Skip to main content

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

  • Review Article
  • Published:

Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death

Key Points

  • The ubiquitin system regulates key components in apoptotic signalling cascades and thus maintains proper homeostasis of multicellular organisms.

  • Ubiquitin ligases (E3s) are the enzymes that specify which substrates are ubiquitylated, whereas deubiquitinases (DUBs) remove ubiquitin moieties. Improper regulation of either E3s or DUBs may result in improper execution of apoptosis and thereby contribute to various diseases.

  • By promoting ubiquitylation and proteasomal degradation of caspases and second mitochondrial activator of caspases (SMAC), X chromosome-linked IAP (XIAP) and cellular inhibitor of apoptosis (c-IAP) proteins can inhibit apoptosis initiated by extrinsic or intrinsic stimuli. In addition, through the regulation of nuclear factor-κB (NF-κB) and tumour necrosis factor-α (TNFα)-stimulated signalling pathways, the E3 ligase activity of c-IAP proteins can determine cell fate in various tissues and cellular settings.

  • Ubiquitylation and deubiquitylation of receptor-interacting protein 1 (RIP1) critically regulates the switch from anti-apoptotic to pro-apoptotic outcome by allowing the formation of kinase-activating signalling complexes or activation of caspases.

  • Pharmacologic inhibitors of ubiquitin ligases and DUBs that promote therapeutic benefit by modulating critical regulators of apoptosis are in pre-clinical development or in clinical trials. The best examples are IAP antagonists, inhibitors of ubiquitin-specific protease 7 (USP7) deubiquitinase activity and compounds that block the p53–MDM2 interaction.

Abstract

The proper regulation of apoptosis is essential for the survival of multicellular organisms. Furthermore, excessive apoptosis can contribute to neurodegenerative diseases, anaemia and graft rejection, and diminished apoptosis can lead to autoimmune diseases and cancer. It has become clear that the post-translational modification of apoptotic proteins by ubiquitylation regulates key components in cell death signalling cascades. For example, ubiquitin E3 ligases, such as MDM2 (which ubiquitylates p53) and inhibitor of apoptosis (IAP) proteins, and deubiquitinases, such as A20 and ubiquitin-specific protease 9X (USP9X) (which regulate the ubiquitylation and degradation of receptor-interacting protein 1 (RIP1) and myeloid leukaemia cell differentiation 1 (MCL1), respectively), have important roles in apoptosis. Therapeutic agents that target apoptotic regulatory proteins, including those that are part of the ubiquitin–proteasome system, might afford clinical benefits.

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

Access options

Buy this article

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

Figure 1: The enzymes and reactions of the UPS.
Figure 2: The intrinsic and extrinsic apoptotic pathways.
Figure 3: Canonical and noncanonical NF-κB signalling pathways.

Similar content being viewed by others

References

  1. Deshaies, R. J. & Joazeiro, C. A. RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78, 399–434 (2009).

    CAS  PubMed  Google Scholar 

  2. Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503–533 (2001).

    CAS  PubMed  Google Scholar 

  3. Deshaies, R. J. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu. Rev. Cell Dev. Biol. 15, 435–467 (1999).

    CAS  PubMed  Google Scholar 

  4. Ikeda, F. & Dikic, I. Atypical ubiquitin chains: new molecular signals. 'Protein modifications: beyond the usual suspects' review series. EMBO Rep. 9, 536–542 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Eddins, M. J., Carlile, C. M., Gomez, K. M., Pickart, C. M. & Wolberger, C. Mms2–Ubc13 covalently bound to ubiquitin reveals the structural basis of linkage-specific polyubiquitin chain formation. Nature Struct. Mol. Biol. 13, 915–920 (2006).

    CAS  Google Scholar 

  6. Rodrigo-Brenni, M. C., Foster, S. A. & Morgan, D. O. Catalysis of lysine 48-specific ubiquitin chain assembly by residues in E2 and ubiquitin. Mol. Cell 39, 548–559 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Wickliffe, K. E., Lorenz, S., Wemmer, D. E., Kuriyan, J. & Rape, M. The mechanism of linkage-specific ubiquitin chain elongation by a single-subunit E2. Cell 144, 769–781 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kirkin, V. & Dikic, I. Role of ubiquitin- and Ubl-binding proteins in cell signaling. Curr. Opin. Cell Biol. 19, 199–205 (2007).

    CAS  PubMed  Google Scholar 

  9. Finley, D., Ciechanover, A. & Varshavsky, A. Ubiquitin as a central cellular regulator. Cell 116, S29–S32 (2004).

    CAS  PubMed  Google Scholar 

  10. Salvesen, G. S. & Abrams, J. M. Caspase activation — stepping on the gas or releasing the brakes? Lessons from humans and flies. Oncogene 23, 2774–2784 (2004).

