Ubiquitin-Regulated Cell Proliferation and Cancer

  • Beatriz Pérez-Benavente
  • Alihamze Fathinajafabadi Nasresfahani
  • Rosa FarràsEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1233)


Ubiquitin ligases (E3) play a crucial role in the regulation of different cellular processes such as proliferation and differentiation via recognition, interaction, and ubiquitination of key cellular proteins in a spatial and temporal regulated manner. The type of ubiquitin chain formed determines the fate of the substrates. The ubiquitinated substrates can be degraded by the proteasome, display altered subcellular localization, or can suffer modifications on their interaction with functional protein complexes. Deregulation of E3 activities is frequently found in various human pathologies, including cancer. The illegitimated or accelerated degradation of oncosuppressive proteins or, inversely, the abnormally high accumulation of oncoproteins, contributes to cell proliferation and transformation. Anomalies in protein abundance may be related to mutations that alter the direct or indirect recognition of proteins by the E3 enzymes or alterations in the level of expression or activity of ubiquitin ligases. Through a few examples, we illustrate here the complexity and diversity of the molecular mechanisms related to protein ubiquitination involved in cell cycle regulation. We will discuss the role of ubiquitin-dependent degradation mediated by the proteasome, the role of non-proteolytic ubiquitination during cell cycle progression, and the consequences of this deregulation on cellular transformation. Finally, we will highlight the novel opportunities that arise from these studies for therapeutic intervention.


Ubiquitin Eukaryotic ubiquitin conjugation E3 ligases Ubiquitin-dependent degradation Non-proteolytic ubiquitination Cell cycle Cancer 


  1. 1.
    Weinberg RA (2014) The biology of cancer, 2nd edn. Garland Science, New YorkGoogle Scholar
  2. 2.
    Lodish H, Berk A, Matsudaira P et al (2003) Molecular cell biology, 5th edn. W.H. Freeman, New YorkGoogle Scholar
  3. 3.
    Malumbres M (2014) Cyclin-dependent kinases. Genome Biol 15:122PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Grant GD, Cook JG (2017) The temporal regulation of S phase proteins during G1. Adv Exp Med Biol 1042:335–369PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Morgan DO (2007) The cell cycle: principles of control. New Science Press, LondonGoogle Scholar
  6. 6.
    Bassermann F, Eichner R, Pagano M (2014) The ubiquitin proteasome system—implications for cell cycle control and the targeted treatment of cancer. Biochim Biophys Acta 1843:150–162PubMedCrossRefGoogle Scholar
  7. 7.
    Nakayama KI, Nakayama K (2005) Regulation of the cell cycle by SCF-type ubiquitin ligases. Semin Cell Dev Biol 16:323–333PubMedCrossRefGoogle Scholar
  8. 8.
    Frescas D, Pagano M (2008) Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 8:438–449PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ang XL, Wade Harper J (2005) SCF-mediated protein degradation and cell cycle control. Oncogene 24:2860–2870PubMedCrossRefGoogle Scholar
  10. 10.
    Nakayama KI, Nakayama K (2006) Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6:369–381PubMedCrossRefGoogle Scholar
  11. 11.
    Kernan J, Bonacci T, Emanuele MJ (2018) Who guards the guardian? Mechanisms that restrain APC/C during the cell cycle. Biochim Biophys Acta Mol Cell Res 1865:1924–1933PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Garnett MJ, Mansfeld J, Godwin C et al (2009) UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Nat Cell Biol 11:1363–1369PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Jin L, Williamson A, Banerjee S et al (2008) Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell 133:653–665PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Matsumoto ML, Wickliffe KE, Dong KC et al (2010) K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody. Mol Cell 39:477–484PubMedCrossRefGoogle Scholar
  15. 15.
    Williamson A, Wickliffe KE, Mellone BG et al (2009) Identification of a physiological E2 module for the human anaphase-promoting complex. Proc Natl Acad Sci USA 106:18213–18218PubMedCrossRefGoogle Scholar
  16. 16.
    Wickliffe KE, Lorenz S, Wemmer DE et al (2011) The mechanism of linkage-specific ubiquitin chain elongation by a single-subunit E2. Cell 144:769–781PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Wickliffe KE, Williamson A, Meyer HJ et al (2011) K11-linked ubiquitin chains as novel regulators of cell division. Trends Cell Biol 21:656–663PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Wu T, Merbl Y, Huo Y et al (2010) UBE2S drives elongation of K11-linked ubiquitin chains by the anaphase-promoting complex. Proc Natl Acad Sci USA 107:1355–1360PubMedCrossRefGoogle Scholar
  19. 19.
