Skip to main content
SpringerLink
Log in

The p53-Mdm2 Loop: A Critical Juncture of Stress Response

  • Chapter
  • First Online:
Mutant p53 and MDM2 in Cancer

Part of the book series: Subcellular Biochemistry ((SCBI,volume 85))

Abstract

The presence of a functional p53 protein is a key factor for the proper suppression of cancer development. A loss of p53 activity, by mutations or inhibition, is often associated with human malignancies. The p53 protein integrates various stress signals into a growth restrictive cellular response. In this way, p53 eliminates cells with a potential to become cancerous. Being a powerful decision maker, it is imperative that p53 will be activated properly, efficiently and temporarily in response to stress. Equally important is that p53 activation will be extinguished upon recovery from stress, and that improper activation of p53 will be avoided. Failure to achieve these aims is likely to have catastrophic consequences for the organism. The machinery that governs this tight regulation is largely based on the major inhibitor of p53, Mdm2, which both blocks p53 activities and promotes its destabilization. The interplay between p53 and Mdm2 involves a complex network of positive and negative feedback loops. Relief from Mdm2 suppression is required for p53 to be stabilized and activated in response to stress. Protection from Mdm2 entails a concerted action of modifying enzymes and partner proteins. The association of p53 with the PML-nuclear bodies may provide an infrastructure in which this complex regulatory network can be orchestrated. In this chapter we use examples to illustrate the regulatory machinery that drives this network.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Zuckerman V et al (2009) Tumour suppression by p53: the importance of apoptosis and cellular senescence. J Pathol 219(1):3–15

    CAS  PubMed  Google Scholar 

  2. Wade M, Li YC, Wahl GM (2013) MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13(2):83–96

    CAS  PubMed  Google Scholar 

  3. Berkers CR et al (2013) Metabolic regulation by p53 family members. Cell Metab 18(5):617–633

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Wang J, Yang J (2009) Interaction of tumor suppressor p53 with DNA and proteins. Curr Pharm Biotechnol 11(1):122–127

    Google Scholar 

  5. Gu B, Zhu WG (2012) Surf the post-translational modification network of p53 regulation. Int J Biol Sci 8(5):672–684

    PubMed Central  PubMed  Google Scholar 

  6. He G et al (2014) AMP-activated protein kinase induces p53 by phosphorylating MDMX and inhibiting its activity. Mol Cell Biol 34(2):148–157

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Appella E, Anderson CW (2000) Signaling to p53: breaking the posttranslational modification code. Pathol Biol (Paris) 48(3):227–245

    CAS  Google Scholar 

  8. Meek DW, Anderson CW (2009) Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb Perspect Biol 1(6):a000950

    PubMed Central  PubMed  Google Scholar 

  9. Taira N, Yoshida K (2012) Post-translational modifications of p53 tumor suppressor: determinants of its functional targets. Histol Histopathol 27(4):437–443

    CAS  PubMed  Google Scholar 

  10. Levine AJ, Oren M (2009) The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9(10):749–758

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Rivlin N, Koifman G, Rotter V (2014) p53 orchestrates between normal differentiation and cancer. Semin Cancer Biol. doi: 10.1016/j.semcancer.2013.12.006. [Epub ahead of print]

  12. Barak Y et al (1993) mdm2 expression is induced by wild type p53 activity. EMBO J 12(2):461–468

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Perry ME, Levine AJ (1993) Tumor-suppressor p53 and the cell cycle. Curr Opin Genet Dev 3(1):50–54

    CAS  PubMed  Google Scholar 

  14. Li Q, Lozano G (2013) Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clin Cancer Res 19(1):34–41

    PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Harris SL, Levine AJ (2005) The p53 pathway: positive and negative feedback loops. Oncogene 24(17):2899–2908

    CAS  PubMed  Google Scholar 

  17. Horn HF, Vousden KH (2007) Coping with stress: multiple ways to activate p53. Oncogene 26(9):1306–1316

    CAS  PubMed  Google Scholar 

  18. Lavin MF, Gueven N (2006) The complexity of p53 stabilization and activation. Cell Death Differ 13(6):941–950

    CAS  PubMed  Google Scholar 

  19. Haupt Y (2004) p53 regulation: a family affair. Cell Cycle 3(7):884–885

    CAS  PubMed  Google Scholar 

  20. Bond GL, Hu W, Levine AJ (2005) MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 5(1):3–8

    CAS  PubMed  Google Scholar 

  21. Hock AK, Vousden KH (2014) The role of ubiquitin modification in the regulation of p53. Biochim Biophys Acta 1843(1):137–149

