Mdm2 links genotoxic stress and metabolism to p53

Zhongfeng Wang, Baojie Li()

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Protein Cell ›› 2010, Vol. 1 ›› Issue (12) : 1063-1072. DOI: 10.1007/s13238-010-0140-9
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REVIEW

Mdm2 links genotoxic stress and metabolism to p53

  • Zhongfeng Wang, Baojie Li()
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Abstract

Mouse double minute 2 (Mdm2) gene was isolated from a cDNA library derived from transformed mouse 3T3 cells, and was classified as an oncogene as it confers 3T3 and Rat2 cells tumorigenicity when overexpressed. It encodes a nucleocytoplasmic shuttling ubiquitin E3 ligase, with its main target being tumor suppressor p53, which is mutated in more than 50% of human primary tumors. Mdm2’s oncogenic activity is mainly mediated by p53, which is activated by various stresses, especially genotoxic stress, via Atm (ataxia telangiectasia mutated) and Atr (Atm and Rad3-related). Activated p53 inhibits cell proliferation, induces apoptosis or senescence, and maintains genome integrity. Mdm2 is also a target gene of p53 transcription factor. Thus, Mdm2 and p53 form a feedback regulatory loop. External and internal cues, through multiple signaling pathways, can act on Mdm2 to regulate p53 levels and cell proliferation, death, and senescence. This review will focus on how Mdm2 is regulated under genotoxic stress, and by the Akt1-mTOR-S6K1 pathway that is activated by insulin, growth factors, amino acids, or energy status.

Keywords

mouse double minute 2 (Mdm2) / p53 / signal transduction / tumorigenesis

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Zhongfeng Wang, Baojie Li. Mdm2 links genotoxic stress and metabolism to p53. Prot Cell, 2010, 1(12): 1063‒1072 https://doi.org/10.1007/s13238-010-0140-9

References

[1] Allred, D.C., Clark, G.M., Elledge, R., Fuqua, S.A., Brown, R.W., Chamness, G.C., Osborne, C.K., and McGuire, W.L. (1993). Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst 85, 200-206 .8423624
[2] Araki, S., Eitel, J.A., Batuello, C.N., Bijangi-Vishehsaraei, K., Xie, X.J., Danielpour, D., Pollok, K.E., Boothman, D.A., and Mayo, L.D. (2010). TGF-beta1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer. J Clin Invest 120, 290-302 .19955655
[3] Ard, P.G., Chatterjee, C., Kunjibettu, S., Adside, L.R., Gralinski, L.E., and McMahon, S.B. (2002). Transcriptional regulation of the mdm2 oncogene by p53 requires TRRAP acetyltransferase complexes. Mol Cell Biol 22, 5650-5661 .12138177
[4] Argentini, M., Barboule, N., and Wasylyk, B. (2000). The contribution of the RING finger domain of MDM2 to cell cycle progression. Oncogene 19, 3849-3857 .10951578
[5] Barak, Y., Gottlieb, E., Juven-Gershon, T., and Oren, M. (1994). Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. Genes Dev 8, 1739-1749 .7958853
[6] Blattner, C., Hay, T., Meek, D.W., and Lane, D.P. (2002). Hypophosphorylation of Mdm2 augments p53 stability. Mol Cell Biol 22, 6170-6182 .12167711
[7] Blaydes, J.P., and Wynford-Thomas, D. (1998). The proliferation of normal human fibroblasts is dependent upon negative regulation of p53 function by mdm2. Oncogene 16, 3317-3322 .9681831