    Meyer HJ, Rape M (2014) Enhanced protein degradation by branched ubiquitin chains. Cell 157:910–921PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Rape M, Kirschner MW (2004) Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry. Nature 432:588–595PubMedCrossRefGoogle Scholar
  21. 21.
    Summers MK, Pan B, Mukhyala K, Jackson PK (2008) The unique N terminus of the UbcH10 E2 enzyme controls the threshold for APC activation and enhances checkpoint regulation of the APC. Mol Cell 31:544–556PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Borg N, Dixit V (2017) Ubiquitin in cell-cycle regulation and dysregulation in cancer. Annu Rev Cancer Biol 1:59–77CrossRefGoogle Scholar
  23. 23.
    Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387:299–303PubMedCrossRefGoogle Scholar
  24. 24.
    Chen D, Brooks CL, Gu W (2006) ARF-BP1 as a potential therapeutic target. Br J Cancer 94:1555–1558PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Kamura T, Hara T, Matsumoto M et al (2004) Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase. Nat Cell Biol 6:1229–1235PubMedCrossRefGoogle Scholar
  26. 26.
    Carrano AC, Eytan E, Hershko A, Pagano M (1999) SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1:193–199PubMedCrossRefGoogle Scholar
  27. 27.
    Welcker M, Clurman BE (2008) FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer 8:83–93PubMedCrossRefGoogle Scholar
  28. 28.
    Ji P, Jiang H, Rekhtman K et al (2004) An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant. Mol Cell 16:47–58PubMedCrossRefGoogle Scholar
  29. 29.
    Binne UK, Classon MK, Dick FA et al (2007) Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol 9:225–232PubMedCrossRefGoogle Scholar
  30. 30.
    Rabie AB, Zhao Z, Shen G et al (2001) Osteogenesis in the glenoid fossa in response to mandibular advancement. Am J Orthod Dentofac Orthop 119:390–400CrossRefGoogle Scholar
  31. 31.
    Okoro DR, Arva N, Gao C et al (2013) Endogenous human MDM2-C is highly expressed in human cancers and functions as a p53-independent growth activator. PLoS One 8:e77643PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Sdek P, Ying H, Zheng H et al (2004) The central acidic domain of MDM2 is critical in inhibition of retinoblastoma-mediated suppression of E2F and cell growth. J Biol Chem 279:53317–53322PubMedCrossRefGoogle Scholar
  33. 33.
    Uchida C, Miwa S, Kitagawa K et al (2005) Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation. EMBO J 24:160–169PubMedCrossRefGoogle Scholar
  34. 34.
    Sdek P, Ying H, Chang DL et al (2005) MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Mol Cell 20:699–708PubMedCrossRefGoogle Scholar
  35. 35.
    Cardozo T, Pagano M (2004) The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol 5:739–751PubMedCrossRefGoogle Scholar
  36. 36.
    Al-Hakim A, Escribano-Diaz C, Landry MC et al (2010) The ubiquitous role of ubiquitin in the DNA damage response. DNA Repair (Amst) 9:1229–1240CrossRefGoogle Scholar
  37. 37.
    Inuzuka H, Tseng A, Gao D et al (2010) Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. Cancer Cell 18:147–159PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Toledo F, Wahl GM (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6:909–923PubMedCrossRefGoogle Scholar
  39. 39.
    Lavin MF, Gueven N (2006) The complexity of p53 stabilization and activation. Cell Death Differ 13:941–950PubMedCrossRefGoogle Scholar
  40. 40.
    Riley T, Sontag E, Chen P, Levine A (2008) Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9:402–412PubMedCrossRefGoogle Scholar
  41. 41.
    Maya R, Balass M, Kim ST et al (2001) ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15:1067–1077PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Agrawal A, Yang J, Murphy RF, Agrawal DK (2006) Regulation of the p14ARF-Mdm2-p53 pathway: an overview in breast cancer. Exp Mol Pathol 81:115–122PubMedCrossRefGoogle Scholar
  43. 43.
    Mantovani F, Gostissa M, Collavin L, Del Sal G (2004) KeePin’ the p53 family in good shape. Cell Cycle 3:905–911PubMedCrossRefGoogle Scholar
  44. 44.
    Busino L, Donzelli M, Chiesa M et al (2003) Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. Nature 426:87–91PubMedCrossRefGoogle Scholar
  45. 45.
    Donzelli M, Busino L, Chiesa M et al (2004) Hierarchical order of phosphorylation events commits Cdc25A to betaTrCP-dependent degradation. Cell Cycle 3:469–471PubMedCrossRefGoogle Scholar
  46. 46.
