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Cooperation between MDM2 and MDMX in the Regulation of p53

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p53

Part of the book series: Molecular Biology Intelligence Unit ((MBIU,volume 1))

Abstract

Murine double minute-2 (MDM2) was first described as a p53-associated protein and potential oncogene in the early 1990s.1,2 Its paralogue MDMX was subsequently identified in a screen for p53-binding proteins.3 Extensive evidence now confirms both proteins to be oncogenic in both mice and humans, largely through their ability to negatively regulate the tumor-suppressor activities of p53. It is now clear that the two proteins form heterodimers, and act in concert to regulate p53 activity in proliferating and stressed cells. In this chapter I firstly review the several mechanisms whereby MDM2 and MDMX are potentially able to regulate p53 function independently of each other. I then examine how heterodimerization between the two molecules influences how they regulate the abundance and activity of both p53, and each other. I conclude by examining current models of how the dynamic equilibrium between p53 and its two negative regulators is maintained in proliferating cells, and is targeted by multiple signaling pathways to control the magnitude and duration of the p53-dependent transcriptional response to genotoxic stress.

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References

  1. Fakharzedeh SS, Trusko SP, George DL. Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO J 1991; 10:1565–1569.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Shvarts A, Steegenga WT, Riteco N et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J 1996; 15:5349–5357.

    PubMed  CAS  Google Scholar 

  4. Xirodimas DP, Chisholm J, Desterro JM et al. P14ARF promotes accumulation of SUMO-1 conjugated (H)Mdm2. FEBS Lett 2002; 528(1–3):207–211.

    Article  PubMed  CAS  Google Scholar 

  5. Cheng TH, Cohen SN. Human MDM2 isoforms translated differentially on constitutive versus p53-regulated transcripts have distinct functions in the p53/MDM2 and TSG101/MDM2 feed-back control loops. Mol Cell Biol 2007; 27(1):111–119.

    Article  PubMed  CAS  Google Scholar 

  6. Sharp DA, Kratowicz SA, Sank MJ et al. Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J Biol Chem 1999; 274(53):38189–38196.

    Article  PubMed  CAS  Google Scholar 

  7. Tanimura S, Ohtsuka S, Mitsui K et al. MDM2 interacts with MDMX through their RING finger domains. FEBS Lett 1999; 447(1):5–9.

    Article  PubMed  CAS  Google Scholar 

  8. Dang J, Kuo ML, Eischen CM et al. The RING domain of Mdm2 can inhibit cell proliferation. Cancer Res 2002; 62(4):1222–1230.

    PubMed  CAS  Google Scholar 

  9. Poyurovsky MV, Priest C, Kentsis A et al. The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity. EMBO J 2007; 26(1):90–101.

    Article  PubMed  CAS  Google Scholar 

  10. 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(1):102–112.

    Article  PubMed  CAS  Google Scholar 

  11. Kostic M, Matt T, Martinez-Yamout MA et al. Solution structure of the Hdm2 C2H2C4 RING, a domain critical for ubiquitination of p53. J Mol Biol 2006; 363(2):433–450.

    Article  PubMed  CAS  Google Scholar 

  12. Kawai H, Lopez-Pajares V, Kim MM et al. RING domain-mediated interaction is a requirement for MDM2’s E3 ligase activity. Cancer Res 2007; 67(13):6026–6030.

    Article  PubMed  CAS  Google Scholar 

  13. 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(15):10901–10907.

    Article  PubMed  CAS  Google Scholar 

  14. Linke K, Mace PD, Smith CA et al. Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ 2008.

    Google Scholar 

  15. Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 1997; 420(1):25–27.

    Article  PubMed  CAS  Google Scholar 

  16. Fang S, Jensen JP, Ludwig RL et al. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 2000; 275(12):8945–8951.

    Article  PubMed  CAS  Google Scholar 

  17. Honda R, Yasuda H. Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase. Oncogene 2000; 19(11):1473–1476.

    Article  PubMed  CAS  Google Scholar 

  18. de Graaf P, Little NA, Ramos YF et al. Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2. J Biol Chem 2003; 278(40):38315–38324.

    Article  PubMed  CAS  Google Scholar 

  19. Kawai H, Wiederschain D, Kitao H et al. DNA damage-induced MDMX degradation is mediated by MDM2. J Biol Chem 2003; 278(46):45946–45953.

    Article  PubMed  CAS  Google Scholar 

  20. Saville MK, Sparks A, Xirodimas DP et al. Regulation of p53 by the ubiquitin-conjugating enzymes UbcH5B/C in vivo. J Biol Chem 2004; 279(40):42169–42181.

