Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

MDM2 oligomers: antagonizers of the guardian of the genome

Oncogene volume 35, pages 6157–6165 (2016)Cite this article

Subjects

Abstract

Over two decades of MDM2 research has resulted in the accumulation of a wealth of knowledge of many aspects of MDM2 regulation and function, particularly with respect to its most prominent target, p53. For example, recent knock-in mouse studies have shown that MDM2 heterooligomer formation with its homolog, MDMX, is necessary and sufficient in utero to suppress p53 but is dispensable during adulthood. However, despite crucial advances such as these, several aspects regarding basic in vivo functions of MDM2 remain unknown. In one such example, although abundant evidence suggests that MDM2 forms homooligomers and heterooligomers with MDMX, the function and regulation of these homo- and heterooligomers in vivo remain incompletely understood. In this review, we discuss the current state of our knowledge of MDM2 oligomerization as well as current efforts to target the MDM2 oligomer as a broad therapeutic option for cancer treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Vogelstein B, Lane D, Levine AJ . Surfing the p53 network. Nature 2000; 408: 307–310.

    Article  CAS  PubMed  Google Scholar 

  2. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C . Emerging landscape of oncogenic signatures across human cancers. Nat Genet 2013; 45: 1127–1133.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kastan M, Onyekwere O, Sidransky D, Vogelstein B, Craig RW . Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991; 51: 6304–6311.

    CAS  PubMed  Google Scholar 

  4. Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M . Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 1991; 352: 345–347.

    CAS  PubMed  Google Scholar 

  5. Nakano K, Vousden KH . PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001; 7: 683–694.

    CAS  PubMed  Google Scholar 

  6. Vousden KH, Ryan KM . p53 and metabolism. Nat Rev Cancer 2009; 9: 691–700.

    CAS  PubMed  Google Scholar 

  7. Kruiswijk F, Labuschagne CF, Vousden KH . p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol 2015; 16: 393–405.

    CAS  PubMed  Google Scholar 

  8. Dittmer D, Pati S, Zambetti G, Chu S, Teresky AK, Moore M et al. Gain of function mutations in p53. Nat Genet 1993; 4: 42–46.

    CAS  PubMed  Google Scholar 

  9. Muller PA, Vousden KH . p53 mutations in cancer. Nat Cell Biol 2013; 15: 2–8.

    CAS  PubMed  Google Scholar 

  10. Lane DP . p53, guardian of the genome. Nature 1992; 358: 15–16.

    CAS  PubMed  Google Scholar 

  11. Haupt Y, Maya R, Kazaz A, Oren M . Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296–299.

    Article  CAS  PubMed  Google Scholar 

  12. Honda R, Tanaka H, Yasuda H . Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 1997; 420: 25–27.

    Article  CAS  PubMed  Google Scholar 

  13. Kubbutat MHG, Jones SN, Vousden KH . Regulation of p53 stability by Mdm2. Nature 1997; 387: 299–303.

    Article  CAS  PubMed  Google Scholar 

  14. Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B . Oncoprotein MDM2 conceals the activation domain of tumor suppressor p53. Nature 1993; 362: 857–860.

    CAS  PubMed  Google Scholar 

  15. Momand J, Zambetti GP, Olson DC, George D, Levine AJ . The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992; 69: 1237–1245.

    CAS  PubMed  Google Scholar 

  16. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B . Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 1992; 358: 80–83.

    CAS  PubMed  Google Scholar 

  17. Bueso-Ramos CE, Yang Y, deLeon E, McCown P, Stass SA, Albitar M . The human MDM-2 oncogene is overexpressed in leukemias. Blood 1993; 82: 2617–2623.

    CAS  PubMed  Google Scholar 

  18. Reifenberger G, Liu L, Ichimura K, Schmidt EE, Collins VP . Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res 1993; 53: 2736–2739.