    Honaker Y, Piwnica-Worms H (2010) Casein kinase 1 functions as both penultimate and ultimate kinase in regulating Cdc25A destruction. Oncogene 29:3324–3334PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Jin J, Shirogane T, Xu L et al (2003) SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev 17:3062–3074PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Timofeev O, Cizmecioglu O, Hu E et al (2009) Human Cdc25A phosphatase has a non-redundant function in G2 phase by activating cyclin A-dependent kinases. FEBS Lett 583:841–847PubMedCrossRefGoogle Scholar
  49. 49.
    Xiao Z, Chen Z, Gunasekera AH et al (2003) Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J Biol Chem 278:21767–21773PubMedCrossRefGoogle Scholar
  50. 50.
    Mailand N, Bekker-Jensen S, Bartek J, Lukas J (2006) Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress. Mol Cell 23:307–318PubMedCrossRefGoogle Scholar
  51. 51.
    Mamely I, van Vugt MA, Smits VA et al (2006) Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr Biol 16:1950–1955PubMedCrossRefGoogle Scholar
  52. 52.
    Peschiaroli A, Dorrello NV, Guardavaccaro D et al (2006) SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response. Mol Cell 23:319–329PubMedCrossRefGoogle Scholar
  53. 53.
    Watanabe N, Arai H, Nishihara Y et al (2004) M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP. Proc Natl Acad Sci USA 101:4419–4424PubMedCrossRefGoogle Scholar
  54. 54.
    Yamasaki L, Pagano M (2004) Cell cycle, proteolysis and cancer. Curr Opin Cell Biol 16:623–628PubMedCrossRefGoogle Scholar
  55. 55.
    Peters JM (2006) The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7:644–656PubMedCrossRefGoogle Scholar
  56. 56.
    Li Y, Gorbea C, Mahaffey D et al (1997) MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity. Proc Natl Acad Sci USA 94:12431–12436PubMedCrossRefGoogle Scholar
  57. 57.
    Fang G, Yu H, Kirschner MW (1998) The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev 12:1871–1883PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Sudakin V, Chan GK, Yen TJ (2001) Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J Cell Biol 154:925–936PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Tang Z, Bharadwaj R, Li B, Yu H (2001) Mad2-independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev Cell 1:227–237PubMedCrossRefGoogle Scholar
  60. 60.
    Fang G (2002) Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex. Mol Biol Cell 13:755–766PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Bashir T, Dorrello NV, Amador V et al (2004) Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature 428:190–193PubMedCrossRefGoogle Scholar
  62. 62.
    Wei W, Ayad NG, Wan Y et al (2004) Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428:194–198PubMedCrossRefGoogle Scholar
  63. 63.
    Fukushima H, Ogura K, Wan L et al (2013) SCF-mediated Cdh1 degradation defines a negative feedback system that coordinates cell-cycle progression. Cell Rep 4:803–816PubMedCrossRefGoogle Scholar
  64. 64.
    Listovsky T, Oren YS, Yudkovsky Y et al (2004) Mammalian Cdh1/Fzr mediates its own degradation. EMBO J 23:1619–1626PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Hsu JY, Reimann JD, Sorensen CS et al (2002) E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nat Cell Biol 4:358–366PubMedCrossRefGoogle Scholar
  66. 66.
    Lim KH, Song MH, Baek KH (2016) Decision for cell fate: deubiquitinating enzymes in cell cycle checkpoint. Cell Mol Life Sci 73:1439–1455PubMedCrossRefGoogle Scholar
  67. 67.
    Gilberto S, Peter M (2017) Dynamic ubiquitin signaling in cell cycle regulation. J Cell Biol 216:2259–2271PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Senft D, Qi J, Ronai ZA (2018) Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer 18:69–88PubMedCrossRefGoogle Scholar
  69. 69.
    Linares JF, Duran A, Yajima T et al (2013) K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 51:283–296PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Wang B, Jie Z, Joo D et al (2017) TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling. Nature 545:365–369PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Chan CH, Li CF, Yang WL et al (2012) The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 151:913–914PubMedCrossRefGoogle Scholar
  72. 72.
    Xu L, Lubkov V, Taylor LJ, Bar-Sagi D (2010) Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Curr Biol 20:1372–1377PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Sasaki AT, Carracedo A, Locasale JW et al (2011) Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors. Sci Signal 4:ra13PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Orthwein A, Noordermeer SM, Wilson MD et al (2015) A mechanism for the suppression of homologous recombination in G1 cells. Nature 528:422–426PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Brodersen MM, Lampert F, Barnes CA et al (2016) CRL4(WDR23)-mediated SLBP ubiquitylation ensures histone supply during DNA replication. Mol Cell 62:627–635PubMedCrossRefGoogle Scholar
  76. 76.