    CAS  PubMed  Google Scholar 

  11. Kaufmann, S. H. & Vaux, D. L. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 22, 7414–7430 (2003).

    CAS  PubMed  Google Scholar 

  12. Youle, R. J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nature Rev. Mol. Cell Biol. 9, 47–59 (2008).

    CAS  Google Scholar 

  13. Du, C., Fang, M., Li, Y., Li, L. & Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33–42 (2000).

    CAS  PubMed  Google Scholar 

  14. Liu, X., Kim, C. N., Yang, J., Jemmerson, R. & Wang, X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86, 147–157 (1996).

    CAS  PubMed  Google Scholar 

  15. Verhagen, A. M. et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43–53 (2000).

    CAS  PubMed  Google Scholar 

  16. Riedl, S. J. & Salvesen, G. S. The apoptosome: signalling platform of cell death. Nature Rev. Mol. Cell Biol. 8, 405–413 (2007).

    CAS  Google Scholar 

  17. Ashkenazi, A. & Dixit, V. M. Death receptors: signaling and modulation. Science 281, 1305–1308 (1998).

    CAS  PubMed  Google Scholar 

  18. Guicciardi, M. E. & Gores, G. J. Life and death by death receptors. FASEB J. 23, 1625–1637 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Strasser, A., Jost, P. J. & Nagata, S. The many roles of FAS receptor signaling in the immune system. Immunity 30, 180–192 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Tschopp, J., Irmler, M. & Thome, M. Inhibition of Fas death signals by FLIPs. Curr. Opin. Immunol. 10, 552–558 (1998).

    CAS  PubMed  Google Scholar 

  21. Salvesen, G. S. & Duckett, C. S. IAP proteins: blocking the road to death's door. Nature Rev. Mol. Cell Biol. 3, 401–410 (2002).

    CAS  Google Scholar 

  22. Vucic, D. et al. Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP. Biochem. J. 385, 11–20 (2005).

    CAS  PubMed  Google Scholar 

  23. Vousden, K. H. & Prives, C. Blinded by the light: the growing complexity of p53. Cell 137, 413–431 (2009).

    CAS  PubMed  Google Scholar 

  24. Huang, J., Plass, C. & Gerhäuser, C. Cancer chemoprevention by targeting the epigenome. Curr. Drug Targets. 15 Dec 2010 [epub ahead of print].

  25. Declercq, W., Vanden Berghe, T. & Vandenabeele, P. RIP kinases at the crossroads of cell death and survival. Cell 138, 229–232 (2009).

    CAS  PubMed  Google Scholar 

  26. Wertz, I. E. & Dixit, V. M. Regulation of death receptor signaling by the ubiquitin system. Cell Death Differ. 17, 14–24 (2010).

    CAS  PubMed  Google Scholar 

  27. Zhang, H. G., Wang, J., Yang, X., Hsu, H. C. & Mountz, J. D. Regulation of apoptosis proteins in cancer cells by ubiquitin. Oncogene 23, 2009–2015 (2004).

    CAS  PubMed  Google Scholar 

  28. Steller, H. Regulation of apoptosis in Drosophila. Cell Death Differ. 15, 1132–1138 (2008).

    CAS  PubMed  Google Scholar 

  29. Sandu, C., Ryoo, H. D. & Steller, H. Drosophila IAP antagonists form multimeric complexes to promote cell death. J. Cell Biol. 190, 1039–1052 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Koto, A., Kuranaga, E. & Miura, M. Temporal regulation of Drosophila IAP1 determines caspase functions in sensory organ development. J. Cell Biol. 187, 219–231 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Broemer, M. et al. Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases. Mol. Cell 40, 810–822 (2010).

    CAS  PubMed  Google Scholar 

  32. Ditzel, M. et al. Inactivation of effector caspases through nondegradative polyubiquitylation. Mol. Cell 32, 540–553 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bader, M., Arama, E. & Steller, H. A novel F-box protein is required for caspase activation during cellular remodeling in Drosophila. Development 137, 1679–1688 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Eckelman, B. P., Salvesen, G. S. & Scott, F. L. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 7, 988–994 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Suzuki, Y., Nakabayashi, Y. & Takahashi, R. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc. Natl Acad. Sci. USA 98, 8662–8667 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Schile, A. J., Garcia-Fernandez, M. & Steller, H. Regulation of apoptosis by XIAP ubiquitin-ligase activity. Genes Dev. 22, 2256–2266 (2008). Demonstrates the importance of XIAP ubiquitin ligase activity for the regulation of apoptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Choi, Y. E. et al. The E3 ubiquitin ligase c-IAP1 binds and ubiquitinates caspase-3 and -7 via unique mechanisms at distinct steps in their processing. J. Biol. Chem. 284, 12772–12782 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Hu, S. & Yang, X. Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO. J. Biol. Chem. 278, 10055–10060 (2003).

    CAS  PubMed  Google Scholar 

  39. MacFarlane, M., Merrison, W., Bratton, S. B. & Cohen, G. M. Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro. J. Biol. Chem. 277, 36611–36616 (2002).