    CAS  PubMed  Google Scholar 

  19. Simon R, Struckmann K, Schraml P, Wagner U, Forster T, Moch H et al. Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer. Oncogene 2002; 21: 2476–2483.

    CAS  PubMed  Google Scholar 

  20. Marchetti A, Buttitta F, Girlando S, Dalla Palma P, Pellegrini S, Fina P et al. mdm2 gene alterations and mdm2 protein expression in breast carcinomas. J Pathol 1995; 175: 31–38.

    Article  CAS  PubMed  Google Scholar 

  21. Wade M, Li YC, Wahl GM . MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013; 13: 83–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tanimura S, Ohtsuka S, Mitsui K, Shirouzu K, Yoshimura A, Ohtsubo M . MDM2 interacts with MDMX through their RING finger domains. FEBS Lett 1999; 447: 5–9.

    Article  CAS  PubMed  Google Scholar 

  23. Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J . Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage. Mol Cell Biol 2011; 31: 4951–4963.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Itahana K, Mao H, Jin A, Itahana Y, Clegg HV, Lindstrom MS et al. Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 2007; 12: 355–366.

    CAS  PubMed  Google Scholar 

  25. Leng P, Brown DR, Shivakumar CV, Deb S, Deb SP . N-terminal 130 amino acids of MDM2 are sufficient to inhibit p53-mediated transcriptional activation. Oncogene 1995; 10: 1275–1282.

    CAS  PubMed  Google Scholar 

  26. Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 1996; 274: 948–953.

    CAS  PubMed  Google Scholar 

  27. Moll UM, Petrenko O . The MDM2-p53 interaction. Mol Cancer Res 2003; 1: 1001–1008.

    CAS  PubMed  Google Scholar 

  28. Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O et al. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 2001; 15: 1067–1077.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Shinozaki T, Nota A, Taya Y, Okamoto K . Functional role of Mdm2 phosphorylation by ATR in attenuation of p53 nuclear export. Oncogene 2003; 22: 8870–8880.

    CAS  PubMed  Google Scholar 

  30. Goldberg Z, Vogt Sionov R, Berger M, Zwang Y, Perets R, Van Etten RA et al. Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. EMBO J 2002; 21: 3715–3727.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Mayo LD, Donner DB . A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001; 98: 11598–11603.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Winter M, Milne D, Dias S, Kulikov R, Knippschild U, Blattner C et al. Protein kinase CK1delta phosphorylates key sites in the acidic domain of murine double-minute clone 2 protein (MDM2) that regulate p53 turnover. Biochemistry 2004; 43: 16356–16364.

    CAS  PubMed  Google Scholar 

  33. Hjerrild M, Milne D, Dumaz N, Hay T, Issinger OG, Meek D . Phosphorylation of murine double minute clone 2 (MDM2) protein at serine-267 by protein kinase CK2 in vitro and in cultured cells. Biochem J 2001; 355: 347–356.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Pereg Y, Shkedy D, de Graaf P, Meulmeester E, Edelson-Averbukh M, Salek M et al. Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage. Proc Natl Acad Sci USA 2005; 102: 5056–5061.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen L, Gilkes DM, Pan Y, Lane WS, Chen J . ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO J 2005; 24: 3411–3422.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zuckerman V, Lenos K, Popowicz GM, Silberman I, Grossman T, Marine JC et al. c-Abl phosphorylates Hdmx and regulates its interaction with p53. J Biol Chem 2009; 284: 4031–4039.

    CAS  PubMed  Google Scholar 

  37. Kawai H, Wiederschain D, Yuan ZM . Critical contribution of the MDM2 acidic domain to p53 ubiquitination. Mol Cell Biol 2003; 23: 4939–4947.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Meulmeester E, Frenk R, Stad R, de Graaf P, Marine JC, Vousden KH et al. Critical role for a central part of Mdm2 in the ubiquitylation of p53. Mol Cell Biol 2003; 23: 4929–4938.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Honda R, Yasuda H . Activity of MDM2, a ubiquitin ligase, toward or itself is dependent on the RING finger domain of the ligase. Oncogene 2000; 19: 1473–1476.