    Dankert JF, Rona G, Clijsters L et al (2016) Cyclin F-mediated degradation of SLBP limits H2A.X accumulation and apoptosis upon genotoxic stress in G2. Mol Cell 64:507–519PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Zaidi IW, Rabut G, Poveda A et al (2008) Rtt101 and Mms1 in budding yeast form a CUL4(DDB1)-like ubiquitin ligase that promotes replication through damaged DNA. EMBO Rep 9:1034–1040PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Han J, Zhang H, Wang Z et al (2013) A Cul4 E3 ubiquitin ligase regulates histone hand-off during nucleosome assembly. Cell 155:817–829PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Moghe S, Jiang F, Miura Y et al (2012) The CUL3-KLHL18 ligase regulates mitotic entry and ubiquitylates Aurora-A. Biol Open 1:82–91PubMedCrossRefGoogle Scholar
  80. 80.
    Guturi KK, Bohgaki M, Bohgaki T et al (2016) RNF168 and USP10 regulate topoisomerase IIalpha function via opposing effects on its ubiquitylation. Nat Commun 7:12638PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Lou Z, Minter-Dykhouse K, Chen J (2005) BRCA1 participates in DNA decatenation. Nat Struct Mol Biol 12:589–593PubMedCrossRefGoogle Scholar
  82. 82.
    Mattiroli F, Vissers JH, van Dijk WJ et al (2012) RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell 150:1182–1195PubMedCrossRefGoogle Scholar
  83. 83.
    Ruchaud S, Carmena M, Earnshaw WC (2007) Chromosomal passengers: conducting cell division. Nat Rev Mol Cell Biol 8:798–812PubMedCrossRefGoogle Scholar
  84. 84.
    Vong QP, Cao K, Li HY et al (2005) Chromosome alignment and segregation regulated by ubiquitination of survivin. Science 310:1499–1504PubMedCrossRefGoogle Scholar
  85. 85.
    Maerki S, Olma MH, Staubli T et al (2009) The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midzone microtubules in anaphase and is required for cytokinesis. J Cell Biol 187:791–800PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Krupina K, Kleiss C, Metzger T et al (2016) Ubiquitin receptor protein UBASH3B drives Aurora B recruitment to mitotic microtubules. Dev Cell 36:63–78PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Beck J, Maerki S, Posch M et al (2013) Ubiquitylation-dependent localization of PLK1 in mitosis. Nat Cell Biol 15:430–439PubMedCrossRefGoogle Scholar
  88. 88.
    Zhuo X, Guo X, Zhang X et al (2015) Usp16 regulates kinetochore localization of Plk1 to promote proper chromosome alignment in mitosis. J Cell Biol 210:727–735PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Yang Y, Liu M, Li D et al (2014) CYLD regulates spindle orientation by stabilizing astral microtubules and promoting dishevelled-NuMA-dynein/dynactin complex formation. Proc Natl Acad Sci USA 111:2158–2163PubMedCrossRefGoogle Scholar
  90. 90.
    Massoumi R (2011) CYLD: a deubiquitination enzyme with multiple roles in cancer. Future Oncol 7:285–297PubMedCrossRefGoogle Scholar
  91. 91.
    Harhaj EW, Dixit VM (2011) Deubiquitinases in the regulation of NF-kappaB signaling. Cell Res 21:22–39PubMedCrossRefGoogle Scholar
  92. 92.
    Tauriello DV, Haegebarth A, Kuper I et al (2010) Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl. Mol Cell 37:607–619PubMedCrossRefGoogle Scholar
  93. 93.
    Yan K, Li L, Wang X et al (2015) The deubiquitinating enzyme complex BRISC is required for proper mitotic spindle assembly in mammalian cells. J Cell Biol 210:209–224PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Dong Y, Hakimi MA, Chen X et al (2003) Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell 12:1087–1099PubMedCrossRefGoogle Scholar
  95. 95.
    Zhang X, Cai J, Zheng Z et al (2015) A novel ER-microtubule-binding protein, ERLIN2, stabilizes cyclin B1 and regulates cell cycle progression. Cell Discov 1:15024PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Niikura Y, Kitagawa R, Ogi H et al (2015) CENP-A K124 ubiquitylation is required for CENP-A deposition at the centromere. Dev Cell 32:589–603PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Qi J, Ronai ZA (2015) Dysregulation of ubiquitin ligases in cancer. Drug Resist Updat 23:1–11PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Knudsen ES, Knudsen KE (2006) Retinoblastoma tumor suppressor: where cancer meets the cell cycle. Exp Biol Med (Maywood) 231:1271–1281CrossRefGoogle Scholar
  100. 100.
    Dyson N, Howley PM, Munger K, Harlow E (1989) The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937PubMedCrossRefGoogle Scholar
  101. 101.