    CAS  PubMed  Google Scholar 

  40. Conze, D. B. et al. Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo. Mol. Cell. Biol. 25, 3348–3356 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Silke, J. et al. Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance. Proc. Natl Acad. Sci. USA 102, 16182–16187 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Dogan, T. et al. X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility. Nature Cell Biol. 10, 1447–1455 (2008).

    CAS  PubMed  Google Scholar 

  43. Xu, L. et al. c-IAP1 cooperates with Myc by acting as a ubiquitin ligase for Mad1. Mol. Cell 28, 914–922 (2007).

    CAS  PubMed  Google Scholar 

  44. Li, X., Yang, Y. & Ashwell, J. D. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 416, 345–347 (2002).

    PubMed  Google Scholar 

  45. Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003). The first description of two distinct signalling complexes initiated by TNFR1 activation that differentially regulate apoptosis and are modulated by distinct ubiquitylation events.

    CAS  PubMed  Google Scholar 

  46. Rothe, M., Pan, M. G., Henzel, W. J., Ayres, T. M. & Goeddel, D. V. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83, 1243–1252 (1995). The authors identify c-IAP proteins in a TNFR-associated signalling complex.

    CAS  PubMed  Google Scholar 

  47. Bertrand, M. J. et al. c-IAP1 and c-IAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell 30, 689–700 (2008).

    CAS  PubMed  Google Scholar 

  48. Dynek, J. N. et al. c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling. EMBO J. 29, 4198–4209 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Varfolomeev, E. et al. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor α (TNFα)-induced NF-κB activation. J. Biol. Chem. 283, 24295–24299 (2008). References 47 and 49 identify c-IAP1 and c-IAP2 as ubiquitin ligases for RIP1.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mahoney, D. J. et al. Both c-IAP1 and c-IAP2 regulate TNFα-mediated NF-κB activation. Proc. Natl Acad. Sci. USA 105, 11778–11783 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ikeda, F., Crosetto, N. & Dikic, I. What determines the specificity and outcomes of ubiquitin signaling? Cell 143, 677–681 (2010).

    CAS  PubMed  Google Scholar 

  52. Gerlach, B. et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591–596 (2011).

    CAS  PubMed  Google Scholar 

  53. Xu, M., Skaug, B., Zeng, W. & Chen, Z. J. A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFα and IL-1β. Mol. Cell 36, 302–314 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Haas, T. L. et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol. Cell 36, 831–844 (2009).

    CAS  PubMed  Google Scholar 

  55. Tokunaga, F. et al. Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nature Cell Biol. 11, 123–132 (2009). The first description of linear polyubiquitination in TNF signalling.

    CAS  PubMed  Google Scholar 

  56. Ikeda, F. et al. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471, 637–641 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Tokunaga, F. et al. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471, 633–636 (2011).

    CAS  PubMed  Google Scholar 

  58. Vallabhapurapu, S. et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling. Nature Immunol. 9, 1364–1370 (2008).

    CAS  Google Scholar 

  59. Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131, 669–681 (2007). Provides evidence that IAP antagonists activate ubiquitin ligase activity of c-IAP proteins and identifies these proteins as crucial E3 ligases for NIK.

    CAS  PubMed  Google Scholar 

  60. Vince, J. E. et al. IAP antagonists target c-IAP1 to induce TNFα-dependent apoptosis. Cell 131, 682–693 (2007). Further evidence that IAP antagonists activate ubiquitin ligase activity of c-IAP proteins.

    CAS  PubMed  Google Scholar 

  61. Zarnegar, B. J. et al. Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors c-IAP1, c-IAP2, TRAF2 and TRAF3 and the kinase NIK. Nature Immunol. 9, 1371–1378 (2008).

    CAS  Google Scholar 

  62. Vince, J. E. et al. TWEAK-FN14 signaling induces lysosomal degradation of a c-IAP1-TRAF2 complex to sensitize tumor cells to TNFα. J. Cell Biol. 182, 171–184 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Dejardin, E. The alternative NF-κB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem. Pharmacol. 72, 1161–1179 (2006).

    CAS  PubMed  Google Scholar 

  64. Varfolomeev, E. & Vucic, D. (Un)expected roles of c-IAPs in apoptotic and NF-κB signaling pathways. Cell Cycle 7, 1511–1521 (2008).

    CAS  PubMed  Google Scholar 

  65. Matsuzawa, A. et al. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 321, 663–668 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gardam, S. et al. Deletion of c-IAP1 and c-IAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response. Blood 117, 4041–4051 (2011).

    CAS  PubMed  Google Scholar 

  67. Petersen, S. L. et al. Autocrine TNFα signaling renders human cancer cells susceptible to smac-mimetic-induced apoptosis. Cancer Cell 12, 445–456 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Vandenabeele, P., Galluzzi, L., Vanden Berghe, T. & Kroemer, G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nature Rev. Mol. Cell Biol. 11, 700–714 (2010).