    CAS  PubMed  Google Scholar 

  40. Kubbutat MH, Ludwig RL, Levine AJ, Vousden KH . Analysis of the degradation function of Mdm2. Cell Growth Diff 1999; 10: 87–92.

    CAS  PubMed  Google Scholar 

  41. Lohrum MAE, Ashcroft M, Kubbutat MHG, Vousden KH . Identification of a cryptic nucleolar-localization signal in MDM2. Nat Cell Biol 2000; 2: 179–181.

    CAS  PubMed  Google Scholar 

  42. Sharp DA, Kratowicz SA, Sank MJ, George DL . Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J Biol Chem 1999; 274: 38189–38196.

    CAS  PubMed  Google Scholar 

  43. Momand J, Villegas A, Belyi VA . The evolution of MDM2 family genes. Gene 2011; 486: 23–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J 1996; 15: 5349–5357.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Marine JC, Jochemsen AG . Mdmx as an essential regulator of p53 activity. Biochem Biophys Res Commun 2005; 331: 750–760.

    CAS  PubMed  Google Scholar 

  46. Egorova O, Mis M, Sheng Y . A site-directed mutagenesis study of the MdmX RING domain. Biochem Biophys Res Commun 2014; 447: 696–701.

    CAS  PubMed  Google Scholar 

  47. Iyappan S, Wollscheid HP, Rojas-Fernandez A, Marquardt A, Tang HC, Singh RK et al. Turning the RING domain protein MdmX into an active ubiquitin-protein ligase. J Biol Chem 2010; 285: 33065–33072.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Li C, Chen L, Chen J . DNA damage induces MDMX nuclear translocation by p53-dependent and -independent mechanisms. Mol Cell Biol 2002; 22: 7562–7571.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Bista M, Petrovich M, Fersht AR . MDMX contains an autoinhibitory sequence element. Proc Natl Acad Sci USA 2013; 110: 17814–17819.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Barak Y, Juven T, Haffner R, Oren M . Mdm-2 expression is induced by wild-type p53 activity. EMBO J 1993; 12: 461–468.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wu X, Bayle JH, Olson D, Levine AJ . The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993; 7: 1126–1132.

    Article  CAS  PubMed  Google Scholar 

  52. Toledo F, Wahl GM . MDM2 and MDM4: p53 regulators as targets in anticancer therapy. Int J Biochem Cell Biol 2007; 39: 1476–1482.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Li B, Cheng Q, Li Z, Chen J . p53 inactivation by MDM2 and MDMX negative feedback loops in testicular germ cell tumors. Cell Cycle 2010; 9: 1411–1420.

    CAS  PubMed  Google Scholar 

  54. Phillips A, Teunisse A, Lam S, Lodder K, Darley M, Emaduddin M et al. HDMX-L is expressed from a functional p53-responsive promoter in the first intron of the HDMX gene and participates in an autoregulatory feedback loop to control p53 activity. J Biol Chem 2010; 285: 29111–29127.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Pan Y, Chen J . MDM2 promotes ubiquitination and degradation of MDMX. Mol Cell Biol 2003; 23: 5113–5121.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. de Graaf P, Little NA, Ramos YF, Meulmeester E, Letteboer SJ, Jochemsen AG . Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2. J Biol Chem 2003; 278: 38315–38324.

    CAS  PubMed  Google Scholar 

  57. Kawai H, Wiederschain D, Kitao H, Stuart J, Tsai KK, Yuan ZM . DNA damage-induced MDMX degradation is mediated by MDM2. J Biol Chem 2003; 278: 45946–45953.

    CAS  PubMed  Google Scholar 

  58. Li X, Gilkes D, Li B, Cheng Q, Pernazza D, Lawrence H et al. Abnormal MDMX degradation in tumor cells due to ARF deficiency. Oncogene 2012; 31: 3721–3732.

