduction by its induced p53 and MDM2 (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google of L5 by its reduced the p53 level in Act cells to of slight reduction of p53 by L5 does not the that against L5 inhibited Act D-induced p53 because the reduction of p53 by L5 in cells with Act D was that in cells Act D treatment note, the slight decrease of p53 in L5 siRNA-treated cells was specific to p53; it was caused by global translational inhibition after reduction of L5 by its the level of was not by L5 treatment and with cells and as shown in L5 treatment not the protein level to and protein to as by and that reduction of L5 in a of L5 level in in not global is also by a recent that for the ribosomal growth and were H. A. Mol. Cell. Biol. 2004; 24: PubMed Scopus Google Scholar). we the interaction L5 and MDM2 after Act D treatment in U2OS cells. The cells were with or of Act D for and used for immunoprecipitation with either or by with or as shown in the interaction endogenous L5 and MDM2 was in cells with Act D as by with either or by with of the The Act D-induced interaction was not because of the induced level of MDM2 by Act D. we the cells with a to the MDM2 Act and cells the enhanced interaction was still in Act cells with cells Act D treatment not these that there is Act D-induced association of L5 and MDM2 in that like L23 and L11 (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, 8Lohrum M.A. Ludwig R.L. Kubbutat M.H. Hanlon M. Vousden K.H. Cancer Cells. 2003; 3: 577-587Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google not L5 also a in Act D-induced p53 MDM2 with L5, L11, and L23 in in the or of have thus that of the L5, L11, and L23 proteins can activate p53 by MDM2-mediated p53 ubiquitination and degradation (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google Scholar). three ribosomal proteins are in complex (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google it is that MDM2 associates with these ribosomal proteins in the To this a set of reciprocal was H1299 cells were with and p53 as in Cell were with or shown in L5, L11, and L23 were with by the in the of p53. The complex was also by and that MDM2 can form a complex with L5, L11, and L23 of p53 in cells. p53 was the level of this MDM2-L5-L11-L23 complex was p53 also with this quadruple complex as by of the and the MDM2, L5, L11, and L23 The complex as the of the in this complex was from that of the quadruple complex and with and was not because of of these as of these proteins were in also that the ribosomal proteins with p53 for binding to MDM2, bind to of MDM2 J. B. PubMed Scopus Google Scholar, J. Marechal V. Levine A.J. Mol. Cell. Biol. PubMed Scopus Google Scholar). proteins not appear to with one as of was with the against of these proteins in the of MDM2 and In p53 not appear to bind to these proteins directly, as p53 was not by against L11, and L23 and were the proteins by the in the of MDM2 In these that L5, L11, and L23 can with MDM2 To whether endogenous MDM2 and proteins form a complex in response to Act D we performed reciprocal against L23 and U2OS cells were with Act D for Cell were with or by with or shown in MDM2, L5, L11, and L23 were with and and after Act D treatment. demonstrate that MDM2, L5, L11, and L23 form a complex in cells in response to Act D consequently leading to inhibition of MDM2-mediated p53 ubiquitination and degradation. The feedback is critical for low of p53; this is for p53 induction and activation in response to M. A. T. D. J. M. Taya Y. A. Y. 2002; PubMed Scopus Google Scholar). biogenesis such as of ribosomal RNA by Act and assembly, also activate p53 (3Ashcroft M. Kubbutat M.H. Vousden K.H. Mol. Cell. Biol. 1999; 19: 1751-1758Crossref PubMed Scopus (379) Google Scholar, 4Pestov D.G. Strezoska Z. Lau L.F. Mol. Cell. Biol. 2001; 21: 4246-4255Crossref PubMed Scopus (293) Google Scholar, 5Strezoska Z. Pestov D.G. Lau L.F. J. Biol. Chem. 2002; 277: 29617-29625Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, M. Taya Y. Vousden K.H. Mol. Cell. Biol. 2000; 20: 3224-3233Crossref PubMed Scopus (324) Google Scholar). two ribosomal L11 and L23, have been shown to p53 activation by the MDM2-p53 (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, 8Lohrum M.A. Ludwig R.L. Kubbutat M.H. Hanlon M. Vousden K.H. Cancer Cells. 