[8] Bond, G.L., Hu, W., Bond, E.E., Robins, H., Lutzker, S.G., Arva, N.C., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., (2004). A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591-602 .15550242
[9] Brady, M., Vlatkovic, N., and Boyd, M.T. (2005). Regulation of p53 and MDM2 activity by MTBP. Mol Cell Biol 25, 545-553 .15632057
[10] Buschmann, T., Fuchs, S.Y., Lee, C.G., Pan, Z.Q., and Ronai, Z. (2000). SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53. Cell 101, 753-762 .10892746
[11] Buschmann, T., Lerner, D., Lee, C.G., and Ronai, Z. (2001). The Mdm-2 amino terminus is required for Mdm2 binding and SUMO-1 conjugation by the E2 SUMO-1 conjugating enzyme Ubc9. J Biol Chem 276, 40389-40395 .11384992
[12] Busuttil, V., Droin, N., McCormick, L., Bernassola, F., Candi, E., Melino, G., and Green, D.R. (2010). NF-{kappa}B inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2. Proc Natl Acad Sci USA 107(42):18061-6.20921405
[13] Candeias, M.M., Malbert-Colas, L., Powell, D.J., Daskalogianni, C., Maslon, M.M., Naski, N., Bourougaa, K., Calvo, F., and F?hraeus, R. (2008). P53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol 10, 1098-1105 .19160491
[14] Canner, J.A., Sobo, M., Ball, S., Hutzen, B., DeAngelis, S., Willis, W., Studebaker, A.W., Ding, K., Wang, S., Yang, D., (2009). MI-63: a novel small-molecule inhibitor targets MDM2 and induces apoptosis in embryonal and alveolar rhabdomyosarcoma cells with wild-type p53. Br J Cancer 101, 774-781 .19707204
[15] Chang, Y.C., Lee, Y.S., Tejima, T., Tanaka, K., Omura, S., Heintz, N.H., Mitsui, Y., and Magae, J. (1998). mdm2 and bax, downstream mediators of the p53 response, are degraded by the ubiquitin-proteasome pathway. Cell Growth Differ 9, 79-84 .9438391
[16] Chen, J., Marechal, V., and Levine, A.J. (1993). Mapping of the p53 and mdm-2 interaction domains. Mol Cell Biol 13, 4107-4114 .7686617
[17] Chen, L., Marechal, V., Moreau, J., Levine, A.J., and Chen, J. (1997). Proteolytic cleavage of the mdm2 oncoprotein during apoptosis. J Biol Chem 272, 22966-22973 .9278461
[18] Cheng, Q., and Chen, J. (2010). Mechanism of p53 stabilization by ATM after DNA damage. Cell Cycle 9, 472-478 .20081365
[19] Cheng, Q., Chen, L., Li, Z., Lane, W.S., and Chen, J. (2009). ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO J 28, 3857-3867 .19816404
[20] Chi, X.Z., Kim, J., Lee, Y.H., Lee, J.W., Lee, K.S., Wee, H., Kim, W.J., Park, W.Y., Oh, B.C., Stein, G.S., (2009). Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination. Cancer Res 69, 8111-8119 .19808967
[21] de Oca Luna M., R., Wagner, D.S., and Lozano, G. (1995). Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203-206 .7477326
[22] Di Stefano, V., Blandino, G., Sacchi, A., Soddu, S., and D’Orazi, G. (2004). HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function. Oncogene 23, 5185-5192 .15122315
[23] Dias, S.S., Milne, D.M., and Meek, D.W. (2006). c-Abl phosphorylates Hdm2 at tyrosine 276 in response to DNA damage and regulates interaction with ARF. Oncogene 25, 6666-6671 .16702947
[24] Ding, K., Lu, Y., Nikolovska-Coleska, Z., Wang, G., Qiu, S., Shangary, S., Gao, W., Qin, D., Stuckey, J., Krajewski, K., (2006). Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 49, 3432-3435 .16759082
[25] Dubs-Poterszman, M.C., Tocque, B., and Wasylyk, B. (1995). MDM2 transformation in the absence of p53 and abrogation of the p107 G1 cell-cycle arrest. Oncogene 11, 2445-2449 .8570197