    CAS  PubMed  Google Scholar 

  59. Okamoto K, Taya Y, Nakagama H . Mdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase. FEBS Lett 2009; 583: 2710–2714.

    CAS  PubMed  Google Scholar 

  60. Linares LK, Hengstermann A, Ciechanover A, Muller S, Scheffner M . HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc Natl Acad Sci USA 2003; 100: 12009–12014.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Badciong JC, Haas AL . MdmX is a RING finger ubiquitin ligase capable of synergistically enhancing Mdm2 ubiquitination. J Biol Chem 2002; 277: 49668–49675.

    CAS  PubMed  Google Scholar 

  62. Kawai H, Lopez-Pajares V, Kim MM, Wiederschain D, Yuan ZM . RING domain-mediated interaction is a requirement for MDM2's E3 ligase activity. Cancer Res 2007; 67: 6026–6030.

    CAS  PubMed  Google Scholar 

  63. Wang X, Wang J, Jiang X . MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination. J Biol Chem 2011; 286: 23725–23734.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Parant J, Chavez-Reyes A, Little NA, Yan W, Reinke V, Jochemsen AG et al. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat Genet 2001; 29: 92–95.

    CAS  PubMed  Google Scholar 

  65. Francoz S, Froment P, Bogaerts S, De Clercq S, Maetens M, Doumont G et al. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc Natl Acad Sci USA 2006; 103: 3232–3237.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Martins CP, Brown-Swigart L, Evan GI . Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 2006; 127: 1323–1334.

    CAS  PubMed  Google Scholar 

  67. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007; 445: 656–660.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007; 445: 661–665.

    CAS  PubMed  Google Scholar 

  69. Poyurovsky MV, Priest C, Kentsis A, Borden KL, Pan ZQ, Pavletich N et al. The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity. EMBO J 2007; 26: 90–101.

    CAS  PubMed  Google Scholar 

  70. Uldrijan S, Pannekoek WJ, Vousden KH . An essential function of the extreme C-terminus of MDM2 can be provided by MDMX. EMBO J 2007; 26: 102–112.

    CAS  PubMed  Google Scholar 

  71. Dolezelova P, Cetkovska K, Vousden KH, Uldrijan S . Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers. Cell Cycle 2012; 11: 953–962.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Linke K, Mace PD, Smith CA, Vaux DL, Silke J, Day CL . Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ 2008; 15: 841–848.

    CAS  PubMed  Google Scholar 

  73. Kostic M, Matt T, Martinez-Yamout MA, Dyson HJ, Wright PE . Solution structure of the Hdm2 C2H2C4 RING, a domain critical for ubiquitination of p53. J Mol Biol 2006; 363: 433–450.

    CAS  PubMed  Google Scholar 

  74. Leslie PL, Ke H, Zhang Y . The MDM2 RING domain and central acidic domain play distinct roles in MDM2 protein homodimerization and MDM2-MDMX protein heterodimerization. J Biol Chem 2015; 290: 12941–12950.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Cheng Q, Song T, Chen L, Chen J . Autoactivation of the MDM2 E3 ligase by intramolecular interaction. Mol Cell Biol 2014; 34: 2800–2810.

    PubMed  PubMed Central  Google Scholar 

  76. Chen L, Borcherds W, Wu S, Becker A, Schonbrunn E, Daughdrill GW et al. Autoinhibition of MDMX by intramolecular p53 mimicry. Proc Natl Acad Sci USA 2015; 112: 4624–4629.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Dang J, Kuo ML, Eischen CM, Stepanova L, Sherr CJ, Roussel MF . The RING domain of Mdm2 can inhibit cell proliferation. Cancer Res 2002; 62: 1222–1230.

