Skip to main content
SpringerLink
Log in

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

  • Chapter
p53

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

  • 1441 Accesses

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 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 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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Zuckerman V, Wolyniec K, Sionov RV et al. Tumor suppression by p53: the importance of apoptosis and cellular senescence. J Pathol 2009; 219(1):3–15.

    PubMed  CAS  Google Scholar 

  2. Sionov RV, Haupt Y. The cellular response to p53: the decision between life and death. Oncogene 1999; 18(45):6145–6157.

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  7. Barak Y, Juven T, Haffner R, Oren M. mdm2 expression is induced by wild type p53 activity. EMBO J 1993; 12(2):461–468.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  14. Haupt Y. p53 Regulation: a family affair. Cell Cycle 2004; 3(7):884–885.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  19. 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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  22. 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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  24. Jones SN, Roe AE, Donehower LA, Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 1995; 378(6553):206–208.

    PubMed  CAS  Google Scholar 

  25. Léveillard T, Gorry P, Niederreither K, Wasylyk B. MDM2 expression during mouse embryogenesis and the requirement of p53. Mech Dev 1998; 74(1–2):189–193.

    PubMed  Google Scholar 

  26. 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; 29(1):92–95.

    PubMed  CAS  Google Scholar 

  27. 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 

  28. Migliorini D, Lazzerini Denchi E 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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  32. Marine JC, Dyer MA, Jochemsen AG. MDMX: from bench to bedside. J Cell Sci 2007; 120(Pt 3):371–378.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  34. 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.

    PubMed  CAS  Google Scholar 

  35. 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.

    PubMed  CAS  Google Scholar 

  36. Ringshausen I, O’Shea CC, Finch AJ et al. Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 2006; 10(6):501–514.

    PubMed  CAS  Google Scholar 

  37. Leng RP, Lin Y, Ma W et al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 2003; 112(6):779–791.

    PubMed  CAS  Google Scholar 

  38. Dornan D, Wertz I, Shimizu H et al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 2004; 429(6987):86–92.

    PubMed  CAS  Google Scholar 

  39. Chen D, Kon N, Li M et al. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 2005; 121(7):1071–1083.

    PubMed  CAS  Google Scholar 

  40. 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.

    PubMed  CAS  Google Scholar 

  41. 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 USA 2000; 97(23):12547–52.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  43. Jin Y, Zeng SX, Lee H, Lu H. MDM2 mediates p300/CREB-binding protein-associated factor ubiquitination and degradation. J Biol Chem 2004; 279(19):20035–43.

    PubMed  CAS  Google Scholar 

  44. 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.

    PubMed  CAS  Google Scholar 

  45. Wang C, Ivanov A, Chen L et al. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J 2005; 24(18):3279–3290.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  48. Lai Z, Ferry KV, Diamond MA et al. Human mdm2 mediates multiple mono-ubiquitination of p53 by a mechanism requiring enzyme isomerization. J Biol Chem 2001; 276(33):31357–67.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  51. Joseph TW, Zaika A, Moll UM. 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 2003; 17(12):1622–1630.

    PubMed  CAS  Google Scholar 

  52. Marchenko ND, Wolff S, Erster S et al. Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J 2007; 26(4):923–934.

    PubMed  CAS  Google Scholar 

  53. Lohrum MA, Woods DB, Ludwig RL et al. C-terminal ubiquitination of p53 contributes to nuclear export. Mol Cell Biol 2001; 21(24):8521–8532.

    PubMed  CAS  Google Scholar 

  54. Feng L, Lin T, Uranishi H, Gu W, Xu Y. Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol Cell Biol 2005; 25(13):5389–5395.

    PubMed  CAS  Google Scholar 

  55. Krummel KA, Lee CJ, Toledo F, Wahl GM. 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 USA 2005; 102(29):10188–93.

    PubMed  CAS  Google Scholar 

  56. 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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  58. Inoue T, Geyer RK, Howard D et al. MDM2 can promote the ubiquitination, nuclear export, and degradation of p53 in the absence of direct binding. J Biol Chem 2001; 276(48):45255–60.

    PubMed  CAS  Google Scholar 

  59. Yap DB, Hsieh JK, Lu X. Mdm2 inhibits the apoptotic function of p53 mainly by targeting it for degradation. J Biol Chem 2000; 275(47):37296–302.

    PubMed  CAS  Google Scholar 

  60. Unger T, Juven-Gershon T, Moallem E et al. Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. EMBO J 1999; 18(7):1805–1814.

    PubMed  CAS  Google Scholar 

  61. 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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  63. Wade M, Wang YV, Wahl GM. The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 2010; [Epub ahead of print].

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  65. Appella E, Anderson CW. Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 2001; 268(10):2764–2772.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  68. Olsson A, Manzl C, Strasser A, Villunger A. How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumor suppression? Cell Death Differ 2007; 14(9):1561–1575.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  70. Sakaguchi K, Saito S, Higashimoto Y et al. 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 2000; 275(13):9278–9283.

    PubMed  CAS  Google Scholar 

  71. Banin S, Moyal L, Shieh S et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 1998; 281(5383):1674–1677.

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  73. Khanna KK, Keating KE, Kozlov S et al. ATM associates with and phosphorylates p53: mapping the region of interaction. Nat Genet 1998; 20(4):398–400.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  75. Berger M, Stahl N, Del Sal G, Haupt Y. Mutations in proline 82 of p53 impair its activation by Pin1 and Chk2 in response to DNA damage. Mol Cell Biol 2005; 25(13):5380–5388.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  78. 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.

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  81. Feng H, Jenkins LM, Durell SR et al. Structural basis for p300 Taz2-p53 TAD1 binding and modulation by phosphorylation. Structure 2009; 17(2):202–210.

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  83. Lambert PF, Kashanchi F, Radonovich MF et al. Phosphorylation of p53 serine 15 increases interaction with CBP. J Biol Chem 1998; 273(49):33048–53.

    PubMed  CAS  Google Scholar 

  84. Lee CW, Arai M, Martinez-Yamout MA et al. Mapping the interactions of the p53 transactivation domain with the KIX domain of CBP. Biochemistry 2009; 48(10):2115–2124.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  86. Sakaguchi K, Herrera JE, Saito S et al. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev 1998; 12(18):2831–2841.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  88. Wu Z, Earle J, Saito S et al. Mutation of mouse p53 Ser23 and the response to DNA damage. Mol Cell Biol 2002; 22(8):2441–2449.

    PubMed  CAS  Google Scholar 

  89. Takai H, Naka K, Okada Y et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J 2002; 21(19):5195–5205.

    PubMed  CAS  Google Scholar 

  90. Vousden KH, Prives C. Blinded by the Light: The Growing Complexity of p53. Cell 2009; 137(3):413–431.

    PubMed  CAS  Google Scholar 

  91. Falck J, Lukas C, Protopopova M et al. Functional impact of concomitant versus alternative defects in the Chk2-p53 tumor suppressor pathway. Oncogene 2001; 20(39):5503–5510.

    PubMed  CAS  Google Scholar 

  92. Chao C, Hergenhahn M, Kaeser MD et al. Cell type-and promoter-specific roles of Ser18 phosphorylation in regulating p53 responses. J Biol Chem 2003; 278(42):41028–33.

    PubMed  CAS  Google Scholar 

  93. Sluss HK, Armata H, Gallant J, Jones SN. Phosphorylation of serine 18 regulates distinct p53 functions in mice. Mol Cell Biol 2004; 24(3):976–984.

    PubMed  CAS  Google Scholar 

  94. Chao C, Herr D, Chun J, Xu Y. Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression. EMBO J 2006; 25(11):2615–2622.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  96. Blattner C, Hay T, Meek DW, Lane DP. Hypophosphorylation of Mdm2 augments p53 stability. Mol Cell Biol 2002; 22(17):6170–6182.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  98. Meek DW, Hupp TR. The regulation of MDM2 by multisite phosphorylation-Opportunities for molecular-based intervention to target tumors? Semin Cancer Biol 2009; [Epub ahead of print].

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  102. Levav-Cohen Y, Goldberg Z, Zuckerman V et al. C-Abl as a modulator of p53. Biochem Biophys Res Commun 2005; 331(3):737–749.

    PubMed  CAS  Google Scholar 

  103. Goldberg Z, Vogt Sionov R, Berger M et al. Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. EMBO J 2002; 21(14):3715–3727.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  105. Khosravi R, Maya R, Gottlieb T et al. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci USA 1999; 96(26):14973–7.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  107. Kharbanda S, Yuan ZM, Weichselbaum R, Kufe D. Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene 1998; 17(25):3309–3318.

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  109. Cheng Q, Chen L, Li Z et al. ATM activates p53 by regulating MDM2 oligomerization and E3 processivity. EMBO J 2009; 28(24):3857–3867.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  111. 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(20):11598–603.

    PubMed  CAS  Google Scholar 

  112. Mayo LD, Dixon JE, Durden DL et al. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem 2002; 277(7):5484–5489.

    PubMed  CAS  Google Scholar 

  113. Ogawara Y, Kishishita S, Obata T et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 2002; 277(24):21843–50.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  115. 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):35510–7.

    PubMed  CAS  Google Scholar 

  116. Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA 2001; 98(20):10983–5.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  119. Oren M, Damalas A, Gottlieb T et al. Regulation of p53: intricate loops and delicate balances. Ann NY Acad Sci 2002; 973:374–383.

    PubMed  CAS  Google Scholar 

  120. Okamoto K, Li H, Jensen MR et al. Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell 2002; 9(4):761–771.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  122. Wu X, Senechal K, Neshat MS et al. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA 1998; 95(26):15587–91.

    PubMed  CAS  Google Scholar 

  123. Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci 2002; 27(9):462–467.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  125. Freeman DJ, Li AG, Wei G et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and-independent mechanisms. Cancer Cell 2003; 3(2):117–130.

    PubMed  CAS  Google Scholar 

  126. Stambolic V, MacPherson D, Sas D et al. Regulation of PTEN transcription by p53. Mol Cell 2001; 8(2):317–325.

    PubMed  CAS  Google Scholar 

  127. Puc J, Keniry M, Li HS et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 2005; 7(2):193–204.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  129. Walker KK, Levine AJ. Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc Natl Acad Sci USA 1996; 93(26):15335–40.

    PubMed  CAS  Google Scholar 

  130. Sakamuro D, Sabbatini P, White E, Prendergast GC. The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 1997; 15(8):887–898.

    PubMed  CAS  Google Scholar 

  131. Venot C, Maratrat M, Dureuil C et al. 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 1998; 17(16):4668–4679.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  134. Baptiste N, Friedlander P, Chen X, Prives C. The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells. Oncogene 2002; 21(1):9–21.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  137. Zacchi P, Gostissa M, Uchida T et al. The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 2002; 419(6909):853–857.

    PubMed  CAS  Google Scholar 

  138. Zheng H, You H, Zhou XZ et al. The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 2002; 419(6909):849–853.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  140. Seo YR, Kelley MR, Smith ML. Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. Proc Natl Acad Sci USA 2002; 99(22):14548–53.

    PubMed  CAS  Google Scholar 

  141. Böttger A, Böttger 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.

    PubMed  Google Scholar 

  142. Buschmann T, Lin Y, Aithmitti N et al. Stabilization and activation of p53 by the coactivator protein TAFII31. J Biol Chem 2001; 276(17):13852–7.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  147. Llanos S, Clark PA, Rowe J, Peters G. Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus. Nat Cell Biol 2001; 3(5):445–452.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  150. Cell 2000; 103(2):321 et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 2000; 103(2):321–30.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  152. Kamijo T, Zindy F, Roussel MF et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 1997; 91(5):649–659.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  155. Christophorou MA, Ringshausen I, Finch AJ et al. The pathological response to DNA damage does not contribute to p53-mediated tumor suppression. Nature 2006; 443(7108):214–217.

    PubMed  CAS  Google Scholar 

  156. Efeyan A, Garcia-Cao I, Herranz D et al. Tumor biology: Policing of oncogene activity by p53. Nature 2006; 443(7108):159.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  158. Jimenez GS, Khan SH, Stommel JM, Wahl GM. p53 regulation by post-translational modification and nuclear retention in response to diverse stresses. Oncogene 1999; 18(53):7656–7665.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  162. Mihara M, Erster S, Zaika A et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell 2003; 11(3):577–590.

    PubMed  CAS  Google Scholar 

  163. Chipuk JE, Kuwana T, Bouchier-Hayes L et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004; 303(5660):1010–1014.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  165. Leu JI, Dumont P, Hafey M et al. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 2004; 6(5):443–450.

    PubMed  CAS  Google Scholar 

  166. Chipuk JE, Bouchier-Hayes L, Kuwana T et al. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science 2005; 309(5741):1732–1735.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  168. Ferbeyre G, de Stanchina E, Querido E et al. PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 2000; 14(16):2015–2027.

    PubMed  CAS  Google Scholar 

  169. Fogal V, Gostissa M, Sandy P et al. Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J 2000; 19(22):6185–6195.

    PubMed  CAS  Google Scholar 

  170. Carbone R, Pearson M, Minucci S, Pelicci PG. PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage. Oncogene 2002; 21(11):1633–1640.

    PubMed  CAS  Google Scholar 

  171. Pearson M, Carbone R, Sebastiani C et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000; 406(6792):207–210.

    PubMed  CAS  Google Scholar 

  172. Guo A, Salomoni P, Luo J et al. The function of PML in p53-dependent apoptosis. Nat Cell Biol 2000; 2(10):730–736.

    PubMed  CAS  Google Scholar 

  173. de Stanchina E, Querido E, Narita M et al. PML is a direct p53 target that modulates p53 effector functions. Mol Cell 2004; 13(4):523–535.

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  175. Vaziri H, Dessain SK, Ng Eaton E et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2001; 107(2):149–159.

    PubMed  CAS  Google Scholar 

  176. Cheng Z, Ke Y, Ding X et al. Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response. Oncogene 2008; 27(7):931–941.

    PubMed  CAS  Google Scholar 

  177. Sykes SM, Mellert HS, Holbert MA et al. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol Cell 2006; 24(6):841–851.

    PubMed  CAS  Google Scholar 

  178. Tang Y, Luo J, Zhang W, Gu W et al. Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell 2006; 24(6):827–839.

    PubMed  CAS  Google Scholar 

  179. Möller A, Sirma H, Hofmann TG et al. 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 2003; 63(15):4310–4314.

    PubMed  Google Scholar 

  180. D’Orazi G, Cecchinelli B, Bruno T et al. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol 2002; 4(1):11–19.

    PubMed  Google Scholar 

  181. Hofmann TG, Möller A, Sirma H et al. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat Cell Biol 2002; 4(1):1–10.

    PubMed  CAS  Google Scholar 

  182. Louria-Hayon I, Grossman T, Sionov RV et al. The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation. J Biol Chem 2003; 278(35):33134–41.

    PubMed  CAS  Google Scholar 

  183. Alsheich-Bartok O, Haupt S, Alkalay-Snir I et al. PML enhances the regulation of p53 by CK1 in response to DNA damage. Oncogene 2008; 27(26):3653–3661.

    PubMed  CAS  Google Scholar 

  184. Schon O, Friedler A, Bycroft M et al. Molecular mechanism of the interaction between MDM2 and p53. J Mol Biol 2002; 323(3):491–501.

    PubMed  CAS  Google Scholar 

  185. Winter M, Milne D, Dias S 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(51):16356–64.

    PubMed  CAS  Google Scholar 

  186. Yang S, Kuo C, Bisi JE, Kim MK. PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nat Cell Biol 2002; 4(11):865–870.

    PubMed  CAS  Google Scholar 

  187. Yang S, Jeong JH, Brown AL et al. Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation. J Biol Chem 2006; 281(36):26645–54.

    PubMed  CAS  Google Scholar 

  188. Wei X, Yu ZK, Ramalingam A et al. Physical and functional interactions between PML and MDM2. J Biol Chem 2003; 278(31):29288–97.

    PubMed  CAS  Google Scholar 

  189. Zhu H, Wu L, Maki CG. MDM2 and promyelocytic leukemia antagonize each other through their direct interaction with p53. J Biol Chem 2003; 278(49):49286–92.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  191. Bernardi R, Scaglioni PP, Bergmann S et al. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol 2004; 6(7):665–672.

    PubMed  CAS  Google Scholar 

  192. Culjkovic B, Topisirovic I, Skrabanek L et al. eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 2006; 175(3):415–426.

    PubMed  CAS  Google Scholar 

  193. Zhu N, Gu L, Findley HW, Zhou M. Transcriptional repression of the eukaryotic initiation factor 4E gene by wild type p53. Biochem Biophys Res Commun 2005; 335(4):1272–1279.

    PubMed  CAS  Google Scholar 

  194. Gostissa M, Morelli M, Mantovani F et al. The transcriptional repressor hDaxx potentiates p53-dependent apoptosis. J Biol Chem 2004; 279(46):48013–23.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  197. Tang J, Qu LK, Zhang J et al. Critical role for Daxx in regulating Mdm2. Nat Cell Biol 2006; 8(8):855–862.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    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. Osnat Alsheich-Bartok
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valentina Zuckerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sue Haupt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ygal Haupt
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Landes Bioscience and Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Levav-Cohen, Y., Goldberg, Z., Alsheich-Bartok, O., Zuckerman, V., Haupt, S., Haupt, Y. (2010). The p53-Mdm2 Loop: A Critical Juncture of Stress Response. In: p53. Molecular Biology Intelligence Unit, vol 1. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8231-5_5

Download citation

Publish with us

Policies and ethics

Search

Navigation