    Article  PubMed  CAS  Google Scholar 

  21. Vander Kooi CW, Ohi MD, Rosenberg JA et al. The Prp19 U-box crystal structure suggests a common dimeric architecture for a class of oligomeric E3 ubiquitin ligases. Biochemistry 2006; 45(1):121–130.

    Article  CAS  Google Scholar 

  22. Badciong JC, Haas AL. MdmX is a RING finger ubiquitin ligase capable of synergistically enhancing Mdm2 ubiquitination. J Biol Chem 2002; 277(51):49668–49675.

    Article  PubMed  CAS  Google Scholar 

  23. Jackson MW, Berberich SJ. MdmX protects p53 from Mdm2-mediated degradation. Mol Cell Biol 2000; 20(3):1001–1007.

    Article  PubMed  CAS  Google Scholar 

  24. Stad R, Ramos YF, Little N et al. Hdmx stabilizes Mdm2 and p53. J Biol Chem 2000; 275(36):28039–28044.

    PubMed  CAS  Google Scholar 

  25. Migliorini D, Danovi D, Colombo E et al. Hdmx recruitment into the nucleus by Hdm2 is essential for its ability to regulate p53 stability and transactivation. J Biol Chem 2002; 277(9):7318–7323.

    Article  PubMed  CAS  Google Scholar 

  26. Marine JC, Francoz S, Maetens M et al. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ 2006; 13(6):927–934.

    Article  PubMed  CAS  Google Scholar 

  27. Marine JC, Jochemsen AG. Mdmx as an essential regulator of p53 activity. Biochem Biophys Res Commun 2005; 331(3):750–760.

    Article  PubMed  CAS  Google Scholar 

  28. Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 2006; 6(12):909–923.

    Article  PubMed  CAS  Google Scholar 

  29. 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(6553):203–206.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Parant J, Chavez-Reyes A, Little NA 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; 20:20.

    Google Scholar 

  32. Migliorini D, Denchi EL, Danovi D et al. Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol Cell Biol 2002; 22(15):5527–5538.

    Article  PubMed  CAS  Google Scholar 

  33. Finch RA, Donoviel DB, Potter D et al. mdmx is a negative regulator of p53 activity in vivo. Cancer Res 2002; 62(11):3221–3225.

    PubMed  CAS  Google Scholar 

  34. Itahana K, Mao H, Jin A 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(4):355–366.

    Article  PubMed  CAS  Google Scholar 

  35. Steinman HA, Hoover KM, Keeler ML et al. Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development. Oncogene 2005; 24(53):7935–7940.

    Article  PubMed  CAS  Google Scholar 

  36. Francoz S, Froment P, Bogaerts S et al. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc Natl Acad Sci U S A 2006; 103(9):3232–3237.

    Article  PubMed  CAS  Google Scholar 

  37. Grier JD, Xiong S, Elizondo-Fraire AC et al. Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4. Mol Cell Biol 2006; 26(1):192–198.

    Article  PubMed  CAS  Google Scholar 

  38. Xiong S, Van Pelt CS, Elizondo-Fraire AC et al. Loss of Mdm4 results in p53-dependent dilated cardiomyopathy. Circulation 2007; 115(23):2925–2930.

    Article  PubMed  CAS  Google Scholar 

  39. Boesten LS, Zadelaar SM, De Clercq S et al. Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death. Cell Death Differ 2006; 13(12):2089–2098.

    Article  PubMed  CAS  Google Scholar 

  40. Mendrysa SM, McElwee MK, Michalowski J et al. mdm2 Is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol Cell Biol 2003; 23(2):462–472.

    Article  PubMed  CAS  Google Scholar 

  41. Alt JR, Greiner TC, Cleveland JL et al. Mdm2 haplo-insufficiency profoundly inhibits Myc-in-duced lymphomagenesis. EMBO J 2003; 22(6):1442–1450.

    Article  PubMed  CAS  Google Scholar 

  42. Mendrysa SM, O’Leary KA, McElwee MK et al. Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev 2006; 20(1):16–21.

    Article  PubMed  CAS  Google Scholar 

  43. Blaydes JP, Wynford-Thomas D. The proliferation of normal human fibroblasts is dependent upon negative regulation of p53 function by mdm2. Oncogene 1998; 16(25):3317–3322.