    CAS  Google Scholar 

  69. Conze, D. B., Zhao, Y. & Ashwell, J. D. Non-canonical NF-κB activation and abnormal B cell accumulation in mice expressing ubiquitin protein ligase-inactive c-IAP2. PLoS Biol. 8, e1000518 (2010).

    PubMed  PubMed Central  Google Scholar 

  70. Zilfou, J. T. & Lowe, S. W. Tumor suppressive functions of p53. Cold Spring Harb. Perspect. Biol. 1, a001883 (2009).

    PubMed  PubMed Central  Google Scholar 

  71. Jain, A. K. & Barton, M. C. Making sense of ubiquitin ligases that regulate p53. Cancer Biol. Ther. 10, 665–672 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Brady, C. A. & Attardi, L. D. p53 at a glance. J. Cell Sci. 123, 2527–2532 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Wade, M., Wang, Y. V. & Wahl, G. M. The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol. 20, 299–309 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Huang, H. & Tindall, D. J. Regulation of FOXO protein stability via ubiquitination and proteasome degradation. Biochim. Biophys. Acta 14 Jan 2011 (doi:10.1016/j.bbamcr.2011.01.007).

    CAS  Google Scholar 

  75. Marine, J. C. & Lozano, G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ. 17, 93–102 (2010).

    CAS  PubMed  Google Scholar 

  76. Maguire, M. et al. MDM2 regulates dihydrofolate reductase activity through monoubiquitination. Cancer Res. 68, 3232–3242 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhu, Y. et al. Ribosomal protein S7 is both a regulator and a substrate of MDM2. Mol. Cell 35, 316–326 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  79. Inuzuka, H. et al. Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCFβ-TRCP ubiquitin ligase. Cancer Cell 18, 147–159 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Brooks, C. L. & Gu, W. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 21, 307–315 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Rossi, M. et al. The ubiquitin-protein ligase Itch regulates p73 stability. EMBO J. 24, 836–848 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Melino, G., Knight, R. A. & Cesareni, G. Degradation of p63 by Itch. Cell Cycle 5, 1735–1739 (2006).

    CAS  PubMed  Google Scholar 

  83. Chang, L. et al. The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover. Cell 124, 601–613 (2006).

    CAS  PubMed  Google Scholar 

  84. Winter, M. et al. Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nature Cell Biol. 10, 812–824 (2008).

    CAS  PubMed  Google Scholar 

  85. Garrison, J. B. et al. ARTS and Siah collaborate in a pathway for XIAP degradation. Mol. Cell 41, 107–116 (2011).

    CAS  PubMed  Google Scholar 

  86. Gottfried, Y., Rotem, A., Lotan, R., Steller, H. & Larisch, S. The mitochondrial ARTS protein promotes apoptosis through targeting XIAP. EMBO J. 23, 1627–1635 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Nakayama, K. & Ronai, Z. Siah: new players in the cellular response to hypoxia. Cell Cycle 3, 1345–1347 (2004).

    CAS  PubMed  Google Scholar 

  88. Kaelin, W. G. Proline hydroxylation and gene expression. Annu. Rev. Biochem. 74, 115–128 (2005).

    CAS  PubMed  Google Scholar 

  89. Skaar, J. R., D'Angiolella, V., Pagan, J. K. & Pagano, M. SnapShot: F box proteins II. Cell 137, 1358.e1–1358.e2 (2009).

    Google Scholar 

  90. Frescas, D. & Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nature Rev. Cancer 8, 438–449 (2008).

    CAS  Google Scholar 

  91. Feinstein-Rotkopf, Y. & Arama, E. Can't live without them, can live with them: roles of caspases during vital cellular processes. Apoptosis 14, 980–995 (2009).

    PubMed  Google Scholar 

  92. Bai, C. et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86, 263–274, (1996).

    CAS  PubMed  Google Scholar 

  93. Guardavaccaro, D. et al. Control of meiotic and mitotic progression by the F box protein β-Trcp1 in vivo. Dev. Cell 4, 799–812 (2003).

    CAS  PubMed  Google Scholar 

  94. Nakayama, K. et al. Impaired degradation of inhibitory subunit of NF-κB (IκB) and β-catenin as a result of targeted disruption of the β-TrCP1 gene. Proc. Natl Acad. Sci. USA 100, 8752–8757 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Busino, L. et al. Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage. Nature 426, 87–91 (2003).

    CAS  PubMed  Google Scholar 

  96. Soldatenkov, V. A., Dritschilo, A., Ronai, Z. & Fuchs, S. Y. Inhibition of homologue of Slimb (HOS) function sensitizes human melanoma cells for apoptosis. Cancer Res. 59, 5085–5088 (1999).