    Werness BA, Levine AJ, Howley PM (1990) Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248:76–79PubMedCrossRefGoogle Scholar
  102. 102.
    Wise-Draper TM, Wells SI (2008) Papillomavirus E6 and E7 proteins and their cellular targets. Front Biosci 13:1003–1017PubMedCrossRefGoogle Scholar
  103. 103.
    Vousden KH (1994) Interactions between papillomavirus proteins and tumor suppressor gene products. Adv Cancer Res 64:1–24PubMedCrossRefGoogle Scholar
  104. 104.
    Hume AJ, Kalejta RF (2009) Regulation of the retinoblastoma proteins by the human herpesviruses. Cell Div 4:1PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Li H, Zhang J, Zhen C et al (2018) Gankyrin as a potential target for tumor therapy: evidence and perspectives. Am J Transl Res 10:1949–1960PubMedPubMedCentralGoogle Scholar
  106. 106.
    Li J, Tsai MD (2002) Novel insights into the INK4-CDK4/6-Rb pathway: counter action of gankyrin against INK4 proteins regulates the CDK4-mediated phosphorylation of Rb. Biochemistry 41:3977–3983PubMedCrossRefGoogle Scholar
  107. 107.
    Dawson S, Higashitsuji H, Wilkinson AJ et al (2006) Gankyrin: a new oncoprotein and regulator of pRb and p53. Trends Cell Biol 16:229–233PubMedCrossRefGoogle Scholar
  108. 108.
    Higashitsuji H, Itoh K, Nagao T et al (2000) Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med 6:96–99PubMedCrossRefGoogle Scholar
  109. 109.
    Higashitsuji H, Itoh K, Sakurai T et al (2005) The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell 8:75–87PubMedCrossRefGoogle Scholar
  110. 110.
    Wang Z, Inuzuka H, Zhong J et al (2012) DNA damage-induced activation of ATM promotes beta-TRCP-mediated Mdm2 ubiquitination and destruction. Oncotarget 3:1026–1035PubMedPubMedCentralGoogle Scholar
  111. 111.
    Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358:15–16PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Petitjean A, Achatz MI, Borresen-Dale AL et al (2007) TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26:2157–2165PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Michael D, Oren M (2002) The p53 and Mdm2 families in cancer. Curr Opin Genet Dev 12:53–59PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Bond GL, Hu W, Bond EE et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591–602PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Vazquez A, Bond EE, Levine AJ, Bond GL (2008) The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 7:979–987PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Van Maerken T, Vandesompele J, Rihani A et al (2009) Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis. Cell Death Differ 16:1563–1572PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495–505PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Zhang Z, Zhang J, Xia N, Zhao Q (2017) Expanded strain coverage for a highly successful public health tool: prophylactic 9-valent human papillomavirus vaccine. Hum Vaccin Immunother 13:2280–2291PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Ougolkov A, Zhang B, Yamashita K et al (2004) Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer. J Natl Cancer Inst 96:1161–1170PubMedCrossRefGoogle Scholar
  122. 122.
    Koch A, Waha A, Hartmann W et al (2005) Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin Cancer Res 11:4295–4304PubMedCrossRefGoogle Scholar
  123. 123.
    Muerkoster S, Arlt A, Sipos B et al (2005) Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells. Cancer Res 65:1316–1324PubMedCrossRefGoogle Scholar
  124. 124.
    Suzuki H, Chiba T, Suzuki T et al (2000) Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination. J Biol Chem 275:2877–2884PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480PubMedCrossRefGoogle Scholar
  126. 126.
    MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17:9–26PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Beavon IR (2000) The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer 36:1607–1620PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    He TC, Sparks AB, Rago C et al (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512PubMedCrossRefGoogle Scholar
  129. 129.
    Tetsu O, McCormick F (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426PubMedCrossRefGoogle Scholar
  130. 130.
    Polakis P (2002) Casein kinase 1: a Wnt’er of disconnect. Curr Biol 12:R499–R501PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Korinek V, Barker N, Morin PJ et al (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 275:1784–1787PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Rubinfeld B, Albert I, Porfiri E et al (1996) Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science 272:1023–1026PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Li VS, Ng SS, Boersema PJ et al (2012) Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell 149:1245–1256PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Carrano AC, Pagano M (2001) Role of the F-box protein Skp2 in adhesion-dependent cell cycle progression. J Cell Biol 153:1381–1390PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Latres E, Chiarle R, Schulman BA et al (2001) Role of the F-box protein Skp2 in lymphomagenesis. Proc Natl Acad Sci USA 98:2515–2520PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Loda M, Cukor B, Tam SW et al (1997) Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3:231–234PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Grimmler M, Wang Y, Mund T et al (2007) Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell 128:269–280CrossRefGoogle Scholar
  139. 139.