    Article  PubMed  CAS  Google Scholar 

  44. Finlay CA. The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth. Mol Cell Biol 1993; 13:301–306.

    PubMed  CAS  Google Scholar 

  45. Sigalas I, Calvert AH, Anderson JJ et al. Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nature Med 1996; 2:912–917.

    Article  PubMed  CAS  Google Scholar 

  46. Fridman JS, Hernando E, Hemann MT et al. Tumor promotion by Mdm2 splice variants unable to bind p53. Cancer Res 2003; 63(18):5703–5706.

    PubMed  CAS  Google Scholar 

  47. Danovi D, Meulmeester E, Pasini D et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol 2004; 24(13):5835–5843.

    Article  PubMed  CAS  Google Scholar 

  48. Laurie NA, Donovan SL, Shih CS et al. Inactivation of the p53 pathway in retinoblastoma. Nature 2006; 444(7115):61–66.

    Article  PubMed  CAS  Google Scholar 

  49. Ganguli G, Wasylyk B. p53-independent functions of MDM2. Mol Cancer Res 2003; 1(14):1027–1035.

    PubMed  CAS  Google Scholar 

  50. Jones SN, Hancock AR, Vogel H et al. Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci U S A 1998; 95(26):15608–15612.

    Article  PubMed  CAS  Google Scholar 

  51. Onel K, Cordon-Cardo C. MDM2 and prognosis. Mol Cancer Res 2004; 2(1):1–8.

    PubMed  CAS  Google Scholar 

  52. Momand J, Jung D, Wilczynski S et al. The MDM2 gene amplification database. Nucleic Acids Res 1998; 26(15):3453–3459.

    Article  PubMed  CAS  Google Scholar 

  53. Bond GL, Hu W, Bond EE et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 2004; 119(5):591–602.

    Article  PubMed  CAS  Google Scholar 

  54. Bond GL, Levine AJ. A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene 2007; 26(9):1317–1323.

    Article  PubMed  CAS  Google Scholar 

  55. Schmidt MK, Reincke S, Broeks A et al. Do MDM2 SNP309 and TP53 R72P interact in breast cancer susceptibility? A large pooled series from the breast cancer association consortium. Cancer Res 2007; 67(19):9584–9590.

    Article  PubMed  CAS  Google Scholar 

  56. Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med 2007; 13(1):23–31.

    Article  PubMed  CAS  Google Scholar 

  57. Dey A, Verma CS, Lane DP. Updates on p53: modulation of p53 degradation as a therapeutic approach. Br J Cancer 2008; 98(1):4–8.

    Article  PubMed  CAS  Google Scholar 

  58. Shangary S, Qin D, McEachern D et al. 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 2008; 105(10):3933–3938.

    Article  PubMed  CAS  Google Scholar 

  59. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000; 408(6810):307–310.

    Article  PubMed  CAS  Google Scholar 

  60. Wang S, El-Deiry WS. p73 or p53 directly regulates human p53 transcription to maintain cell cycle checkpoints. Cancer Res 2006; 66(14):6982–6989.

    Article  PubMed  CAS  Google Scholar 

  61. Yin Y, Stephen CW, Luciani MG et al. p53 Stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products. Nat Cell Biol 2002; 4(6):462–467.

    Article  PubMed  CAS  Google Scholar 

  62. Wawrzynow B, Zylicz A, Wallace M et al. MDM2 chaperones the p53 tumor suppressor. J Biol Chem 2007; 282(45):32603–32612.

    Article  PubMed  CAS  Google Scholar 

  63. Espinosa JM, Verdun RE, Emerson BM. p53 functions through stress-and promoter-specific recruitment of transcription initiation components before and after DNA damage. Mol Cell 2003; 12(4):1015–1027.

    Article  PubMed  CAS  Google Scholar 

  64. An W, Kim J, Roeder RG. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 2004; 117(6):735–748.

    Article  PubMed  CAS  Google Scholar 

  65. Oliner JD, Pietenpol JA, Thiagalingam S et al. Oncoprotein MDM2 conceals the activation domain of tumor suppressor p53. Nature (London) 1993; 362:857–860.

    Article  CAS  Google Scholar 

  66. Kussie PH, Gorina S, Marechal V et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain [comment]. Science 1996; 274(5289):948–953.

    Article  PubMed  CAS  Google Scholar 

  67. Uesugi M, Verdine GL. The alpha-helical FXXPhiPhi motif in p53: TAF interaction and discrimination by MDM2. Proc Natl Acad Sci U S A 1999; 96(26):14801–14806.