    CAS  PubMed  Google Scholar 

  22. Haupt Y et al (1997) Mdm2 promotes the rapid degradation of p53. Nature 387(6630):296–299

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  24. Marine JC, Lozano G (2010) Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ 17(1):93–102

    CAS  PubMed  Google Scholar 

  25. Brooks CL, Gu W (2011) p53 regulation by ubiquitin. FEBS Lett 585(18):2803–2809

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Satija YK, Bhardwaj A, Das S (2013) A portrayal of E3 ubiquitin ligases and deubiquitylases in cancer. Int J Cancer 133(12):2759–2768

    CAS  PubMed  Google Scholar 

  27. Momand J, Wu HH, Dasgupta G (2000) MDM2 – master regulator of the p53 tumor suppressor protein. Gene 242(1–2):15–29

    CAS  PubMed  Google Scholar 

  28. Marine JC (2010) Pharmacological rescue of p53 in cancer therapy: widening the sensitive tumor spectrum by targeting MDMX. Cancer Cell 18(5):399–400

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  30. Bond GL, Hu W, Levine A (2005) A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. Cancer Res 65(13):5481–5484

    CAS  PubMed  Google Scholar 

  31. Levine AJ, Hu W, Feng Z (2006) The P53 pathway: what questions remain to be explored? Cell Death Differ 13(6):1027–1036

    CAS  PubMed  Google Scholar 

  32. Mendrysa SM et al (2003) mdm2 is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol Cell Biol 23(2):462–472

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Lozano G (2010) Mouse models of p53 functions. Cold Spring Harb Perspect Biol 2(4):a001115

    PubMed Central  PubMed  Google Scholar 

  34. Juven-Gershon T, Oren M (1999) Mdm2: the ups and downs. Mol Med 5(2):71–83

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Jones SN et al (1995) Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378(6553):206–208

    CAS  PubMed  Google Scholar 

  36. Leveillard T et al (1998) MDM2 expression during mouse embryogenesis and the requirement of p53. Mech Dev 74(1–2):189–193

    CAS  PubMed  Google Scholar 

  37. Parant J et al (2001) Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat Genet 29(1):92–95

    CAS  PubMed  Google Scholar 

  38. Finch RA et al (2002) mdmx is a negative regulator of p53 activity in vivo. Cancer Res 62(11):3221–3225

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Marine JC, Jochemsen AG (2004) Mdmx and Mdm2: brothers in arms? Cell Cycle 3(7):900–904

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  42. Laurie NA et al (2006) Inactivation of the p53 pathway in retinoblastoma. Nature 444(7115):61–66

    CAS  PubMed  Google Scholar 

  43. Lenos K, Jochemsen AG (2011) Functions of MDMX in the modulation of the p53-response. J Biomed Biotechnol 2011:876173

    PubMed Central  PubMed  Google Scholar 

  44. Jochemsen AG (2012) Mdmx: a p53 activator? Cell Cycle 11(5):843

    CAS  PubMed  Google Scholar 

  45. Wade M, Wahl GM (2009) Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol Cancer Res 7(1):1–11

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Honda R, 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(11):1473–1476

    CAS  PubMed  Google Scholar 

  47. Fang S et al (2000) Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 275(12):8945–8951

    CAS  PubMed  Google Scholar 

  48. Woods DB, Vousden KH (2001) Regulation of p53 function. Exp Cell Res 264(1):56–66

    CAS  PubMed  Google Scholar 

  49. Ringshausen I et al (2006) Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 10(6):501–514

    CAS  PubMed  Google Scholar 

  50. Leng RP et al (2003) Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112(6):779–791

    CAS  PubMed  Google Scholar 

  51. Dornan D et al (2004) The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429(6987):86–92

    CAS  PubMed  Google Scholar 

  52. Chen D et al (2005) ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 121(7):1071–1083

    CAS  PubMed  Google Scholar 

  53. Boutell C, Everett RD (2003) The herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 interacts with and Ubiquitinates p53. J Biol Chem 278(38):36596–36602

    CAS  PubMed  Google Scholar 

  54. Rajendra R et al (2004) Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J Biol Chem 279(35):36440–36444

    CAS  PubMed  Google Scholar 

  55. Esser C, Scheffner M, Hohfeld J (2005) The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J Biol Chem 280(29):27443–27448

    CAS  PubMed  Google Scholar 

  56. Laine A et al (2006) Regulation of p53 localization and activity by Ubc13. Mol Cell Biol 26(23):8901–8913

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Yamasaki S et al (2007) Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase ‘Synoviolin’. EMBO J 26(1):113–122