2003; 3: 577-587Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google Scholar). Our reveals ribosomal protein, L5, that also a crucial in p53 activation after the stress induced by of Act D. lines of this we the interaction L5 and MDM2 in vitro and in cells (10Marechal V. Elenbaas B. Piette J. Nicolas J.C. Levine A.J. Mol. Cell. Biol. 1994; 14: 7414-7420Crossref PubMed Scopus (294) Google we were to we also the interaction endogenous MDM2 and L5 in we that overexpression of L5 induced endogenous p53 and stabilized p53 and Consequently, p53 transcriptional activity was to induce and G1 arrest and L11 and L23, L5 also inhibited MDM2-mediated p53 ubiquitination ribosomal stress caused by to a low dose of Act D enhanced the interaction and p53 activation, which was by of L5 a recent by Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google not this L5 be because L5 was not in experiments there was not a L5 Our demonstrate that L5 is also important in the ribosomal biogenesis the three ribosomal L5, L11, and L23, have been to activate p53 by the MDM2-mediated feedback inhibition of p53 in response to the of caused by Act D (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, 8Lohrum M.A. Ludwig R.L. Kubbutat M.H. Hanlon M. Vousden K.H. Cancer Cells. 2003; 3: 577-587Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google Scholar). studies suggest a pathway to activate p53 in response to ribosomal stress. such as inhibition of rRNA or ribosomal assembly, ribosomal L5, L11, and L23 which in turn with MDM2 and thus inhibit its ubiquitin ligase activity toward p53, leading to p53 induction and activation as a of these three proteins can inhibit MDM2 and activate p53 M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, 8Lohrum M.A. Ludwig R.L. Kubbutat M.H. Hanlon M. Vousden K.H. Cancer Cells. 2003; 3: 577-587Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google and this these ribosomal proteins can also form a quadruple complex with MDM2 in response to Act D treatment in to the MDM2 feedback regulation of p53. this is the that the level of of these proteins by Act D-induced p53 also that of these ribosomal proteins is for p53 as the of one of Act D-induced p53 activation (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google not The that the quadruple complex is reduced in the of of p53 that these ribosomal proteins with p53 for binding to a low level of the complex was also this complex might be or the ribosomal proteins can inhibit MDM2-mediated p53 ubiquitination M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google and 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google and this it is that such by with MDM2 a that the of the ubiquitin from to p53 note, of these ribosomal proteins to bind to the MDM2 the (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google Scholar, 8Lohrum M.A. Ludwig R.L. Kubbutat M.H. Hanlon M. Vousden K.H. Cancer Cells. 2003; 3: 577-587Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 9Zhang Y. Wolf G.W. Bhat K. Jin A. Allio T. Burkhart W.A. Xiong Y. Mol. Cell. Biol. 2003; 23: 8902-8912Crossref PubMed Scopus (460) Google Scholar, 11Elenbaas B. Dobbelstein M. Roth J. Shenk T. Levine A.J. Mol. Med. 1996; 2: 439-451Crossref PubMed Google and this has been shown to be critical for MDM2-mediated p53 degradation H. D. Mol. Cell. Biol. 2003; 23: PubMed Scopus Google Scholar, J.C. Vousden K.H. Mol. Cell. Biol. 2003; 23: PubMed Scopus Google Scholar). It is also that p53 by L5, L11, and L23 in response to ribosomal stress the of MDM2 by these the of MDM2 to the regulation of p53 is unclear H. D. Mol. Cell. Biol. 2003; 23: PubMed Scopus Google Scholar, J.C. Vousden K.H. Mol. Cell. Biol. 2003; 23: PubMed Scopus Google Scholar). The that L5 induces p53 by the MDM2-p53 feedback important whether L5 the MDM2 and p53 because L5 has been to be rRNA (5 M. T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In addition to binding to MDM2, L5 also to the M. M. H. M. D. J. A. PubMed Scopus Google which is a critical of the of Both MDM2 and are proteins J. Cell. Full Text PDF PubMed Scopus Google Scholar, Y. Xiong Y. Cell 2001; Google and the pathways for and rRNA J. Cell. Full Text PDF PubMed Scopus Google Scholar). Furthermore, L5 a and a B. D. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). it is that L5 MDM2 We have shown that the and (7Dai M.S. Zeng S.X. Jin Y. Sun X.X. David L. Lu H. Mol. Cell. Biol.,. 2004; 24: 7654-7668Crossref PubMed Scopus (413) Google interaction can in the and the because mutant of MDM2 that is in the was with L5 and L23. Another be that L5, L11, or L23 as proteins for We Zeng for and for critically the and of the for We for L11