    CAS  PubMed  Google Scholar 

  78. Zhang Y, Xiong Y, Yarbrough WG . ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998; 92: 725–734.

    CAS  PubMed  Google Scholar 

  79. Marechal V, Elenbaas B, Piette J, Nicolas J-C, Levine AJ . The ribosomal protein L5 is associated with mdm-2 and mdm2-p53 complexes. Mol Cell Biol 1994; 14: 7414–7420.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Dai MS, Lu H . Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. J Biol Chem 2004; 279: 44475–44482.

    CAS  PubMed  Google Scholar 

  81. Zhang Y, Wolf GW, Bhat K, Jin A, Allio T, Burkhart WA et al. Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol 2003; 23: 8902–8912.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Lohrum MA, Ludwig RL, Kubbutat MH, Hanlon M, Vousden KH . Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell 2003; 3: 577–587.

    CAS  PubMed  Google Scholar 

  83. Zheng J, Lang Y, Zhang Q, Cui D, Sun H, Jiang L et al. Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation. Genes Dev 2015; 29: 1524–1534.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Chen L, Li C, Pan Y, Chen J . Regulation of p53-MDMX interaction by casein kinase 1 alpha. Mol Cell Biol 2005; 25: 6509–6520.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Fahraeus R, Olivares-Illana V . MDM2's social network. Oncogene 2014; 33: 4365–4376.

    CAS  PubMed  Google Scholar 

  86. Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP . PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol 2004; 6: 665–672.

    CAS  PubMed  Google Scholar 

  87. Cheng Q, Chen L, Li Z, Lane WS, Chen J . ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO J 2009; 28: 3857–3867.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang X, Arooz T, Siu WY, Chiu CH, Lau A, Yamashita K et al. MDM2 and MDMX can interact differently with ARF and members of the p53 family. FEBS Lett 2001; 490: 202–208.

    CAS  PubMed  Google Scholar 

  89. Gilkes DM, Chen L, Chen J . MDMX regulation of p53 response to ribosomal stress. EMBO J 2006; 25: 5614–5625.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Xiong X, Zhao Y, Tang F, Wei D, Thomas D, Wang X et al. Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis. Elife 2014; 3: e02236.

    PubMed  PubMed Central  Google Scholar 

  91. Jones SN, Roe AE, Donehower LA, Bradley A . Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 1995; 378: 206–208.

    CAS  PubMed  Google Scholar 

  92. Montes de Oca Luna R, Wagner DS, Lozano G . Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 1995; 378: 203–206.

    CAS  PubMed  Google Scholar 

  93. Steinman HA, Hoover KM, Keeler ML, Sands AT, Jones SN . Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development. Oncogene 2005; 24: 7935–7940.

    CAS  PubMed  Google Scholar 

  94. Pant V, Xiong S, Iwakuma T, Quintas-Cardama A, Lozano G . Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability. Proc Natl Acad Sci USA 2011; 108: 11995–12000.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Huang L, Yan Z, Liao X, Li Y, Yang J, Wang ZG et al. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci USA 2011; 108: 12001–12006.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Schmid P, Lorenz A, Hameister H, Montenarh M . Expression of p53 during mouse embryogenesis. Development 1991; 113: 857–865.

    CAS  PubMed  Google Scholar 

  97. Tollini LA, Jin A, Park J, Zhang Y . Regulation of p53 by Mdm2 E3 ligase function is dispensable in embryogenesis and development, but essential in response to DNA damage. Cancer Cell 2014; 26: 235–247.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Wade M, Wang YV, Wahl GM . The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 2010; 20: 299–309.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Chavez-Reyes A, Parant JM, Amelse LL, de Oca Luna RM, Korsmeyer SJ, Lozano G . Switching mechanisms of cell death in mdm2- and mdm4-null mice by deletion of p53 downstream targets. Cancer Res 2003; 63: 8664–8669.