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Le Cam L et al (2006) E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. Cell 127(4):14

    Google Scholar 

  59. Yang W et al (2007) CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradation. J Biol Chem 282(5):3273–3281

    CAS  PubMed  Google Scholar 

  60. Laine A, Ronai Z (2007) Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene 26(10):1477–1483

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Kruse JP, Gu W (2009) MSL2 promotes Mdm2-independent cytoplasmic localization of p53. J Biol Chem 284(5):3250–3263

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Lee JT, Gu W (2010) The multiple levels of regulation by p53 ubiquitination. Cell Death Differ 17(1):86–92

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Itahana K et al (2007) Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 12(4):355–366

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Ito A et al (2001) p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 20(6):1331–1340

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Jin Y et al (2004) MDM2 mediates p300/CREB-binding protein-associated factor ubiquitination and degradation. J Biol Chem 279(19):20035–20043

    CAS  PubMed  Google Scholar 

  67. Ito A et al (2002) MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J 21(22):6236–6245

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Wang C et al (2005) MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J 24(18):3279–3290

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Xirodimas DP et al (2004) Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell 118(1):83–97

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  71. Lai Z et al (2001) Human mdm2 mediates multiple mono-ubiquitination of p53 by a mechanism requiring enzyme isomerization. J Biol Chem 276(33):31357–31367

    CAS  PubMed  Google Scholar 

  72. Carter S et al (2007) C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol 9(4):428–435

    CAS  PubMed  Google Scholar 

  73. Li M et al (2003) Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302(5652):1972–1975

    CAS  PubMed  Google Scholar 

  74. Joseph TW, Zaika A, Moll UM (2003) Nuclear and cytoplasmic degradation of endogenous p53 and HDM2 occurs during down-regulation of the p53 response after multiple types of DNA damage. FASEB J 17(12):1622–1630

    CAS  PubMed  Google Scholar 

  75. Marchenko ND et al (2007) Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J 26(4):923–934

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Lohrum MA et al (2001) C-terminal ubiquitination of p53 contributes to nuclear export. Mol Cell Biol 21(24):8521–8532

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Feng L et al (2005) Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol Cell Biol 25(13):5389–5395

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Krummel KA et al (2005) The C-terminal lysines fine-tune P53 stress responses in a mouse model but are not required for stability control or transactivation. Proc Natl Acad Sci U S A 102(29):10188–10193

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Chan WM et al (2006) Ubiquitination of p53 at multiple sites in the DNA-binding domain. Mol Cancer Res 4(1):15–25

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  81. Inoue T et al (2001) MDM2 can promote the ubiquitination, nuclear export, and degradation of p53 in the absence of direct binding. J Biol Chem 276(48):45255–45260

    CAS  PubMed  Google Scholar 

  82. Yap DB, Hsieh JK, Lu X (2000) Mdm2 inhibits the apoptotic function of p53 mainly by targeting it for degradation. J Biol Chem 275(47):37296–37302

    CAS  PubMed  Google Scholar 

  83. Unger T et al (1999) Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. EMBO J 18(7):1805–1814

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Marine JC et al (2006) Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ 13(6):927–934

    CAS  PubMed  Google Scholar 

  85. Clegg HV, Itahana K, Zhang Y (2008) Unlocking the Mdm2-p53 loop: ubiquitin is the key. Cell Cycle 7(3):287–292

    CAS  PubMed  Google Scholar 

  86. Wade M, Wang YV, Wahl GM (2010) The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 20(5):299–309

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Stommel JM, Wahl GM (2005) A new twist in the feedback loop: stress-activated MDM2 destabilization is required for p53 activation. Cell Cycle 4(3):411–417

    CAS  PubMed  Google Scholar 

  88. Bode AM, Dong Z (2004) Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4(10):793–805

    CAS  PubMed  Google Scholar 

  89. Kruse JP, Gu W (2008) SnapShot: p53 posttranslational modifications. Cell 133(5):930–930.e1

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Olsson A et al (2007) How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumour suppression? Cell Death Differ 14(9):1561–1575

    CAS  PubMed  Google Scholar 

  91. Bean LJ, Stark GR (2002) Regulation of the accumulation and function of p53 by phosphorylation of two residues within the domain that binds to Mdm2. J Biol Chem 277(3):1864–1871

    CAS  PubMed  Google Scholar 

  92. Sakaguchi K et al (2000) Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding. J Biol Chem 275(13):9278–9283

    CAS  PubMed  Google Scholar 

  93. Banin S et al (1998) Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281(5383):1674–1677

    CAS  PubMed  Google Scholar 

  94. Canman CE, Lim DS (1998) The role of ATM in DNA damage responses and cancer. Oncogene 17(25):3301–3308

    PubMed  Google Scholar 

  95. Khanna KK et al (1998) ATM associates with and phosphorylates p53: mapping the region of interaction. Nat Genet 20(4):398–400