[26] Efeyan, A., Ortega-Molina, A., Velasco-Miguel, S., Herranz, D., Vassilev, L.T., and Serrano, M. (2007). Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin. Cancer Res 67, 7350-7357 .17671205
[27] Fang, S., Jensen, J.P., Ludwig, R.L., Vousden, K.H., and Weissman, A.M. (2000). Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 275, 8945-8951 .10722742
[28] Feng, J., Tamaskovic, R., Yang, Z., Brazil, D.P., Merlo, A., Hess, D., and Hemmings, B.A. (2004). Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. J Biol Chem 279, 35510-35517 .15169778
[29] Fu, W., Ma, Q., Chen, L., Li, P., Zhang, M., Ramamoorthy, S., Nawaz, Z., Shimojima, T., Wang, H., Yang, Y., (2009). MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. J Biol Chem 284, 13987-14000 .19321440
[30] Fu, X., Yucer, N., Liu, S., Li, M., Yi, P., Mu, J.J., Yang, T., Chu, J., Jung, S.Y., O’Malley, B.W., (2010). RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc Natl Acad Sci U S A 107, 4579-4584 .20173098
[31] Fuchs, S.Y., Adler, V., Buschmann, T., Wu, X., and Ronai, Z. (1998). Mdm2 association with p53 targets its ubiquitination. Oncogene 17, 2543-2547 .9824166
[32] Goldberg, Z., Vogt Sionov, R., Berger, M., Zwang, Y., Perets, R., Van Etten, R.A., Oren, M., Taya, Y., and Haupt, Y. (2002). Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. EMBO J 21, 3715-3727 .12110584
[33] Grünbaum, U., Meye, A., Bache, M., Bartel, F., Würl, P., Schmidt, H., Dunst, J., and Taubert, H. (2001). Transfection with mdm2-antisense or wtp53 results in radiosensitization and an increased apoptosis of a soft tissue sarcoma cell line. Anticancer Res 21, 2065-2071 .11497299
[34] Gu, H., Wang, X., Rao, S., Wang, J., Zhao, J., Ren, F.L., Mu, R., Yang, Y., Qi, Q., Liu, W., (2008a). Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells. Mol Cancer Ther 7, 3298-3305 .18852133
[35] Gu, L., Zhu, N., Findley, H.W., and Zhou, M. (2008b). MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2. Leukemia 22, 730-739 .18273046
[36] Halaschek-Wiener, J., Wacheck, V., Kloog, Y., and Jansen, B. (2004). Ras inhibition leads to transcriptional activation of p53 and down-regulation of Mdm2: two mechanisms that cooperatively increase p53 function in colon cancer cells. Cell Signal 16, 1319-1327 .15337531
[37] Hjerpe, R., Aillet, F., Lopitz-Otsoa, F., Lang, V., Torres-Ramos, M., Farrás, R., Hay, R.T., and Rodríguez, M.S. (2010). Oligomerization conditions Mdm2-mediated efficient p53 polyubiquitylation but not its proteasomal degradation. Int J Biochem Cell Biol 42, 725-735 .20080206
[38] Hogan, C., Hutchison, C., Marcar, L., Milne, D., Saville, M., Goodlad, J., Kernohan, N., and Meek, D. (2008). Elevated levels of oncogenic protein kinase Pim-1 induce the p53 pathway in cultured cells and correlate with increased Mdm2 in mantle cell lymphoma. J Biol Chem 283, 18012-18023 .18467333
[39] Hollenhorst, P.C., Shah, A.A., Hopkins, C., and Graves, B.J. (2007). Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes Dev 21, 1882-1894 .17652178
[40] Honda, R., and Yasuda, H. (2000). Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase. Oncogene 19, 1473-1476 .10723139