    CAS  PubMed  Google Scholar 

  100. Xiong S, Van Pelt CS, Elizondo-Fraire AC, Liu G, Lozano G . Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development. Proc Natl Acad Sci USA 2006; 103: 3226–3231.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Ringshausen I, O'Shea CC, Finch AJ, Swigart LB, Evan GI . Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 2006; 10: 501–514.

    CAS  PubMed  Google Scholar 

  102. Garcia D, Warr MR, Martins CP, Brown Swigart L, Passegue E, Evan GI . Validation of MdmX as a therapeutic target for reactivating p53 in tumors. Genes Dev 2011; 25: 1746–1757.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Noguchi T, Oishi S, Honda K, Kondoh Y, Saito T, Kubo T et al. Affinity-based screening of MDM2/MDMX-p53 interaction inhibitors by chemical array: identification of novel peptidic inhibitors. Bioorg Med Chem Lett 2013; 23: 3802–3805.

    CAS  PubMed  Google Scholar 

  104. Lamberti A, Sgammato R, Desiderio D, Punzo C, Raimo G, Novellino E et al. Native PAGE to study the interaction between the oncosuppressor p53 and its protein ligands. Electrophoresis 2015; 36: 552–555.

    CAS  PubMed  Google Scholar 

  105. Singh RK, Iyappan S, Scheffner M . Hetero-oligomerization with MdmX rescues the ubiquitin/Nedd8 ligase activity of RING finger mutants of Mdm2. J Biol Chem 2007; 282: 10901–10907.

    CAS  PubMed  Google Scholar 

  106. Argentini M, Barboule N, Wasylyk B . The contribution of the acidic domain of MDM2 to p53 and MDM2 stability. Oncogene 2001; 20: 1267–1275.

    CAS  PubMed  Google Scholar 

  107. Zhu Q, Yao J, Wani G, Wani MA, Wani AA . Mdm2 mutant defective in binding p300 promotes ubiquitination but not degradation of p53: evidence for the role of p300 in integrating ubiquitination and proteolysis. J Biol Chem 2001; 276: 29695–29701.

    CAS  PubMed  Google Scholar 

  108. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303: 844–848.

    CAS  PubMed  Google Scholar 

  109. Zhang Z, Chu XJ, Liu JJ, Ding Q, Zhang J, Bartkovitz D et al. Discovery of potent and orally active p53-MDM2 inhibitors RO5353 and RO2468 for potential clinical development. ACS Med Chem Lett 2014; 5: 124–127.

    PubMed  Google Scholar 

  110. Ray-Coquard I, Blay JY, Italiano A, Le Cesne A, Penel N, Zhi J et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012; 13: 1133–1140.

    CAS  PubMed  Google Scholar 

  111. Wade M, Li YC, Matani AS, Braun SM, Milanesi F, Rodewald LW et al. Functional analysis and consequences of Mdm2 E3 ligase inhibition in human tumor cells. Oncogene 2012; 31: 4789–4797.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Hu B, Gilkes DM, Farooqi B, Sebti SM, Chen J . MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J Biol Chem 2006; 281: 33030–33035.

    CAS  PubMed  Google Scholar 

  113. Patton JT, Mayo LD, Singhi AD, Gudkov AV, Stark GR, Jackson MW . Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3. Cancer Res 2006; 66: 3169–3176.

    CAS  PubMed  Google Scholar 

  114. Wade M, Wong ET, Tang M, Stommel JM, Wahl GM . Hdmx modulates the outcome of p53 activation in human tumor cells. J Biol Chem 2006; 281: 33036–33044.

    CAS  PubMed  Google Scholar 

  115. Aziz MH, Shen H, Maki CG . Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3. Oncogene 2011; 30: 4678–4686.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Michaelis M, Rothweiler F, Barth S, Cinatl J, van Rikxoort M, Loschmann N et al. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis 2011; 2: e243.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Riedinger C, McDonnell JM . Inhibitors of MDM2 and MDMX: a structural perspective. Future Med Chem 2009; 1: 1075–1094.