    CAS  PubMed  Google Scholar 

  96. Lakin ND, Hann BC, Jackson SP (1999) The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53. Oncogene 18(27):3989–3995

    CAS  PubMed  Google Scholar 

  97. Berger M et al (2005) Mutations in proline 82 of p53 impair its activation by Pin1 and Chk2 in response to DNA damage. Mol Cell Biol 25(13):5380–5388

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Bartek J, Falck J, Lukas J (2001) CHK2 kinase – a busy messenger. Nat Rev Mol Cell Biol 2(12):877–886

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Dornan D, Hupp TR (2001) Inhibition of p53-dependent transcription by BOX-I phospho-peptide mimetics that bind to p300. EMBO Rep 2(2):139–144

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Dumaz N, Meek DW (1999) Serine15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2. EMBO J 18(24):7002–7010

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Feng H et al (2009) Structural basis for p300 Taz2-p53 TAD1 binding and modulation by phosphorylation. Structure 17(2):202–210

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Jenkins LM et al (2009) Two distinct motifs within the p53 transactivation domain bind to the Taz2 domain of p300 and are differentially affected by phosphorylation. Biochemistry 48(6):1244–1255

    PubMed  Google Scholar 

  105. Lambert PF et al (1998) Phosphorylation of p53 serine 15 increases interaction with CBP. J Biol Chem 273(49):33048–33053

    CAS  PubMed  Google Scholar 

  106. Lee CW et al (2009) Mapping the interactions of the p53 transactivation domain with the KIX domain of CBP. Biochemistry 48(10):2115–2124

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Teufel DP, Bycroft M, Fersht AR (2009) Regulation by phosphorylation of the relative affinities of the N-terminal transactivation domains of p53 for p300 domains and Mdm2. Oncogene 28(20):2112–2118

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Sakaguchi K et al (1998) DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev 12(18):2831–2841

    CAS  PubMed Central  PubMed  Google Scholar 

  109. MacPherson D et al (2004) Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23. EMBO J 23(18):3689–3699

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Wu Z et al (2002) Mutation of mouse p53 Ser23 and the response to DNA damage. Mol Cell Biol 22(8):2441–2449

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Takai H et al (2002) Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J 21(19):5195–5205

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Maclaine NJ, Hupp TR (2009) The regulation of p53 by phosphorylation: a model for how distinct signals integrate into the p53 pathway. Aging (Albany, NY) 1(5):12

    Google Scholar 

  113. Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137(3):413–431

    CAS  PubMed  Google Scholar 

  114. Falck J et al (2001) Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway. Oncogene 20(39):5503–5510

    CAS  PubMed  Google Scholar 

  115. Bartek J, Bartkova J, Lukas J (2007) DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 26(56):7773–7779

    CAS  PubMed  Google Scholar 

  116. Chao C et al (2003) Cell type- and promoter-specific roles of Ser18 phosphorylation in regulating p53 responses. J Biol Chem 278(42):41028–41033

    CAS  PubMed  Google Scholar 

  117. Sluss HK et al (2004) Phosphorylation of serine 18 regulates distinct p53 functions in mice. Mol Cell Biol 24(3):976–984

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Chao C et al (2006) Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression. EMBO J 25(11):2615–2622

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Hay TJ, Meek DW (2000) Multiple sites of in vivo phosphorylation in the MDM2 oncoprotein cluster within two important functional domains. FEBS Lett 478(1–2):183–186

    CAS  PubMed  Google Scholar 

  120. Blattner C et al (2002) Hypophosphorylation of Mdm2 augments p53 stability. Mol Cell Biol 22(17):6170–6182

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Meek DW, Hupp TR (2010) The regulation of MDM2 by multisite phosphorylation-opportunities for molecular-based intervention to target tumours? Semin Cancer Biol 20(1):19–28

    CAS  PubMed  Google Scholar 

  122. Kruse JP, Gu W (2009) Modes of p53 regulation. Cell 137(4):609–622

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Meek DW, Hupp TR (2010) The regulation of MDM2 by multisite phosphorylation – opportunities for molecular-based intervention to target tumours? Semin Cancer Biol 20(1):19–28

    CAS  PubMed  Google Scholar 

  124. Mayo LD, Turchi JJ, Berberich SJ (1997) Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. Cancer Res 57(22):5013–5016