    CAS  PubMed  Google Scholar 

  97. Dehan, E. et al. βTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis. Mol. Cell 33, 109–116 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Tan, M. et al. SAG–ROC-SCFβ-TrCP E3 ubiquitin ligase promotes pro–caspase-3 degradation as a mechanism of apoptosis protection. Neoplasia 8, 1042–1054 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Gallegos, J. R. et al. SCFβTrCP1 activates and ubiquitylates TAp63γ. J. Biol. Chem. 283, 66–75 (2008).

    CAS  PubMed  Google Scholar 

  100. Xia, Y. et al. Phosphorylation of p53 by IκB kinase 2 promotes its degradation by β-TrCP. Proc. Natl Acad. Sci. USA 106, 2629–2634 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Soond, S. M. et al. ERK and the F-box protein βTRCP target STAT1 for degradation. J. Biol. Chem. 283, 16077–16083 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Dorrello, N. V. et al. S6K1- and βTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314, 467–471 (2006).

    CAS  PubMed  Google Scholar 

  103. Ding, Q. et al. Degradation of Mcl-1 by β-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol. Cell. Biol. 27, 4006–4017 (2007).

    CAS  PubMed  Google Scholar 

  104. Kanemori, Y., Uto, K. & Sagata, N. β-TrCP recognizes a previously undescribed nonphosphorylated destruction motif in Cdc25A and Cdc25B phosphatases. Proc. Natl Acad. Sci. USA 102, 6279–6284 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Tetzlaff, M. T. et al. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein. Proc. Natl Acad. Sci. USA 101, 3338–3345 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Welcker, M. & Clurman, B. E. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nature Rev. Cancer 8, 83–93 (2008).

    CAS  Google Scholar 

  107. Hoeck, J. D. et al. Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun. Nature Neurosci. 13, 1365–1372 (2010).

    CAS  PubMed  Google Scholar 

  108. Crusio, K. M., King, B., Reavie, L. B. & Aifantis, I. The ubiquitous nature of cancer: the role of the SCFFbw7 complex in development and transformation. Oncogene 29, 4865–4873 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Schwanbeck, R., Martini, S., Bernoth, K. & Just, U. The Notch signaling pathway: molecular basis of cell context dependency. Eur. J. Cell Biol. 90, 572–581 (2010).

    PubMed  Google Scholar 

  110. Mazumder, S., DuPree, E. L. & Almasan, A. A dual role of cyclin E in cell proliferation and apoptosis may provide a target for cancer therapy. Curr. Cancer Drug Targets 4, 65–75 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Moberg, K. H., Mukherjee, A., Veraksa, A., Artavanis-Tsakonas, S. & Hariharan, I. K. The Drosophila F-box protein Archipelago regulates dMyc protein levels in vivo. Curr. Biol. 14, 965–974 (2004).

    CAS  PubMed  Google Scholar 

  112. Nateri, A. S., Riera-Sans, L., Da Costa, C. & Behrens, A. The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science 303, 1374–1378 (2004).

    CAS  PubMed  Google Scholar 

  113. Welcker, M. et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc. Natl Acad. Sci. USA 101, 9085–9090 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Yada, M. et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J. 23, 2116–2125 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Sánchez, I. & Yuan, J. A convoluted way to die. Neuron 29, 563–566 (2001).

    PubMed  Google Scholar 

  116. Inuzuka, H. et al. SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471, 104–109 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Wertz, I. E. et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471, 110–114 (2011).

    CAS  PubMed  Google Scholar 

  118. Zhong, Q., Gao, W., Du, F. & Wang, X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121, 1085–1095 (2005).

    CAS  PubMed  Google Scholar 

  119. Harley, M. E., Allan L. A., Sanderson H. S. & Clarke, P. R. Phosphorylation of Mcl-1 by CDK1–cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO J. 29, 2407–2420 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Wertz, I. E. & Dixit, V. M. Signaling to NF-κB: regulation by ubiquitination. Cold Spring Harb. Perspect. Biol. 2, a003350 (2010).

    PubMed  PubMed Central  Google Scholar 

  121. Vaux, D. L. & Silke, J. IAPs, RINGs and ubiquitylation. Nature Rev. Mol. Cell Biol. 6, 287–297 (2005).

    CAS  Google Scholar 

  122. Bosanac, I. et al. Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling. Mol. Cell 40, 548–557 (2010).

    CAS  PubMed  Google Scholar 

  123. Heyninck, K. & Beyaert, R. A20 inhibits NFκB activation by dual ubiquitin-editing functions. Trends Biochem. Sci. 30, 1–4 (2005).

    CAS  PubMed  Google Scholar 

  124. Wertz, I. E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 430, 694–699 (2004).

    CAS  PubMed  Google Scholar 

  125. Dixit, V. M. et al. Tumor necrosis factor-α induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin. J. Biol. Chem. 265, 2973–2978 (1990).