    Chu IM, Hengst L, Slingerland JM (2008) The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8:253–267PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Yokoi S, Yasui K, Saito-Ohara F et al (2002) A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am J Pathol 161:207–216PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Liang J, Slingerland JM (2003) Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2:339–345PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Jonason JH, Gavrilova N, Wu M et al (2007) Regulation of SCF(SKP2) ubiquitin E3 ligase assembly and p27(KIP1) proteolysis by the PTEN pathway and cyclin D1. Cell Cycle 6:951–961PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Wang Y, Penfold S, Tang X et al (1999) Deletion of the Cul1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E. Curr Biol 9:1191–1194PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Welcker M, Orian A, Grim JE et al (2004) A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size. Curr Biol 14:1852–1857PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Bai J, Zhou Y, Chen G et al (2011) Overexpression of Cullin1 is associated with poor prognosis of patients with gastric cancer. Hum Pathol 42:375–383PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Min KW, Kim DH, Do SI et al (2012) Diagnostic and prognostic relevance of Cullin1 expression in invasive ductal carcinoma of the breast. J Clin Pathol 65:896–901PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Zhu CQ, Blackhall FH, Pintilie M et al (2004) Skp2 gene copy number aberrations are common in non-small cell lung carcinoma, and its overexpression in tumors with ras mutation is a poor prognostic marker. Clin Cancer Res 10:1984–1991PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Shim EH, Johnson L, Noh HL et al (2003) Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate. Cancer Res 63:1583–1588PubMedGoogle Scholar
  149. 149.
    Delogu S, Wang C, Cigliano A et al (2015) SKP2 cooperates with N-Ras or AKT to induce liver tumor development in mice. Oncotarget 6:2222–2234PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Zhao H, Bauzon F, Fu H et al (2013) Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors. Cancer Cell 24:645–659PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Lin HK, Chen Z, Wang G et al (2010) Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature 464:374–379PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Sistrunk C, Kim SH, Wang X et al (2013) Skp2 deficiency inhibits chemical skin tumorigenesis independent of p27(Kip1) accumulation. Am J Pathol 182:1854–1864PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Wang H, Bauzon F, Ji P et al (2010) Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice. Nat Genet 42:83–88PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Slotky M, Shapira M, Ben-Izhak O et al (2005) The expression of the ubiquitin ligase subunit Cks1 in human breast cancer. Breast Cancer Res 7:R737–R744PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Shapira M, Ben-Izhak O, Linn S et al (2005) The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer 103:1336–1346PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Yeh CH, Bellon M, Nicot C (2018) FBXW7: a critical tumor suppressor of human cancers. Mol Cancer 17:115PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Davis RJ, Welcker M, Clurman BE (2014) Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities. Cancer Cell 26:455–464PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Rajagopalan H, Jallepalli PV, Rago C et al (2004) Inactivation of hCDC4 can cause chromosomal instability. Nature 428:77–81PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Strohmaier H, Spruck CH, Kaiser P et al (2001) Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413:316–322PubMedCrossRefGoogle Scholar
  160. 160.
    Wang Z, Liu Y, Zhang P et al (2013) FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7. Oncotarget 4:2476–2486PubMedPubMedCentralGoogle Scholar
  161. 161.
    Mu Y, Zou H, Chen B et al (2017) FAM83D knockdown regulates proliferation, migration and invasion of colorectal cancer through inhibiting FBXW7/Notch-1 signalling pathway. Biomed Pharmacother 90:548–554PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Gregory MA, Hann SR (2000) c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt’s lymphoma cells. Mol Cell Biol 20:2423–2435PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Bahram F, von der Lehr N, Cetinkaya C, Larsson LG (2000) c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. Blood 95:2104–2110PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Popov N, Wanzel M, Madiredjo M et al (2007) The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol 9:765–774PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Schulein-Volk C, Wolf E, Zhu J et al (2014) Dual regulation of Fbw7 function and oncogenic transformation by Usp28. Cell Rep 9:1099–1109PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Diefenbacher ME, Popov N, Blake SM et al (2014) The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer. J Clin Invest 124:3407–3418PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Kim SY, Herbst A, Tworkowski KA et al (2003) Skp2 regulates Myc protein stability and activity. Mol Cell 11:1177–1188PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    von der Lehr N, Johansson S, Wu S et al (2003) The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. Mol Cell 11:1189–1200PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    Welcker M, Orian A, Jin J et al (2004) The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA 101:9085–9090PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Kim CM, Koike K, Saito I et al (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320PubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Lee S, Kim W, Ko C, Ryu WS (2016) Hepatitis B virus X protein enhances Myc stability by inhibiting SCF(Skp2) ubiquitin E3 ligase-mediated Myc ubiquitination and contributes to oncogenesis. Oncogene 35:1857–1867PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Weng AP, Ferrando AA, Lee W et al (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306:269–271PubMedCrossRefPubMedCentralGoogle Scholar
  173. 173.
    Nateri AS, Riera-Sans L, Da Costa C, Behrens A (2004) The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science 303:1374–1378PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Wei W, Jin J, Schlisio S et al (2005) The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell 8:25–33PubMedCrossRefPubMedCentralGoogle Scholar
  175. 175.
    Perez-Benavente B, Farras R (2013) Regulation of GSK3beta-FBXW7-JUNB axis. Oncotarget 4:956–957PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Spruck CH, Strohmaier H, Sangfelt O et al (2002) hCDC4 gene mutations in endometrial cancer. Cancer Res 62:4535–4539PubMedGoogle Scholar
  177. 177.
    Ye X, Nalepa G, Welcker M et al (2004) Recognition of phosphodegron motifs in human cyclin E by the SCF(Fbw7) ubiquitin ligase. J Biol Chem 279:50110–50119PubMedCrossRefGoogle Scholar
  178. 178.
    Liu Y, Ren S, Castellanos-Martin A et al (2012) Multiple novel alternative splicing forms of FBXW7alpha have a translational modulatory function and show specific alteration in human cancer. PLoS One 7:e49453PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Fuchs SY, Fried VA, Ronai Z (1998) Stress-activated kinases regulate protein stability. Oncogene 17:1483–1490PubMedCrossRefGoogle Scholar
  180. 180.
    Harley ME, Allan LA, Sanderson HS, Clarke PR (2010) Phosphorylation of Mcl-1 by CDK1-cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO J 29:2407–2420PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Bolesta E, Pfannenstiel LW, Demelash A et al (2012) Inhibition of Mcl-1 promotes senescence in cancer cells: implications for preventing tumor growth and chemotherapy resistance. Mol Cell Biol 32:1879–1892PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Wertz IE, Kusam S, Lam C et al (2011) Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471:110–114PubMedCrossRefGoogle Scholar
  183. 183.
    Wang Q, Moyret-Lalle C, Couzon F et al (2003) Alterations of anaphase-promoting complex genes in human colon cancer cells. Oncogene 22:1486–1490PubMedCrossRefGoogle Scholar
  184. 184.
    Lehman NL, Verschuren EW, Hsu JY et al (2006) Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells. Cell Cycle 5:1569–1573PubMedCrossRefGoogle Scholar
  185. 185.
    Mondal G, Sengupta S, Panda CK et al (2007) Overexpression of Cdc20 leads to impairment of the spindle assembly checkpoint and aneuploidization in oral cancer. Carcinogenesis 28:81–92PubMedCrossRefGoogle Scholar
  186. 186.
    Okamoto Y, Ozaki T, Miyazaki K et al (2003) UbcH10 is the cancer-related E2 ubiquitin-conjugating enzyme. Cancer Res 63:4167–4173PubMedGoogle Scholar
  187. 187.
    Pallante P, Berlingieri MT, Troncone G et al (2005) UbcH10 overexpression may represent a marker of anaplastic thyroid carcinomas. Br J Cancer 93:464–471PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Berlingieri MT, Pallante P, Sboner A et al (2007) UbcH10 is overexpressed in malignant breast carcinomas. Eur J Cancer 43:2729–2735PubMedCrossRefGoogle Scholar
  189. 189.
    Jiang L, Huang CG, Lu YC et al (2008) Expression of ubiquitin-conjugating enzyme E2C/UbcH10 in astrocytic tumors. Brain Res 1201:161–166PubMedCrossRefGoogle Scholar
  190. 190.
    van Ree JH, Jeganathan KB, Malureanu L, van Deursen JM (2010) Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation. J Cell Biol 188:83–100PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Chen S, Chen Y, Hu C et al (2010) Association of clinicopathological features with UbcH10 expression in colorectal cancer. J Cancer Res Clin Oncol 136:419–426PubMedCrossRefGoogle Scholar
  192. 192.
    Chen SM, Jiang CY, Wu JY et al (2010) RNA interference-mediated silencing of UBCH10 gene inhibits colorectal cancer cell growth in vitro and in vivo. Clin Exp Pharmacol Physiol 37:525–529PubMedCrossRefGoogle Scholar
  193. 193.
    Li SZ, Song Y, Zhang HH et al (2014) UbcH10 overexpression increases carcinogenesis and blocks ALLN susceptibility in colorectal cancer. Sci Rep 4:6910PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Richardson PG, Barlogie B, Berenson J et al (2006) Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial. Cancer 106:1316–1319PubMedCrossRefGoogle Scholar
  195. 195.
    Chauhan D, Hideshima T, Mitsiades C et al (2005) Proteasome inhibitor therapy in multiple myeloma. Mol Cancer Ther 4:686–692PubMedCrossRefGoogle Scholar
  196. 196.
    Hideshima T, Mitsiades C, Akiyama M et al (2003) Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101:1530–1534PubMedCrossRefGoogle Scholar
  197. 197.
    Demo SD, Kirk CJ, Aujay MA et al (2007) Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67:6383–6391PubMedCrossRefGoogle Scholar
  198. 198.
    Kortuem KM, Stewart AK (2013) Carfilzomib. Blood 121:893–897PubMedCrossRefGoogle Scholar
  199. 199.
    Shrikhande GV, Scali ST, da Silva CG et al (2010) O-glycosylation regulates ubiquitination and degradation of the anti-inflammatory protein A20 to accelerate atherosclerosis in diabetic ApoE-null mice. PLoS One 5:e14240PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Scortegagna M, Kim H, Li JL et al (2014) Fine tuning of the UPR by the ubiquitin ligases Siah1/2. PLoS Genet 10:e1004348PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Tsunematsu R, Nakayama K, Oike Y et al (2004) Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. J Biol Chem 279:9417–9423PubMedCrossRefGoogle Scholar
  202. 202.
    Shakya R, Reid LJ, Reczek CR et al (2011) BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334:525–528PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Antoniou A, Pharoah PD, Narod S et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117–1130PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Zhang Y, Bai Y, Guan J, Chen L (2012) The MDM2 309 T/G polymorphism is associated with head and neck cancer risk especially in nasopharyngeal cancer: a meta-analysis. Onkologie 35:666–670PubMedCrossRefGoogle Scholar
  205. 205.
    Jeon YJ, Khelifa S, Ratnikov B et al (2015) Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. Cancer Cell 27:354–369PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Goldberg Z, Vogt Sionov R, Berger M et al (2002) Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. EMBO J 21:3715–3727PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Durcan TM, Fon EA (2015) The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes Dev 29:989–999PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Yang Y, Ludwig RL, Jensen JP et al (2005) Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7:547–559PubMedCrossRefGoogle Scholar
  209. 209.
    Vassilev LT (2004) Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 3:419–421PubMedCrossRefGoogle Scholar
  210. 210.
    Issaeva N, Bozko P, Enge M et al (2004) Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10:1321–1328PubMedCrossRefGoogle Scholar
  211. 211.
    Leverson JD, Zhang H, Chen J et al (2015) Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis 6:e1590PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Xiang W, Yang CY, Bai L (2018) MCL-1 inhibition in cancer treatment. Onco Targets Ther 11:7301–7314PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Sakamoto KM, Kim KB, Kumagai A et al (2001) Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA 98:8554–8559PubMedCrossRefPubMedCentralGoogle Scholar
  214. 214.
    Lai AC, Crews CM (2017) Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov 16:101–114PubMedCrossRefGoogle Scholar
  215. 215.
    Guedat P, Colland F (2007) Patented small molecule inhibitors in the ubiquitin proteasome system. BMC Biochem 8(Suppl 1):S14PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Kategaya L, Di Lello P, Rouge L et al (2017) USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature 550:534–538PubMedCrossRefPubMedCentralGoogle Scholar
  217. 217.
    Turnbull AP, Ioannidis S, Krajewski WW et al (2017) Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature 550:481–486PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Lill JR, Wertz IE (2014) Toward understanding ubiquitin-modifying enzymes: from pharmacological targeting to proteomics. Trends Pharmacol Sci 35:187–207PubMedCrossRefGoogle Scholar
  219. 219.
    Nalepa G, Rolfe M, Harper JW (2006) Drug discovery in the ubiquitin-proteasome system. Nat Rev Drug Discov 5:596–613PubMedCrossRefGoogle Scholar
  220. 220.
    Hoeller D, Dikic I (2009) Targeting the ubiquitin system in cancer therapy. Nature 458:438–444PubMedCrossRefGoogle Scholar
  221. 221.
    Huang X, Dixit VM (2016) Drugging the undruggables: exploring the ubiquitin system for drug development. Cell Res 26:484–498PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Beatriz Pérez-Benavente
    • 1
  • Alihamze Fathinajafabadi Nasresfahani
    • 1
  • Rosa Farràs
    • 1
    Email author
  1. 1.Oncogenic Signaling LaboratoryCentro de Investigación Príncipe FelipeValenciaSpain

Personalised recommendations