    CAS  PubMed  Google Scholar 

  125. Zhang Y, Xiong Y (2001) A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation. Science 292(5523):1910–1915

    CAS  PubMed  Google Scholar 

  126. Sionov RV et al (2001) c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination. Mol Cell Biol 21(17):5869–5878

    CAS  PubMed  Google Scholar 

  127. Levav-Cohen Y et al (2005) C-Abl as a modulator of p53. Biochem Biophys Res Commun 331(3):737–749

    CAS  PubMed  Google Scholar 

  128. Goldberg Z et al (2002) Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. EMBO J 21(14):3715–3727

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Dias SS, Milne DM, Meek DW (2006) c-Abl phosphorylates Hdm2 at tyrosine 276 in response to DNA damage and regulates interaction with ARF. Oncogene 25(50):6666–6671

    CAS  PubMed  Google Scholar 

  130. Khosravi R et al (1999) Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci U S A 96(26):14973–14977

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Maya R et al (2001) ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15(9):1067–1077

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Kharbanda S et al (1998) Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene 17(25):3309–3318

    PubMed  Google Scholar 

  133. Zhu J, Wang JY (2004) Death by Abl: a matter of location. Curr Top Dev Biol 59:165–192

    CAS  PubMed  Google Scholar 

  134. Cheng Q et al (2009) ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO J 28(24):3857–3867

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Cheng Q, Chen J (2010) Mechanism of p53 stabilization by ATM after DNA damage. Cell Cycle 9(3):472–478

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Wang X, Jiang X (2012) Mdm2 and MdmX partner to regulate p53. FEBS Lett 586(10):1390–1396

    CAS  PubMed  Google Scholar 

  137. Pei D, Zhang Y, Zheng J (2012) Regulation of p53: a collaboration between Mdm2 and Mdmx. Oncotarget 3(3):228–235

    PubMed Central  PubMed  Google Scholar 

  138. Shadfan M, Lopez-Pajares V, Yuan ZM (2012) MDM2 and MDMX: Alone and together in regulation of p53. Transl Cancer Res 1(2):88–89

    PubMed Central  PubMed  Google Scholar 

  139. Mayo LD, Donner DB (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(20):11598–11603

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Mayo LD et al (2002) PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem 277(7):5484–5489

    CAS  PubMed  Google Scholar 

  141. Ogawara Y et al (2002) Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 277(24):21843–21850

    CAS  PubMed  Google Scholar 

  142. Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408(6811):433–439

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  144. Meek DW, Knippschild U (2003) Posttranslational modification of MDM2. Mol Cancer Res 1(14):1017–1026

    CAS  PubMed  Google Scholar 

  145. Testa JR, Bellacosa A (2001) AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A 98(20):10983–10985

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Song MS et al (2008) The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex. EMBO J 27(13):1863–1874

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Levav-Cohen Y, Haupt S, Haupt Y (2005) Mdm2 in growth signaling and cancer. Growth Factors 23(3):183–192

    CAS  PubMed  Google Scholar 

  148. Gottlieb TM et al (2002) Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 21(8):1299–1303

    CAS  PubMed  Google Scholar 

  149. Oren M et al (2002) Regulation of p53: intricate loops and delicate balances. Ann N Y Acad Sci 973:374–383

    CAS  PubMed  Google Scholar 

  150. Nag S et al (2013) The MDM2-p53 pathway revisited. J Biomed Res 27(4):254–271

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Fahraeus R, Olivares-Illana V (2013) MDM2’s social network. Oncogene. doi: 10.1038/onc.2013.410. [Epub ahead of print]

  152. Okamoto K et al (2002) Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell 9(4):761–771

    CAS  PubMed  Google Scholar 

  153. Kimura SH et al (2001) Cyclin G1 is involved in G2/M arrest in response to DNA damage and in growth control after damage recovery. Oncogene 20(25):3290–3300

    CAS  PubMed  Google Scholar 

  154. Wu X et al (1998) The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 95(26):15587–15591

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Lee MH, Lozano G (2006) Regulation of the p53-MDM2 pathway by 14-3-3 sigma and other proteins. Semin Cancer Biol 16(3):225–234

    CAS  PubMed  Google Scholar 

  156. Chalhoub N, Baker SJ (2009) PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4:127–150

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28(6):9

    Google Scholar 

  158. Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13(5):283–296

    CAS  PubMed  Google Scholar 

  159. Freeman DJ et al (2003) PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 3(2):117–130

    CAS  PubMed  Google Scholar 

  160. Stambolic V et al (2001) Regulation of PTEN transcription by p53. Mol Cell 8(2):317–325

    CAS  PubMed  Google Scholar 

  161. Puc J et al (2005) Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 7(2):193–204

    CAS  PubMed  Google Scholar 

  162. Puc J, Parsons R (2005) PTEN loss inhibits CHK1 to cause double stranded-DNA breaks in cells. Cell Cycle 4(7):927–929