[41] Inoue, T., Geyer, R.K., Howard, D., Yu, Z.K., and Maki, C.G. (2001). MDM2 can promote the ubiquitination, nuclear export, and degradation of p53 in the absence of direct binding. J Biol Chem 276, 45255-45260 .11572869
[42] Iwakuma, T., and Lozano, G. (2003). MDM2, an introduction. Mol Cancer Res 1, 993-1000 .14707282
[43] Izumi, T., Takaori-Kondo, A., Shirakawa, K., Higashitsuji, H., Itoh, K., Io, K., Matsui, M., Iwai, K., Kondoh, H., Sato, T., (2009). MDM2 is a novel E3 ligase for HIV-1 Vif. Retrovirology 6, 1.19128510
[44] Jones, S., Roe, A., Donehower, L., and Bradley, A. (1995). Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378 , 206-208 .7477327
[45] Juven, T., Barak, Y., Zauberman, A., George, D.L., and Oren, M. (1993). Wild type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene. Oncogene 8, 3411-3416 .8247544
[46] Kastan, M.B., and Bartek, J. (2004). Cell-cycle checkpoints and cancer. Nature 432, 316-323 .15549093
[47] Khosravi, R., Maya, R., Gottlieb, T., Oren, M., Shiloh, Y., and Shkedy, D. (1999). Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci U S A 96, 14973-14977 .10611322
[48] Kim, D., Song, J., and Jin, E.J. (2010). MicroRNA-221 regulates chondrogenic differentiation through promoting proteosomal degradation of slug by targeting Mdm2. J Biol Chem 285, 26900-26907 .20576614
[49] Kojima, K., Konopleva, M., Samudio, I.J., Shikami, M., Cabreira-Hansen, M., McQueen, T., Ruvolo, V., Tsao, T., Zeng, Z., Vassilev, L.T., (2005). MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood 106, 3150-3159 .16014563
[50] Kondo, S., Barnett, G.H., Hara, H., Morimura, T., and Takeuchi, J. (1995). MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis. Oncogene 10, 2001-2006 .7761100
[51] Kussie, P.H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A.J., and Pavletich, N.P. (1996). Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274, 948-953 .8875929
[52] Lai, K.P., Leong, W.F., Chau, J.F., Jia, D., Zeng, L., Liu, H., He, L., Hao, A., Zhang, H., Meek, D., (2010). S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response. EMBO J 29, 2994-3006 .20657550
[53] Lee, M.H., Lee, S.W., Lee, E.J., Choi, S.J., Chung, S.S., Lee, J.I., Cho, J.M., Seol, J.H., Baek, S.H., Kim, K.I., (2006). SUMO-specific protease SUSP4 positively regulates p53 by promoting Mdm2 self-ubiquitination. Nat Cell Biol 8, 1424-1431 .17086174
[54] Li, B. (2005). c-Abl in oxidative stress, aging and cancer. Cell Cycle 4, 246-248 .15655364
[55] Li, M., Brooks, C.L., Kon, N., and Gu, W. (2004). A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell 13, 879-886 .15053880
[56] Li, M., Brooks, C.L., Wu-Baer, F., Chen, D., Baer, R., and Gu, W. (2003). Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302, 1972-1975 .14671306
[57] Lu, X., Ma, O., Nguyen, T.A., Jones, S.N., Oren, M., and Donehower, L.A. (2007). The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell 12, 342-354 .17936559
[58] Lu, X., Nguyen, T.A., Zhang, X., and Donehower, L.A. (2008). The Wip1 phosphatase and Mdm2: cracking the “Wip” on p53 stability. Cell Cycle 7, 164-168 .18333294
[59] Maguire, M., Nield, P.C., Devling, T., Jenkins, R.E., Park, B.K., Polański, R., Vlatkovi?, N., and Boyd, M.T. (2008). MDM2 regulates dihydrofolate reductase activity through monoubiquitination. Cancer Res 68, 3232-3242 .18451149
[60] Maki, C.G. (1999). Oligomerization is required for p53 to be efficiently ubiquitinated by MDM2. J Biol Chem 274, 16531-16535 .10347217
[61] Manfredi, J.J. (2010). The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev 24, 1580-1589 .20679392
[62] Maya, R., Balass, M., Kim, S.T., Shkedy, D., Leal, J.F., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., (2001). ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15, 1067-1077 .11331603
[63] Mayo, L.D., and Donner, D.B. (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A 98, 11598-11603 .11504915
[64] Meek, D.W., and Hupp, T.R. (2010). The regulation of MDM2 by multisite phosphorylation—opportunities for molecular-based intervention to target tumours? Semin Cancer Biol 20, 19-28 .19897041
[65] Meng, L.H., Kohlhagen, G., Liao, Z.Y., Antony, S., Sausville, E., and Pommier, Y. (2005). DNA-protein cross-links and replication-dependent histone H2AX phosphorylation induced by aminoflavone (NSC 686288), a novel anticancer agent active against human breast cancer cells. Cancer Res 65, 5337-5343 .15958581
[66] Meulmeester, E., Pereg, Y., Shiloh, Y., and Jochemsen, A.G. (2005). ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 4, 1166-1170 .16082221
[67] Milne, D., Kampanis, P., Nicol, S., Dias, S., Campbell, D.G., Fuller-Pace, F., and Meek, D. (2004). A novel site of AKT-mediated phosphorylation in the human MDM2 onco-protein. FEBS Lett 577, 270-276 .15527798
[68] Mo, P., Wang, H., Lu, H., Boyd, D.D., and Yan, C. (2010). MDM2 mediates ubiquitination and degradation of activating transcription factor 3. J Biol Chem 285, 26908-26915 .20592017
[69] Moll, U.M., and Petrenko, O. (2003). The MDM2-p53 interaction. Mol Cancer Res 1, 1001-1008 .14707283
[70] Momand, J., Zambetti, G.P., Olson, D.C., George, D., and Levine, A.J. (1992). The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69, 1237-1245 .1535557
[71] Naski, N., Gajjar, M., Bourougaa, K., Malbert-Colas, L., F?hraeus, R., and Candeias, M.M. (2009). The p53 mRNA-Mdm2 interaction. Cell Cycle 8, 31-34 .19106616
[72] Ofir-Rosenfeld, Y., Boggs, K., Michael, D., Kastan, M.B., and Oren, M. (2008). Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26. Mol Cell 32, 180-189 .18951086
[73] Pettersson, S., Kelleher, M., Pion, E., Wallace, M., and Ball, K.L. (2009). Role of Mdm2 acid domain interactions in recognition and ubiquitination of the transcription factor IRF-2. Biochem J 418, 575-585 .19032150
[74] Phelps, M., Darley, M., Primrose, J.N., and Blaydes, J.P. (2003). p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. Cancer Res 63, 2616-2623 .12750288
[75] Pikkarainen, S., Kennedy, R.A., Marshall, A.K., Tham, L., Lay, K., Kriz, T.A., Handa, B.S., Clerk, A., and Sugden, P.H. (2009). Regulation of expression of the rat orthologue of mouse double minute 2 (MDM2) by H(2)O(2)-induced oxidative stress in neonatal rat cardiac myocytes. J Biol Chem 284, 27195-27210 .19638633
[76] Pochampally, R., Fodera, B., Chen, L., Lu, W., and Chen, J. (1999). Activation of an MDM2-specific caspase by p53 in the absence of apoptosis. J Biol Chem 274, 15271-15277 .10329737
[77] Poyurovsky, M.V., Katz, C., Laptenko, O., Beckerman, R., Lokshin, M., Ahn, J., Byeon, I.J., Gabizon, R., Mattia, M., Zupnick, A., (2010). The C terminus of p53 binds the N-terminal domain of MDM2. Nat Struct Mol Biol 17, 982-989 .20639885
[78] Poyurovsky, M.V., Priest, C., Kentsis, A., Borden, K.L., Pan, Z.Q., Pavletich, N., and Prives, C. (2007). The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity. EMBO J 26, 90-101 .17170710
[79] Qi, J.S., Yuan, Y., Desai-Yajnik, V., and Samuels, H.H. (1999). Regulation of the mdm2 oncogene by thyroid hormone receptor. Mol Cell Biol 19, 864-872 .9858609
[80] Ray, R.M., Bhattacharya, S., and Johnson, L.R. (2010). Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of PUMA and Siva-1. Apoptosis 2010 Sep 2 . [Epub ahead of print] PMID: 2081203010.1007/s10495-010-0538-0
[81] Ries, S., Biederer, C., Woods, D., Shifman, O., Shirasawa, S., Sasazuki, T., McMahon, M., Oren, M., and McCormick, F. (2000). Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 103, 321-330 .11057904
[82] Rong, J.J., Hu, R., Qi, Q., Gu, H.Y., Zhao, Q., Wang, J., Mu, R., You, Q.D., and Guo, Q.L. (2009). Gambogic acid down-regulates MDM2 oncogene and induces p21(Waf1/CIP1) expression independent of p53. Cancer Lett 284, 102-112 .19428175
[83] Samudio, I.J., Duvvuri, S., Clise-Dwyer, K., Watt, J.C., Mak, D., Kantarjian, H., Yang, D., Ruvolo, V., and Borthakur, G. (2010). Activation of p53 signaling by MI-63 induces apoptosis in acute myeloid leukemia cells. Leuk Lymphoma 51, 911-919 .20423286
[84] Sashida, G., Liu, Y., Elf, S., Miyata, Y., Ohyashiki, K., Izumi, M., Menendez, S., and Nimer, S.D. (2009). ELF4/MEF activates MDM2 expression and blocks oncogene-induced p16 activation to promote transformation. Mol Cell Biol 29, 3687-3699 .19380490
[85] Sato, N., Mizumoto, K., Maehara, N., Kusumoto, M., Nishio, S., Urashima, T., Ogawa, T., and Tanaka, M. (2000). Enhancement of drug-induced apoptosis by antisense oligodeoxynucleotides targeted against Mdm2 and p21WAF1/CIP1. Anticancer Res 20, 837-842 .10810363
[86] Shangary, S., Qin, D., McEachern, D., Liu, M., Miller, R.S., Qiu, S., Nikolovska-Coleska, Z., Ding, K., Wang, G., Chen, J., (2008). Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci U S A 105, 3933-3938 .18316739
[87] Sheikh, M.S., Shao, Z.M., Hussain, A., and Fontana, J.A. (1993). The p53-binding protein MDM2 gene is differentially expressed in human breast carcinoma. Cancer Res 53, 3226-3228 .8324731
[88] Shinozaki, T., Nota, A., Taya, Y., and Okamoto, K. (2003). Functional role of Mdm2 phosphorylation by ATR in attenuation of p53 nuclear export. Oncogene 22, 8870-8880 .14654783
[89] Slack, A., Chen, Z., Tonelli, R., Pule, M., Hunt, L., Pession, A., and Shohet, J.M. (2005). The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proc Natl Acad Sci U S A 102, 731-736 .15644444
[90] Song, M.S., Song, S.J., Kim, S.Y., Oh, H.J., and Lim, D.S. (2008). The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex. EMBO J 27, 1863-1874 .18566590
[91] Stad, R., Little, N.A., Xirodimas, D.P., Frenk, R., van der Eb, A.J., Lane, D.P., Saville, M.K., and Jochemsen, A.G. (2001). Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2, 1029-1034 .11606419
[92] Stevenson, L.F., Sparks, A., Allende-Vega, N., Xirodimas, D.P., Lane, D.P., and Saville, M.K. (2007). The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J 26, 976-986 .17290220
[93] Sun, P., Dong, P., Dai, K., Hannon, G.J., and Beach, D. (1998). p53-independent role of MDM2 in TGF-beta1 resistance. Science 282, 2270-2272 .9856953