    CAS  PubMed  Google Scholar 

  118. Chang YS, Graves B, Guerlavais V, Tovar C, Packman K, To KH et al. Stapled alpha-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci USA 2013; 110: E3445–E3454.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Lee JH, Kang E, Lee J, Kim J, Lee KH, Han J et al. Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor. Nat Commun 2014; 5: 3814.

    CAS  PubMed  Google Scholar 

  120. Graves B, Thompson T, Xia M, Janson C, Lukacs C, Deo D et al. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci USA 2012; 109: 11788–11793.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Khoo KH, Verma CS, Lane DP . Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov 2014; 13: 217–236.

    CAS  PubMed  Google Scholar 

  122. Burgess A, Chia KM, Haupt S, Thomas D, Haupt Y, Lim E . Clinical overview of MDM2/X-targeted therapies. Front Oncol 2016; 6: 7.

    PubMed  PubMed Central  Google Scholar 

  123. Stad R, Ramos YFM, Litle N, Grivell S, Attema J, van der Eb AJ et al. Hdmx stabilizes Mdm2 and p53. J Biol Chem 2000; 275: 28039–28044.

    CAS  PubMed  Google Scholar 

  124. Yang Y, Ludwig RL, Jensen JP, Pierre SA, Medaglia MV, Davydov IV et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 2005; 7: 547–559.

    CAS  PubMed  Google Scholar 

  125. Herman AG, Hayano M, Poyurovsky MV, Shimada K, Skouta R, Prives C et al. Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay. Cancer Discov 2011; 1: 312–325.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Pellegrino M, Mancini F, Luca R, Coletti A, Giacche N, Manni I et al. Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy. Cancer Res 2015; 75: 4560–4572.

    CAS  PubMed  Google Scholar 

  127. Lehmann S, Bykov VJ, Ali D, Andren O, Cherif H, Tidefelt U et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol 2012; 30: 3633–3639.

    CAS  PubMed  Google Scholar 

  128. Bykov VJ, Zache N, Stridh H, Westman J, Bergman J, Selivanova G et al. PRIMA-1(MET) synergizes with cisplatin to induce tumor cell apoptosis. Oncogene 2005; 24: 3484–3491.

    CAS  PubMed  Google Scholar 

  129. Nahi H, Lehmann S, Mollgard L, Bengtzen S, Selivanova G, Wiman KG et al. Effects of PRIMA-1 on chronic lymphocytic leukaemia cells with and without hemizygous p53 deletion. Br J Haematol 2004; 127: 285–291.

    CAS  PubMed  Google Scholar 

  130. Takimoto R, Wang W, Dicker DT, Rastinejad F, Lyssikatos J, el-Deiry WS . The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein. Cancer Biol Ther 2002; 1: 47–55.

    CAS  PubMed  Google Scholar 

  131. Chen L, Rashid F, Shah A, Awan HM, Wu M, Liu A et al. The isolation of an RNA aptamer targeting to p53 protein with single amino acid mutation. Proc Natl Acad Sci USA 2015; 112: 10002–10007.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported, in whole or in part, by National Institutes of Health Grants CA127770 and CA167637 (to YZ). This work was also supported by a fellowship from the University of North Carolina Genetics and Molecular Biology Training Grant 5T32 GM007092 (to PL), and grants from the NSFC and Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy (to YZ).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    P L Leslie & Y Zhang

  2. Curriculum in Genetics and Molecular Biology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    P L Leslie

  3. Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, China

    Y Zhang

Authors
  1. P L Leslie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Zhang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leslie, P., Zhang, Y. MDM2 oligomers: antagonizers of the guardian of the genome. Oncogene 35, 6157–6165 (2016). https://doi.org/10.1038/onc.2016.88

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2016.88

This article is cited by

Search

Advanced search

Quick links