    CAS  PubMed  Google Scholar 

  163. Walker KK, Levine AJ (1996) Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc Natl Acad Sci U S A 93(26):15335–15340

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Sakamuro D et al (1997) The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 15(8):887–898

    CAS  PubMed  Google Scholar 

  165. Venot C et al (1998) The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression. EMBO J 17(16):4668–4679

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Toledo F et al (2006) A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network. Cancer Cell 9(4):273–285

    CAS  PubMed  Google Scholar 

  167. Zhu J et al (1999) Differential regulation of cellular target genes by p53 devoid of the PXXP motifs with impaired apoptotic activity. Oncogene 18(12):2149–2155

    CAS  PubMed  Google Scholar 

  168. Baptiste N et al (2002) The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells. Oncogene 21(1):9–21

    CAS  PubMed  Google Scholar 

  169. Berger M et al (2001) A role for the polyproline domain of p53 in its regulation by Mdm2. J Biol Chem 276(6):3785–3790

    CAS  PubMed  Google Scholar 

  170. Zilfou JT et al (2001) The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation. Mol Cell Biol 21(12):3974–3985

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Zacchi P et al (2002) The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419(6909):853–857

    CAS  PubMed  Google Scholar 

  172. Zheng H et al (2002) The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419(6909):849–853

    CAS  PubMed  Google Scholar 

  173. Bergamaschi D et al (2006) iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nat Genet 38(10):1133–1141

    CAS  PubMed  Google Scholar 

  174. Seo YR, Kelley MR, Smith ML (2002) Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. Proc Natl Acad Sci U S A 99(22):14548–14553

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  176. Buschmann T et al (2001) Stabilization and activation of p53 by the coactivator protein TAFII31. J Biol Chem 276(17):13852–13857

    CAS  PubMed  Google Scholar 

  177. Bai L, Merchant JL (2001) ZBP-89 promotes growth arrest through stabilization of p53. Mol Cell Biol 21(14):4670–4683

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Biderman L, Manley JL, Prives C (2012) Mdm2 and MdmX as regulators of gene expression. Genes Cancer 3(3–4):264–273

    PubMed Central  PubMed  Google Scholar 

  179. Hock A, Vousden KH (2010) Regulation of the p53 pathway by ubiquitin and related proteins. Int J Biochem Cell Biol 42(10):1618–1621

    CAS  PubMed  Google Scholar 

  180. Matheu A, Maraver A, Serrano M (2008) The Arf/p53 pathway in cancer and aging. Cancer Res 68(15):6031–6034

    CAS  PubMed  Google Scholar 

  181. Ozenne P et al (2010) The ARF tumor suppressor: structure, functions and status in cancer. Int J Cancer 127(10):2239–2247

    CAS  PubMed  Google Scholar 

  182. Dominguez-Brauer C et al (2010) Tumor suppression by ARF: gatekeeper and caretaker. Cell Cycle 9(1):86–89

    CAS  PubMed  Google Scholar 

  183. Itahana Y, Itahana K (2012) Emerging roles of mitochondrial p53 and ARF. Curr Drug Targets 13(13):1633–1640

    CAS  PubMed  Google Scholar 

  184. Sherr CJ (2001) Parsing Ink4a/Arf: “pure” p16-null mice. Cell 106(5):531–534

    CAS  PubMed  Google Scholar 

  185. Sherr CJ, Weber JD (2000) The ARF/p53 pathway. Curr Opin Genet Dev 10(1):94–99

    CAS  PubMed  Google Scholar 

  186. Damalas A et al (2001) Deregulated beta-catenin induces a p53- and ARF-dependent growth arrest and cooperates with Ras in transformation. EMBO J 20(17):4912–4922

    CAS  PubMed Central  PubMed  Google Scholar 

  187. Llanos S et al (2001) Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus. Nat Cell Biol 3(5):445–452

    CAS  PubMed  Google Scholar 

  188. Honda R, Yasuda H (1999) Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 18(1):22–27

    CAS  PubMed Central  PubMed  Google Scholar 

  189. Rocha S, Campbell KJ, Perkins ND (2003) p53- and Mdm2-independent repression of NF-kappa B transactivation by the ARF tumor suppressor. Mol Cell 12(1):15–25