    CAS  PubMed  Google Scholar 

  126. Krikos, A., Laherty, C. D. & Dixit, V. M. Transcriptional activation of the tumor necrosis factor α-inducible zinc finger protein, A20, is mediated by κB elements. J. Biol. Chem. 267, 17971–17976 (1992).

    CAS  PubMed  Google Scholar 

  127. Hymowitz, S. G. & Wertz, I. E. A20: from ubiquitin editing to tumour suppression. Nature Rev. Cancer 10, 332–341 (2010).

    CAS  Google Scholar 

  128. Lee, E. G. et al. Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science 289, 2350–2354 (2000). Reveals the critical importance of the A20 protein in regulating NF-κB signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Verstrepen, L. et al. Expression, biological activities and mechanisms of action of A20 (TNFAIP3). Biochem. Pharmacol. 80, 2009–2020 (2010).

    CAS  PubMed  Google Scholar 

  130. Wertz, I. E. et al. Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. Science 303, 1371–1374 (2004).

    CAS  PubMed  Google Scholar 

  131. Vereecke, L. et al. Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor-induced toxicity and experimental colitis. J. Exp. Med. 207, 1513–1523 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Malynn, B. A. & Ma, A. Ubiquitin makes its mark on immune regulation. Immunity 33, 843–852 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Jin, Z. et al. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 137, 721–735 (2009).

    CAS  PubMed  Google Scholar 

  134. Bignell, G. R. et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nature Genet. 25, 160–165 (2000). Describes the characterization of the CYLD tumour suppressor gene.

    CAS  PubMed  Google Scholar 

  135. Saggar, S. et al. CYLD mutations in familial skin appendage tumours. J. Med. Genet. 45, 298–302 (2008).

    CAS  PubMed  Google Scholar 

  136. Sun, S. C. CYLD: a tumor suppressor deubiquitinase regulating NF-κB activation and diverse biological processes. Cell Death Differ. 17, 25–34 (2010).

    CAS  PubMed  Google Scholar 

  137. Kovalenko, A. et al. The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination. Nature 424, 801–805 (2003).

    CAS  PubMed  Google Scholar 

  138. Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A. & Fassler, R. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-κB signaling. Cell 125, 665–677 (2006).

    CAS  PubMed  Google Scholar 

  139. Zhang, J. et al. Impaired regulation of NF-κB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice. J. Clin. Invest. 116, 3042–3049 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Wright, A. et al. Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD. Dev. Cell 13, 705–716 (2007).

    CAS  PubMed  Google Scholar 

  141. Wang, L., Du, F. & Wang, X. TNF-α induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).

    CAS  PubMed  Google Scholar 

  142. Vanlangenakker, N. et al. c-IAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent reactive oxygen species production. Cell Death Differ. 18, 656–665 (2011).

    CAS  PubMed  Google Scholar 

  143. Lee, M. J., Lee, B. H., Hanna, J., King, R. W. & Finley, D. Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes. Mol. Cell Proteomics 10, R110.003871 (2010).

    PubMed  PubMed Central  Google Scholar 

  144. Crimmins, S. et al. Transgenic rescue of ataxia mice reveals a male-specific sterility defect. Dev. Biol. 325, 33–42 (2009).

    CAS  PubMed  Google Scholar 

  145. Ehlers, M. D. Ubiquitin and synaptic dysfunction: ataxic mice highlight new common themes in neurological disease. Trends Neurosci. 26, 4–7 (2003).

    CAS  PubMed  Google Scholar 

  146. Crimmins, S. et al. Transgenic rescue of ataxia mice with neuronal-specific expression of ubiquitin-specific protease 14. J. Neurosci. 26, 11423–11431 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Lee, B. H. et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179–184 (2010). The authors describe the development of a USP14 small molecule inhibitor to definitively demonstrate the role of USP14 in ubiquitin chain editing at the proteasome.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Shi, D. & Grossman, S. R. Ubiquitin becomes ubiquitous in cancer: emerging roles of ubiquitin ligases and deubiquitinases in tumorigenesis and as therapeutic targets. Cancer Biol. Ther. 10, 737–747 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Pantaleon, M. et al. FAM deubiquitylating enzyme is essential for preimplantation mouse embryo development. Mech. Dev. 109, 151–160 (2001).

    CAS  PubMed  Google Scholar 

  150. Sacco, J. J., Coulson, J. M., Clague, M. J. & Urbe, S. Emerging roles of deubiquitinases in cancer-associated pathways. IUBMB life 62, 140–157 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Jolly, L. A., Taylor, V. & Wood, S. A. USP9X enhances the polarity and self-renewal of embryonic stem cell-derived neural progenitors. Mol. Biol. Cell 20, 2015–2029 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Wrana, J. L. The secret life of Smad4. Cell 136, 13–14 (2009).