[94] Tang, J., Qu, L.K., Zhang, J., Wang, W., Michaelson, J.S., Degenhardt, Y.Y., El-Deiry, W.S., and Yang, X. (2006). Critical role for Daxx in regulating Mdm2. Nat Cell Biol 8, 855-862 .16845383
[95] Tortora, G., Caputo, R., Damiano, V., Bianco, R., Chen, J., Agrawal, S., Bianco, A.R., and Ciardiello, F. (2000). A novel MDM2 anti-sense oligonucleotide has anti-tumor activity and potentiates cytotoxic drugs acting by different mechanisms in human colon cancer. Int J Cancer 88, 804-809 .11072252
[96] Truong, A.H., Cervi, D., Lee, J., and Ben-David, Y. (2005). Direct transcriptional regulation of MDM2 by Fli-1. Oncogene 24, 962-969 .15592502
[97] Tyner, S.D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., (2002). p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45-53 .11780111
[98] Vassilev, L.T., Vu, B.T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., (2004). In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848 .14704432
[99] Wang, P., Gao, H., Ni, Y., Wang, B., Wu, Y., Ji, L., Qin, L., Ma, L., and Pei, G. (2003). Beta-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of oncoprotein Mdm2. J Biol Chem 278, 6363-6370 .12488444
[100] Waning, D.L., Lehman, J.A., Batuello, C.N., and Mayo, L.D. (2010). Controlling the Mdm2-Mdmx-p53 Circuit. Pharmaceuticals (Basel) 3, 1576-1593 .20651945
[101] Wood, N.T., Meek, D.W., and Mackintosh, C. (2009). 14-3-3 Binding to Pim-phosphorylated Ser166 and Ser186 of human Mdm2—Potential interplay with the PKB/Akt pathway and p14(ARF). FEBS Lett 583, 615-620 .19166854
[102] Wu, X., Bayle, J.H., Olson, D., and Levine, A.J. (1993). The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7, 1126-1132 .8319905
[103] Yan, J., Zhang, D., Di, Y., Shi, H., Rao, H., and Huo, K. (2010). A newly identified Pirh2 substrate SCYL1-BP1 can bind to MDM2 and accelerate MDM2 self-ubiquitination. FEBS Lett 584, 3275-3278 .20598683
[104] Yang, H.Y., Wen, Y.Y., Lin, Y.I., Pham, L., Su, C.H., Yang, H., Chen, J., and Lee, M.H. (2007). Roles for negative cell regulator 14-3-3sigma in control of MDM2 activities. Oncogene 26, 7355-7362 .17546054
[105] Zhang, X., Gu, L., Li, J., Shah, N., He, J., Yang, L., Hu, Q., and Zhou, M. (2010). Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells.[Epub ahead of print] [PMID: 20935220] Cancer Res 2010, 23.20935220
[106] Zhang, X.C., Chen, J., Su, C.H., Yang, H.Y., and Lee, M.H. (2008). Roles for CSN5 in control of p53/MDM2 activities. J Cell Biochem 103, 1219-1230 .17879958
[107] Zheng, T., Wang, J., Chen, X., Meng, X., Song, X., Lu, Z., Jiang, H., and Liu, L. (2010). Disruption of p73-MDM2 binding synergizes with gemcitabine to induce apoptosis in HuCCT1 cholangiocarcinoma cell line with p53 mutation. Tumour Biol 31, 287-295 .20422343
[108] Zhou, B.B., and Elledge, S.J. (2000). The DNA damage response: putting checkpoints in perspective. Nature 408, 433-439 .11100718
[109] Zhou, B.P., and Hung, M.C. (2002). Novel targets of Akt, p21(Cipl/WAF1), and MDM2. Semin Oncol 29, 62-70 .12138399
[110] Zhou, B.P., Liao, Y., Xia, W., Zou, Y., Spohn, B., and Hung, M.C. (2001). HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 3, 973-982 .11715018
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