    CAS  PubMed  Google Scholar 

  190. Ries S et al (2000) Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 103(2):321–330

    CAS  PubMed  Google Scholar 

  191. Hayon IL, Haupt Y (2002) p53: an internal investigation. Cell Cycle 1(2):111–116

    CAS  PubMed  Google Scholar 

  192. Kamijo T et al (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91(5):649–659

    CAS  PubMed  Google Scholar 

  193. Collins CJ, Sedivy JM (2003) Involvement of the INK4a/Arf gene locus in senescence. Aging Cell 2(3):145–150

    CAS  PubMed  Google Scholar 

  194. Ruas M, Peters G (1998) The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1378(2):F115–F177

    CAS  PubMed  Google Scholar 

  195. Christophorou MA et al (2006) The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443(7108):214–217

    CAS  PubMed  Google Scholar 

  196. Efeyan A et al (2006) Tumour biology: policing of oncogene activity by p53. Nature 443(7108):159

    CAS  PubMed  Google Scholar 

  197. Khan SH, Moritsugu J, Wahl GM (2000) Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion. Proc Natl Acad Sci U S A 97(7):3266–3271

    CAS  PubMed Central  PubMed  Google Scholar 

  198. Jimenez GS et al (1999) p53 regulation by post-translational modification and nuclear retention in response to diverse stresses. Oncogene 18(53):7656–7665

    CAS  PubMed  Google Scholar 

  199. Liang SH, Clarke MF (2001) Regulation of p53 localization. Eur J Biochem 268(10):2779–2783

    CAS  PubMed  Google Scholar 

  200. Murray-Zmijewski F, Slee EA, Lu X (2008) A complex barcode underlies the heterogeneous response of p53 to stress. Nat Rev Mol Cell Biol 9(9):702–712

    CAS  PubMed  Google Scholar 

  201. You H, Yamamoto K, Mak TW (2006) Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3a. Proc Natl Acad Sci U S A 103(24):9051–9056

    CAS  PubMed Central  PubMed  Google Scholar 

  202. Mihara M et al (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11(3):577–590

    CAS  PubMed  Google Scholar 

  203. Chipuk JE et al (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303(5660):1010–1014

    CAS  PubMed  Google Scholar 

  204. Tomita Y et al (2006) WT p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization. J Biol Chem 281(13):8600–8606

    CAS  PubMed  Google Scholar 

  205. Leu JI et al (2004) Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6(5):443–450

    CAS  PubMed  Google Scholar 

  206. Chipuk JE et al (2005) PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science 309(5741):1732–1735

    CAS  PubMed  Google Scholar 

  207. Bernardi R, Pandolfi PP (2007) Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 8(12):1006–1016

    CAS  PubMed  Google Scholar 

  208. de The H, Le Bras M, Lallemand-Breitenbach V (2012) The cell biology of disease: acute promyelocytic leukemia, arsenic, and PML bodies. J Cell Biol 198(1):11–21

    PubMed Central  PubMed  Google Scholar 

  209. Ferbeyre G et al (2000) PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14(16):2015–2027

    CAS  PubMed Central  PubMed  Google Scholar 

  210. Fogal V et al (2000) Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J 19(22):6185–6195

    CAS  PubMed Central  PubMed  Google Scholar 

  211. Carbone R et al (2002) PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage. Oncogene 21(11):1633–1640

    CAS  PubMed  Google Scholar 

  212. Pearson M et al (2000) PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406(6792):207–210

    CAS  PubMed  Google Scholar 

  213. Guo A et al (2000) The function of PML in p53-dependent apoptosis. Nat Cell Biol 2(10):730–736

    CAS  PubMed  Google Scholar 

  214. Pearson M, Pelicci PG (2001) PML interaction with p53 and its role in apoptosis and replicative senescence. Oncogene 20(49):7250–7256

    CAS  PubMed  Google Scholar 

  215. de Stanchina E et al (2004) PML is a direct p53 target that modulates p53 effector functions. Mol Cell 13(4):523–535

    PubMed  Google Scholar 

  216. Langley E et al (2002) Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 21(10):2383–2396

    CAS  PubMed Central  PubMed  Google Scholar 

  217. Vaziri H et al (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107(2):149–159

    CAS  PubMed  Google Scholar 

  218. Cheng Z et al (2008) Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response. Oncogene 27(7):931–941

    CAS  PubMed  Google Scholar 

  219. Sykes SM et al (2006) Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol Cell 24(6):841–851

    CAS  PubMed Central  PubMed  Google Scholar 

  220. Tang Y et al (2006) Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell 24(6):827–839

    CAS  PubMed  Google Scholar 

  221. Moller A et al (2003) PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-mediated p53 phosphorylation and cell cycle arrest but is dispensable for the formation of HIPK domains. Cancer Res 63(15):4310–4314

    PubMed  Google Scholar 

  222. D’Orazi G et al (2002) Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol 4(1):11–19

    PubMed  Google Scholar 

  223. Hofmann TG et al (2002) Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat Cell Biol 4(1):1–10

    CAS  PubMed  Google Scholar 

  224. Louria-Hayon I et al (2003) The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation. J Biol Chem 278(35):33134–33141

    CAS  PubMed  Google Scholar 

  225. Alsheich-Bartok O et al (2008) PML enhances the regulation of p53 by CK1 in response to DNA damage. Oncogene 27(26):3653–3661

    CAS  PubMed  Google Scholar 

  226. Schon O et al (2002) Molecular mechanism of the interaction between MDM2 and p53. J Mol Biol 323(3):491–501

    CAS  PubMed  Google Scholar 

  227. Winter M et al (2004) Protein kinase CK1delta phosphorylates key sites in the acidic domain of murine double-minute clone 2 protein (MDM2) that regulate p53 turnover. Biochemistry 43(51):16356–16364

    CAS  PubMed  Google Scholar 

  228. Yang S et al (2002) PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nat Cell Biol 4(11):865–870

    CAS  PubMed  Google Scholar 

  229. Yang S et al (2006) Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation. J Biol Chem 281(36):26645–26654

    CAS  PubMed  Google Scholar 

  230. Wei X et al (2003) Physical and functional interactions between PML and MDM2. J Biol Chem 278(31):29288–29297

    CAS  PubMed  Google Scholar 

  231. Zhu H, Wu L, Maki CG (2003) MDM2 and promyelocytic leukemia antagonize each other through their direct interaction with p53. J Biol Chem 278(49):49286–49292

    CAS  PubMed  Google Scholar 

  232. Kurki S, Latonen L, Laiho M (2003) Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization. J Cell Sci 116(Pt 19):3917–3925

    CAS  PubMed  Google Scholar 

  233. Bernardi R et al (2004) PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol 6(7):665–672

    CAS  PubMed  Google Scholar 

  234. Culjkovic B et al (2006) eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 175(3):415–426

    CAS  PubMed Central  PubMed  Google Scholar 

  235. Zhu N et al (2005) Transcriptional repression of the eukaryotic initiation factor 4E gene by wild type p53. Biochem Biophys Res Commun 335(4):1272–1279

    CAS  PubMed  Google Scholar 

  236. Gostissa M et al (2004) The transcriptional repressor hDaxx potentiates p53-dependent apoptosis. J Biol Chem 279(46):48013–48023

    CAS  PubMed  Google Scholar 

  237. Li Q et al (2007) Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death. Cancer Res 67(1):66–74

    CAS  PubMed  Google Scholar 

  238. Cummins JM, Vogelstein B (2004) HAUSP is required for p53 destabilization. Cell Cycle 3(6):689–692

    CAS  PubMed  Google Scholar 

  239. Tang J et al (2006) Critical role for Daxx in regulating Mdm2. Nat Cell Biol 8(8):855–862

    CAS  PubMed  Google Scholar 

Download references

Acknowledgment

Due to space limitations many original important studies have not been cited directly but rather through reviews. We are grateful to Mati Goldberg for drawing the illustrations. Work in the authors laboratory is supported by NHMRC project grants (1026990, 1026988, 1049179, 1063389) and NHMRC Fellowship to YH (9628426), by the VESKI award, and by the CASS Foundation.

Author information

Authors and Affiliations

  1. Lautenberg Center, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Yaara Levav-Cohen, Zehavit Goldberg, Osnat Alsheich-Bartok & Valentina Zuckerman

  2. Research Division, The Peter MacCallum Cancer Centre, St. Andrew’s Place, East Melbourne, 3002, VIC, Australia

    Kah Hin Tan, Sue Haupt & Ygal Haupt

Authors
  1. Yaara Levav-Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zehavit Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kah Hin Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Osnat Alsheich-Bartok
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Valentina Zuckerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sue Haupt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ygal Haupt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ygal Haupt .

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Molecular Biology, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Swati Palit Deb

  2. Department of Biochemistry and Molecular Biology, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Sumitra Deb

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Levav-Cohen, Y. et al. (2014). The p53-Mdm2 Loop: A Critical Juncture of Stress Response. In: Deb, S., Deb, S. (eds) Mutant p53 and MDM2 in Cancer. Subcellular Biochemistry, vol 85. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9211-0_9

Download citation

Publish with us

Policies and ethics

Search

Navigation