    CAS  PubMed  Google Scholar 

  153. Schwickart, M. et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463, 103–107 (2010).

    CAS  PubMed  Google Scholar 

  154. Nagai, H. et al. Ubiquitin-like sequence in ASK1 plays critical roles in the recognition and stabilization by USP9X and oxidative stress-induced cell death. Mol. Cell 36, 805–818 (2009).

    CAS  PubMed  Google Scholar 

  155. Everett, R. D. et al. A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. EMBO J. 16, 1519–1530 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Faustrup, H., Bekker-Jensen, S., Bartek, J., Lukas, J. & Mailand, N. USP7 counteracts SCFβTrCP- but not APCCdh1-mediated proteolysis of Claspin. J. Cell Biol. 184, 13–19 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  158. Sureda, F. X. et al. Antiapoptotic drugs: a therapautic strategy for the prevention of neurodegenerative diseases. Curr. Pharm. Des. 17, 230–245 (2011).

    CAS  PubMed  Google Scholar 

  159. Dynek, J. N. et al. Microphthalmia-associated transcription factor is a critical transcriptional regulator of melanoma inhibitor of apoptosis in melanomas. Cancer Res. 68, 3124–3132 (2008).

    CAS  PubMed  Google Scholar 

  160. Hunter, A. M., LaCasse, E. C. & Korneluk, R. G. The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 12, 1543–1568 (2007).

    CAS  PubMed  Google Scholar 

  161. Imoto, I. et al. Expression of c-IAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy. Cancer Res. 62, 4860–4866 (2002).

    CAS  PubMed  Google Scholar 

  162. Dierlamm, J. et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa- associated lymphoid tissue lymphomas. Blood 93, 3601–3609 (1999).

    CAS  PubMed  Google Scholar 

  163. Isaacson, P. G. Update on MALT lymphomas. Best Pract. Res. Clin. Haematol. 18, 57–68 (2005).

    CAS  PubMed  Google Scholar 

  164. Zhou, H., Du, M. Q. & Dixit, V. M. Constitutive NF-κB activation by the t(11;18)(q21;q21) product in MALT lymphoma is linked to deregulated ubiquitin ligase activity. Cancer Cell 7, 425–431 (2005).

    CAS  PubMed  Google Scholar 

  165. Ndubaku, C., Cohen, F., Varfolomeev, E. & Vucic, D. Targeting inhibitor of apoptosis (IAP) proteins for therapeutic intervention. Future Med. Chem. 1, 1509–1525 (2009).

    CAS  PubMed  Google Scholar 

  166. Sun, H. et al. Design, synthesis, and characterization of a potent, nonpeptide, cell-permeable, bivalent Smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAP. J. Am. Chem. Soc. 129, 15279–15294 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Vereecke, L., Beyaert, R. & van Loo, G. The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol. 30, 383–391 (2009).

    CAS  PubMed  Google Scholar 

  168. Coornaert, B. et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-κB inhibitor A20. Nature Immunol. 9, 263–271 (2008).

    CAS  Google Scholar 

  169. Duwel, M. et al. A20 negatively regulates T cell receptor signaling to NF-κB by cleaving Malt1 ubiquitin chains. J. Immunol. 182, 7718–7728 (2009).

    PubMed  Google Scholar 

  170. Malynn, B. A. & Ma, A. A20 takes on tumors: tumor suppression by an ubiquitin-editing enzyme. J. Exp. Med. 206, 977–980 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Dynek, J. N. & Vucic, D. Antagonists of IAP proteins as cancer therapeutics. Cancer Lett. 2 Aug 2010 (doi:10.1016/j.canlet.2010.06.013).

    CAS  PubMed  Google Scholar 

  172. Baud, V. & Karin, M. Is NF-κB a good target for cancer therapy? Hopes and pitfalls. Nature Rev. Drug Discov. 8, 33–40 (2009).

    CAS  Google Scholar 

  173. Packham, G. The role of NF-κB in lymphoid malignancies. Br. J. Haematol. 143, 3–15 (2008).

    CAS  PubMed  Google Scholar 

  174. Baker, K. P. et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 48, 3253–3265 (2003).

    CAS  PubMed  Google Scholar 

  175. Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 756–765 (2009).

    CAS  PubMed  Google Scholar 

  176. Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68, 3421–3428 (2008).

    CAS  PubMed  Google Scholar 

  177. Karin, M. The IκB kinase — a bridge between inflammation and cancer. Cell Res. 18, 334–342 (2008).

    CAS  PubMed  Google Scholar 

  178. Cheok, C. F., Verma, C. S., Baselga, J. & Lane, D. P. Translating p53 into the clinic. Nature Rev. Clin. Oncol. 8, 25–37 (2011).

    CAS  Google Scholar 

  179. Di Cintio, A., Di Gennaro, E. & Budillon, A. Restoring p53 function in cancer: novel therapeutic approaches for applying the brakes to tumorigenesis. Recent Pat. Anticancer Drug Discov. 5, 1–13 (2010).