    Article  PubMed  CAS  Google Scholar 

  68. Thut CJ, Chen J-L, Klemm R et al. p53 transcriptional activation mediated by coactivators TAF-II40 and TAF-II60. Science 1995; 267:100–104.

    Article  PubMed  CAS  Google Scholar 

  69. Brooks CL, Gu W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol 2003; 15(2):164–171.

    Article  PubMed  CAS  Google Scholar 

  70. Minsky N, Oren M. The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression. Mol Cell 2004; 16(4):631–639.

    Article  PubMed  CAS  Google Scholar 

  71. White DE, Talbott KE, Arva NC et al. Mouse double minute 2 associates with chromatin in the presence of p53 and is released to facilitate activation of transcription. Cancer Res 2006; 66(7):3463–3470.

    Article  PubMed  CAS  Google Scholar 

  72. Tang Y, Zhao W, Chen Y et al. Acetylation is indispensable for p53 activation. Cell 2008; 133(4):612–626.

    Article  PubMed  CAS  Google Scholar 

  73. Bottger V, Bottger A, Garcia-Echeverria C et al. Comparative study of the p53-mdm2 and p53-MDMX interfaces. Oncogene 1999; 18(1):189–199.

    Article  PubMed  CAS  Google Scholar 

  74. Chen JD, Lin JY, Levine AJ. Regulation of transcription functions of the p53 tumor suppressor by the mdm-2 oncogene. Mol Med 1995; 1:141–152.

    Google Scholar 

  75. Rallapalli R, Strachan G, Cho B et al. A novel MDMX transcript expressed in a variety of transformed cell lines encodes a truncated protein with potent p53 repressive activity. J Biol Chem 1999; 274(12):8299–8308.

    Article  PubMed  CAS  Google Scholar 

  76. Dornan D, Shimizu H, Perkins ND et al. DNA-dependent acetylation of p53 by the transcription coactivator p300. J Biol Chem 2003; 278(15):13431–13441.

    Article  PubMed  CAS  Google Scholar 

  77. Sabbatini P, McCormick F. MDMX inhibits the p300/CBP-mediated acetylation of p53. DNA Cell Biol 2002; 21(7):519–525.

    Article  PubMed  CAS  Google Scholar 

  78. Kobet E, Zeng X, Zhu Y et al. MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins. Proc Natl Acad Sci U S A 2000; 97(23):12547–12552.

    Google Scholar 

  79. Ito A, Kawaguchi Y, Lai CH et al. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J 2002; 21(22):6236–6245.

    Article  PubMed  CAS  Google Scholar 

  80. Thut CJ, Goodrich JA, Tjian R. Repression of p53-mediated transcription by MDM2: a dual mechanism. Genes Dev 1997; 11(15):1974–1986.

    Article  PubMed  CAS  Google Scholar 

  81. Mirnezami AH, Campbell SJ, Darley M et al. Hdm2 recruits a hypoxia sensitive corepressor to negatively regulate p53-dependent transcription. Curr Biol 2003; 13:1234–1239.

    Article  PubMed  CAS  Google Scholar 

  82. Linares LK, Hengstermann A, Ciechanover A et al. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc Natl Acad Sci U S A 2003; 100(21):12009–12014.

    Article  PubMed  CAS  Google Scholar 

  83. Yu GW, Rudiger S, Veprintsev D et al. The central region of HDM2 provides a second binding site for p53. Proc Natl Acad Sci U S A 2006; 103(5):1227–1232.

    Article  PubMed  CAS  Google Scholar 

  84. Ma J, Martin JD, Zhang H et al. A second p53 binding site in the central domain of Mdm2 is essential for p53 ubiquitination. Biochemistry 2006; 45(30):9238–9245.

    Article  PubMed  CAS  Google Scholar 

  85. Wallace M, Worrall E, Pettersson S et al. Dual-site regulation of MDM2 E3-ubiquitin ligase activity. Mol Cell 2006; 23(2):251–263.

    Article  PubMed  CAS  Google Scholar 

  86. Meulmeester E, Frenk R, Stad R et al. Critical role for a central part of Mdm2 in the ubiquitylation of p53. Mol Cell Biol 2003; 23(14):4929–4938.

    Article  PubMed  CAS  Google Scholar 

  87. Nakamura S, Roth JA, Mukhopadhyay T. Multiple lysine mutations in the C-terminal domain of p53 interfere with MDM2-dependent protein degradation and ubiquitination. Mol Cell Biol 2000; 20(24):9391–9398.

    Article  PubMed  CAS  Google Scholar 

  88. Rodriguez MS, Desterro JM, Lain S et al. Multiple C-terminal lysine residues target p53 for ubiquitin-proteasomemediated degradation. Mol Cell Biol 2000; 20(22):8458–8467.

    Article  PubMed  CAS  Google Scholar 

  89. Xirodimas DP, Saville MK, Bourdon JC et al. Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell 2004; 118(1):83–97.

    Article  PubMed  CAS  Google Scholar 

  90. Chan WM, Mak MC, Fung TK et al. Ubiquitination of p53 at multiple sites in the DNA-binding domain. Mol Cancer Res 2006; 4(1):15–25.

    Article  PubMed  CAS  Google Scholar 

  91. Li M, Brooks CL, Wu-Baer F et al. Mono-versus polyubiquitination: differential control of p53 fate by Mdm2. Science 2003; 302(5652):1972–1975.

    Article  PubMed  CAS  Google Scholar 

  92. Grossman SR, Deato ME, Brignone C et al. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 2003; 300(5617):342–344.

    Article  PubMed  CAS  Google Scholar 

  93. Brooks CL, Gu W. p53 ubiquitination: Mdm2 and beyond. Mol Cell 2006; 21(3):307–315.

    Article  PubMed  CAS  Google Scholar 

  94. Brooks CL, Li M, Gu W. Mechanistic studies of MDM2-mediated ubiquitination in p53 regulation. J Biol Chem 2007; 282(31):22804–22815.

    Article  PubMed  CAS  Google Scholar 

  95. Carter S, Bischof O, Dejean A et al. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol 2007; 9(4):428–435.

    Article  PubMed  CAS  Google Scholar 

  96. Haupt Y, Maya R, Kazaz A et al. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387(6630):296–299.

    Article  PubMed  CAS  Google Scholar 

  97. Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature 1997; 387(6630):299–303.

    Article  PubMed  CAS  Google Scholar 

  98. Xirodimas DP, Stephen CW, Lane DP. Cocompartmentalization of p53 and Mdm2 is a major determinant for Mdm2-mediated degradation of p53. Exp Cell Res 2001; 270(1):66–77.

    Article  PubMed  CAS  Google Scholar 

  99. Shirangi TR, Zaika A, Moll UM. Nuclear degradation of p53 occurs during down-regulation of the p53 response after DNA damage. FASEB J 2002; 16(3):420–422.

    PubMed  CAS  Google Scholar 

  100. Brooks CL, Li M, Gu W. Monoubiquitination: the signal for p53 nuclear export? Cell Cycle 2004; 3(4):436–438.

    Article  PubMed  CAS  Google Scholar 

  101. Xiong S, Van Pelt CS, Elizondo-Fraire AC et al. Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development. Proc Natl Acad Sci U S A 2006; 103(9):3226–3231.

    Article  PubMed  CAS  Google Scholar 

  102. Bottger A, Bottger V, Sparks A et al. Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo. Curr Biol 1997; 7(11):860–869.

    Article  PubMed  CAS  Google Scholar 

  103. Vassilev LT, Vu BT, Graves B et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303(5659):844–848..

    Article  PubMed  CAS  Google Scholar 

  104. Steinmeyer K, Maacke H, Deppert W. Cell cycle control by p53 in normal (3T3) and chemically transformed (Meth A) mouse cells. I. regulation of p53 expression. Oncogene 1990; 5:1691–1699.

    PubMed  CAS  Google Scholar 

  105. Fu L, Benchimol S. Participation of the human p53 3’UTR in translational repression and activation following gamma-irradiation. EMBO J 1997; 16(13):4117–4125.

    Article  PubMed  CAS  Google Scholar 

  106. Wahl GM. Mouse bites dogma: how mouse models are changing our views of how P53 is regulated in vivo. Cell Death Differ 2006; 13(6):973–983.

    Article  PubMed  CAS  Google Scholar 

  107. Brignone C, Bradley KE, Kisselev AF et al. A post-ubiquitination role for MDM2 and hHR23A in the p53 degradation pathway. Oncogene 2004; 23(23):4121–4129.

    Article  PubMed  CAS  Google Scholar 

  108. Sdek P, Ying H, Chang DL et al. MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Mol Cell 2005; 20(5):699–708.

    Article  PubMed  CAS  Google Scholar 

  109. Stad R, Little NA, Xirodimas DP et al. Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2001; 2(11):1029–1034.

    Article  PubMed  CAS  Google Scholar 

  110. Gu J, Kawai H, Nie L et al. Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem 2002; 277(22):19251–19254.

    Article  PubMed  CAS  Google Scholar 

  111. Feng J, Tamaskovic R, Yang Z et al. Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. J Biol Chem 2004; 279(34):35510–35517.

    Article  PubMed  CAS  Google Scholar 

  112. Gilkes DM, Pan Y, Coppola D et al. Regulation of MDMX expression by mitogenic signaling. Mol Cell Biol 2008.

    Google Scholar 

  113. Li C, Chen L, Chen J. DNA damage induces MDMX nuclear translocation by p53-dependent and-independent mechanisms. Mol Cell Biol 2002; 22(21):7562–7571.

    Article  PubMed  CAS  Google Scholar 

  114. LeBron C, Chen L, Gilkes DM et al. Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3. EMBO J 2006; 25(6):1196–1206.

    Article  PubMed  CAS  Google Scholar 

  115. Stommel JM, Wahl GM. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J 2004; 23(7):1547–1556.

    Article  PubMed  CAS  Google Scholar 

  116. Chen L, Gilkes DM, Pan Y et al. ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO J 2005; 24(19):3411–3422.

    Article  PubMed  CAS  Google Scholar 

  117. Pan Y, Chen J. MDM2 promotes ubiquitination and degradation of MDMX. Mol Cell Biol 2003; 23(15):5113–5121.

    Article  PubMed  CAS  Google Scholar 

  118. Meulmeester E, Maurice MM, Boutell C et al. Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Mol Cell 2005; 18(5):565–576.

    Article  PubMed  CAS  Google Scholar 

  119. Rallapalli R, Strachan G, Tuan RS et al. Identification of a domain within MDMX-S that is responsible for its high affinity interaction with p53 and high-level expression in mammalian cells. J Cell Biochem 2003; 89(3):563–575.

    Article  PubMed  CAS  Google Scholar 

  120. Wade M, Wong ET, Tang M et al. Hdmx modulates the outcome of p53 activation in human tumor cells. J Biol Chem 2006.

    Google Scholar 

  121. Agarwal ML, Ramana CV, Hamilton M et al. Regulation of p53 expression by the RAS-MAP kinase pathway. Oncogene 2001; 20(20):2527–2536.

    Article  PubMed  CAS  Google Scholar 

  122. Lin AW, Lowe SW. Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation. Proc Natl Acad Sci U S A 2001; 98(9):5025–5030.

    Article  PubMed  CAS  Google Scholar 

  123. Zauberman A, Flusberg D, Barak Y et al. A functional p53-responsive intronic promoter is contained within the human mdm2 gene. Nucleic Acids Res 1995; 23:2584–2592.

    Article  PubMed  CAS  Google Scholar 

  124. Phelps M, Darley M, Primrose JN et al. 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 2003; 63(10):2616–2623.

    PubMed  CAS  Google Scholar 

  125. Ries S, Biederer C, Woods D et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 2000; 103:321–330.

    Article  PubMed  CAS  Google Scholar 

  126. Phillips A, Blaydes JP. MNK1 and EIF4E are downstream effectors of MEKs in the regulation of the nuclear export of HDM2 mRNA. Oncogene 2007.

    Google Scholar 

  127. Ashcroft M, Ludwig RL, Woods DB et al. Phosphorylation of HDM2 by Akt. Oncogene 2002; 21(13):1955–1962.

    Article  PubMed  CAS  Google Scholar 

  128. Meulmeester E, Pereg Y, Shiloh Y et al. ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 2005; 4(9):1166–1170.

    Article  PubMed  CAS  Google Scholar 

  129. Li M, Chen D, Shiloh A et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 2002; 416(6881):648–653.

    Article  PubMed  CAS  Google Scholar 

  130. Okamoto K, Kashima K, Pereg Y et al. DNA damage-induced phosphorylation of MdmX at serine 367 activates p53 by targeting MdmX for Mdm2-dependent degradation. Mol Cell Biol 2005; 25(21):9608–9620.

    Article  PubMed  CAS  Google Scholar 

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  1. School of Medicine, University of Southampton, Somers Cancer Research Building, MP824 Southampton General Hospital, Southampton, SO16 6YD, UK

    Jeremy Blaydes

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Blaydes, J. (2010). Cooperation between MDM2 and MDMX in the Regulation of p53. In: p53. Molecular Biology Intelligence Unit, vol 1. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8231-5_6

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