    CAS  PubMed  Google Scholar 

  180. Mandinova, A. & Lee, S. W. The p53 pathway as a target in cancer therapeutics: obstacles and promise. Sci. Transl. Med. 3, 64rv1 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Brown, C. J., Cheok, C. F., Verma, C. S. & Lane, D. P. Reactivation of p53: from peptides to small molecules. Trends Pharmacol. Sci. 32, 53–62 (2011).

    CAS  PubMed  Google Scholar 

  182. Petroski, M. D. The ubiquitin system, disease, and drug discovery. BMC Biochem. 9 (Suppl. 1), S7 (2008).

    PubMed  PubMed Central  Google Scholar 

  183. Vu, B. T. & Vassilev, L. Small-molecule inhibitors of the p53-MDM2 interaction. Curr. Top. Microbiol. Immunol. 348, 151–172 (2011).

    CAS  PubMed  Google Scholar 

  184. Colland, F. et al. Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol. Cancer Ther. 8, 2286–2295 (2009).

    CAS  PubMed  Google Scholar 

  185. Nicholson, B., Marblestone, J. G., Butt, T. R. & Mattern, M. R. Deubiquitinating enzymes as novel anticancer targets. Future Oncol. 3, 191–199 (2007).

    CAS  PubMed  Google Scholar 

  186. Adams, J. & Kauffman, M. Development of the proteasome inhibitor Velcade (bortezomib). Cancer Invest. 22, 304–311 (2004).

    CAS  PubMed  Google Scholar 

  187. McConkey, D. J. & Zhu, K. Mechanisms of proteasome inhibitor action and resistance in cancer. Drug Resist. Updat. 11, 164–179 (2008).

    CAS  PubMed  Google Scholar 

  188. Eldridge, A. G. & O'Brien, T. Therapeutic strategies within the ubiquitin proteasome system. Cell Death Differ. 17, 4–13 (2010).

    CAS  PubMed  Google Scholar 

  189. Grimm, S., Höhn, A. & Grune, T. Oxidative protein damage and the proteasome. Amino Acids 17 Jun 2010 (doi:10.1007/s00726-010-064620118).

  190. Rodriguez-Gonzalez, A. et al. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene 27, 7201–7211 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Lee, J. T. & Gu, W. The multiple levels of regulation by p53 ubiquitination. Cell Death Differ. 17, 86–92 (2010).

    CAS  PubMed  Google Scholar 

  192. Cummins, J. M. et al. Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature 1 Apr 2004 (doi:10.1038/nature02501). Definitive evidence that the DUB HAUSP stabilizes p53 indirectly through MDM2 deubiquitylation.

    PubMed  Google Scholar 

  193. Kon, N. et al. Inactivation of HAUSP in vivo modulates p53 function. Oncogene 29, 1270–1279 (2010).

    CAS  PubMed  Google Scholar 

  194. Kon, N. et al. Roles of HAUSP-mediated p53 regulation in central nervous system development. Cell Death Differ. 25 Feb 2011 (doi:10.1038/cdd.2011.12).

    CAS  Google Scholar 

  195. Meulmeester, E., Pereg, Y., Shiloh, Y. & Jochemsen, A. G. ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 4, 1166–1170 (2005).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank researchers from Genentech Inc., South San Francisco, California, USA, for their helpful comments and critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Domagoj Vucic or Ingrid E. Wertz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Domagoj Vucic's homepage

Vishva M. Dixit's homepage

Ingrid E. Wertz's homepage

Glossary

Thioester linkage

An ATP-dependent linkage formed between the carboxy-terminal group of ubiquitin and the Cys thiol group of E1 enzymes.

Isopeptide linkage

An amide bond that forms between a side-chain carboxyl group and amino group and is not present on the main chain of a protein. In the case of ubiquitylation, isopeptide linkages form between the -nitrogen of Lys side chains and the C-terminus of the incoming ubiquitin, and constitute the basis of polyubiquitin chains.

RING domain

A ubiquitin ligase domain that is defined by the presence of a catalytic zinc-finger-like module that chelates two zinc ions in a unique 'cross-brace' structure.

HECT domain

Homologous to the E6AP (also known as UBE3A) carboxyl terminus, the HECT domain is a ubiquitin ligase domain that contains a catalytic Cys residue, allowing it to accept the charged ubiquitin from the E2 enzymes and transfer it directly to a substrate.

BIR domain

(Baculovirus inhibitor of apoptosis (IAP) repeat domain). Coordinates zinc binding and is required for the anti-apoptotic activity of IAP proteins.

WD40 domains

Protein domains that comprise multiple WD40 repeats that form a scaffold for protein-protein interactions. WD40 repeats are structural motifs of 40 amino acids that terminate in Trp (W) and Asp (D) residues.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vucic, D., Dixit, V. & Wertz, I. Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol 12, 439–452 (2011). https://doi.org/10.1038/nrm3143

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3143

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing