Skip to main content
SpringerLink
Log in
Book cover

SCF and APC E3 Ubiquitin Ligases in Tumorigenesis pp 89–111Cite as

The Role of APC E3 Ubiquitin Ligase Complex in Tumorigenesis

  • Chapter
  • First Online:

Part of the book series: SpringerBriefs in Cancer Research ((BRIEFSCANCER))

Abstract

E3 ubiquitin ligases, especially the SCF (Skp1-Cul1-F-box protein) and APC (Anaphase-promoting complex, also known as APC/C), have been extensively studied in the past decades. These two ubiquitin E3 ligases primarily function in the regulation of cell cycle progression through timely and coordinated degradation of key cell cycle regulators. Mounting evidence has revealed not only that the SCF plays a critical role in tumorigenesis but also that the APC is important for cancer development. Genetically modified mouse models have demonstrated that the APC co-activator Cdh1 primarily functions as a tumor suppressor, while another co-activator, Cdc20, exhibits an oncogenic role. Consistently, Cdh1 is frequently lost or inactivated in human cancers (Bassermann et al., Cell 134(2):256–267, 2008; Fujita et al., Clin Cancer Res 14(7):1966–1975, 2008; Fujita et al., Am J Pathol 173(1):217–228, 2008), while the overexpression of Cdc20 is observed in human malignancies (Mondal et al., Carcinogenesis 28(1):81–92, 2007; Jiang et al., Biochem Biophys Res Commun 415(2):325–329, 2011; Rajkumar et al., BMC Cancer 11:80, 2011; Chang et al., J Hematol Oncol 5:15, 2012; Kato et al., J Surg Oncol 106(4):423–430, 2012). Here, we discuss the identified substrates of APC, and summarize the reported phenotypes of genetically modified mouse models, which support the role of APC in the pathogenesis of human cancers and other relevant human diseases. Finally, we offer perspectives for developing APC pathway-specific inhibitors to treat various types of human cancers.

This is a preview of subscription content, 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   39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   54.99
Price excludes VAT (USA)
  • Compact, lightweight 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

Learn about institutional subscriptions

References

  1. Bassermann F, et al. The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell. 2008;134(2):256–67.

    PubMed  CAS  PubMed Central  Google Scholar 

  2. Fujita T, et al. Dissection of the APCCdh1-Skp2 cascade in breast cancer. Clin Cancer Res. 2008;14(7):1966–75.

    PubMed  CAS  Google Scholar 

  3. Fujita T, et al. Regulation of Skp2-p27 axis by the Cdh1/anaphase-promoting complex pathway in colorectal tumorigenesis. Am J Pathol. 2008;173(1):217–28.

    PubMed  CAS  PubMed Central  Google Scholar 

  4. Mondal G, et al. Overexpression of Cdc20 leads to impairment of the spindle assembly checkpoint and aneuploidization in oral cancer. Carcinogenesis. 2007;28(1):81–92.

    PubMed  CAS  Google Scholar 

  5. Jiang J, Jedinak A, Sliva D. Ganodermanontriol (GDNT) exerts its effect on growth and invasiveness of breast cancer cells through the down-regulation of CDC20 and uPA. Biochem Biophys Res Commun. 2011;415(2):325–9.

    PubMed  CAS  Google Scholar 

  6. Rajkumar T, et al. Identification and validation of genes involved in cervical tumourigenesis. BMC Cancer. 2011;11:80.

    PubMed  PubMed Central  Google Scholar 

  7. Chang DZ, et al. Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression. J Hematol Oncol. 2012;5:15.

    PubMed  CAS  PubMed Central  Google Scholar 

  8. Kato T, et al. Overexpression of CDC20 predicts poor prognosis in primary non-small cell lung cancer patients. J Surg Oncol. 2012;106(4):423–30.

    PubMed  CAS  Google Scholar 

  9. Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem. 2009;78:399–434.

    PubMed  CAS  Google Scholar 

  10. Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 2006;6(5):369–81.

    PubMed  CAS  Google Scholar 

  11. Lipkowitz S, Weissman AM. RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nat Rev Cancer. 2011;11(9):629–43.

    PubMed  CAS  PubMed Central  Google Scholar 

  12. Foe I, Toczyski D. Structural biology: a new look for the APC. Nature. 2011;470(7333):182–3.

    PubMed  CAS  Google Scholar 

  13. Schreiber A, et al. Structural basis for the subunit assembly of the anaphase-promoting complex. Nature. 2011;470(7333):227–32.

    PubMed  CAS  Google Scholar 

  14. Vodermaier HC, et al. TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1. Curr Biol. 2003;13(17):1459–68.

    PubMed  CAS  Google Scholar 

  15. Wasch R, Robbins JA, Cross FR. The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression. Oncogene. 2010;29(1):1–10.

    PubMed  CAS  PubMed Central  Google Scholar 

  16. Penas C, Ramachandran V, Ayad NG. The APC/C ubiquitin ligase: from cell biology to tumorigenesis. Front Oncol. 2011;1:60.

    PubMed  PubMed Central  Google Scholar 

  17. Wang Z, et al. Cdc20: a potential novel therapeutic target for cancer treatment. Curr Pharm Des. 2013;19(18):3210–4.

    PubMed  CAS  Google Scholar 

  18. Wang Q, et al. Alterations of anaphase-promoting complex genes in human colon cancer cells. Oncogene. 2003;22(10):1486–90.

    PubMed  CAS  Google Scholar 

  19. Tang Z, et al. APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex. Mol Biol Cell. 2001;12(12):3839–51.

    PubMed  CAS  PubMed Central  Google Scholar 

  20. Yu H, et al. Identification of a cullin homology region in a subunit of the anaphase-promoting complex. Science. 1998;279(5354):1219–22.

    PubMed  CAS  Google Scholar 

  21. Wirth KG, et al. Loss of the anaphase-promoting complex in quiescent cells causes unscheduled hepatocyte proliferation. Genes Dev. 2004;18(1):88–98.

    PubMed  CAS  PubMed Central  Google Scholar 

  22. Yamanaka H, et al. Expression of Apc2 during mouse development. Brain Res Gene Expr Patterns. 2002;1(2):107–14.

    PubMed  CAS  Google Scholar 

  23. Gieffers C, et al. Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons. Proc Natl Acad Sci U S A. 1999;96(20):11317–22.

    PubMed  CAS  PubMed Central  Google Scholar 

  24. Kuczera T, et al. The anaphase promoting complex is required for memory function in mice. Learn Mem. 2011;18(1):49–57.

    PubMed  CAS  Google Scholar 

  25. Van Valen P. Oligosyndactylism, an early embryonic lethal in the mouse. J Embryol Exp Morphol. 1966;15(2):119–24.

    PubMed  Google Scholar 

  26. Stewart AD, Stewart J. Studies on syndrome of diabetes insipidus associated with oligosyndactyly in mice. Am J Physiol. 1969;217(4):1191–8.

    PubMed  CAS  Google Scholar 

  27. Magnuson T, Epstein CJ. Oligosyndactyly: a lethal mutation in the mouse that results in mitotic arrest very early in development. Cell. 1984;38(3):823–33.

    PubMed  CAS  Google Scholar 

  28. Pravtcheva DD, Wise TL. Disruption of Apc10/Doc1 in three alleles of oligosyndactylism. Genomics. 2001;72(1):78–87.

    PubMed  CAS  Google Scholar 

  29. Pravtcheva DD, Wise TL. A transgene-induced mitotic arrest mutation in the mouse allelic with oligosyndactylism. Genetics. 1996;144(4):1747–56.

    PubMed  CAS  PubMed Central  Google Scholar 

  30. Almeida A, Bolanos JP, Moreno S. Cdh1/Hct1-APC is essential for the survival of postmitotic neurons. J Neurosci. 2005;25(36):8115–21.

    PubMed  CAS  Google Scholar 

  31. Marucci G, et al. Gene expression profiling in glioblastoma and immunohistochemical evaluation of IGFBP-2 and CDC20. Virchows Arch. 2008;453(6):599–609.

    PubMed  CAS  Google Scholar 

  32. Manchado E, et al. Targeting mitotic exit leads to tumor regression in vivo: modulation by Cdk1, Mastl, and the PP2A/B55alpha, delta phosphatase. Cancer Cell. 2010;18(6):641–54.

    PubMed  CAS  Google Scholar 

  33. Garcia-Higuera I, et al. Genomic stability and tumour suppression by the APC/C cofactor Cdh1. Nat Cell Biol. 2008;10(7):802–11.

    PubMed  Google Scholar 

  34. Li M, York JP, Zhang P. Loss of Cdc20 causes a securin-dependent metaphase arrest in two-cell mouse embryos. Mol Cell Biol. 2007;27(9):3481–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  35. Yin S, et al. Cdc20 is required for the anaphase onset of the first meiosis but not the second meiosis in mouse oocytes. Cell Cycle. 2007;6(23):2990–2.

    PubMed  CAS  Google Scholar 

  36. Jin F, et al. Cdc20 is critical for meiosis I and fertility of female mice. PLoS Genet. 2010;6(9):e1001147.

    PubMed  PubMed Central  Google Scholar 

  37. Engelbert D, et al. The ubiquitin ligase APC(Cdh1) is required to maintain genome integrity in primary human cells. Oncogene. 2008;27(7):907–17.

    PubMed  CAS  Google Scholar 

  38. Carter SL, et al. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet. 2006;38(9):1043–8.

    PubMed  CAS  Google Scholar 

  39. Li M, et al. The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory. Nat Cell Biol. 2008;10(9):1083–9.

    PubMed  CAS  PubMed Central  Google Scholar 

  40. Bashir T, et al. Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature. 2004;428(6979):190–3.

    PubMed  CAS  Google Scholar 

  41. Wei W, et al. Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature. 2004;428(6979):194–8.

    PubMed  CAS  Google Scholar 

  42. Rape M, Kirschner MW. Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry. Nature. 2004;432(7017):588–95.

    PubMed  CAS  Google Scholar 

  43. Castro A, et al. Xkid is degraded in a D-box, KEN-box, and A-box-independent pathway. Mol Cell Biol. 2003;23(12):4126–38.

    PubMed  CAS  PubMed Central  Google Scholar 

  44. Glotzer M, Murray AW, Kirschner MW. Cyclin is degraded by the ubiquitin pathway. Nature. 1991;349(6305):132–8.

    PubMed  CAS  Google Scholar 

  45. Pfleger CM, Kirschner MW. The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1. Genes Dev. 2000;14(6):655–65.

    PubMed  CAS  PubMed Central  Google Scholar 

  46. Castro A, et al. The D-Box-activating domain (DAD) is a new proteolysis signal that stimulates the silent D-Box sequence of Aurora-A. EMBO Rep. 2002;3(12):1209–14.

    PubMed  CAS  PubMed Central  Google Scholar 

  47. Littlepage LE, Ruderman JV. Identification of a new APC/C recognition domain, the A box, which is required for the Cdh1-dependent destruction of the kinase Aurora-A during mitotic exit. Genes Dev. 2002;16(17):2274–85.

    PubMed  CAS  PubMed Central  Google Scholar 

  48. Araki M, et al. Degradation of origin recognition complex large subunit by the anaphase-promoting complex in Drosophila. EMBO J. 2003;22(22):6115–26.

    PubMed  CAS  PubMed Central  Google Scholar 

  49. Reis A, et al. The CRY box: a second APCcdh1-dependent degron in mammalian cdc20. EMBO Rep. 2006;7(10):1040–5.

    PubMed  CAS  PubMed Central  Google Scholar 

  50. Schvartzman JM, Sotillo R, Benezra R. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer. 2010;10(2):102–15.

    PubMed  CAS  Google Scholar 

  51. Holland AJ, Cleveland DW. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol. 2009;10(7):478–87.

    PubMed  CAS  PubMed Central  Google Scholar 

  52. Sudakin V, Chan GK, Yen TJ. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J Cell Biol. 2001;154(5):925–36.

    PubMed  CAS  PubMed Central  Google Scholar 

  53. Pinsky BA, Biggins S. The spindle checkpoint: tension versus attachment. Trends Cell Biol. 2005;15(9):486–93.

    PubMed  CAS  Google Scholar 

  54. Yu H. Regulation of APC-Cdc20 by the spindle checkpoint. Curr Opin Cell Biol. 2002;14(6):706–14.

    PubMed  CAS  Google Scholar 

  55. Musacchio A. Spindle assembly checkpoint: the third decade. Philos Trans R Soc Lond B Biol Sci. 2011;366(1584):3595–604.

    PubMed  CAS  PubMed Central  Google Scholar 

  56. Dobles M, et al. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell. 2000;101(6):635–45.

    PubMed  CAS  Google Scholar 

  57. Michel LS, et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature. 2001;409(6818):355–9.

    PubMed  CAS  Google Scholar 

  58. Chi YH, et al. Spindle assembly checkpoint and p53 deficiencies cooperate for tumorigenesis in mice. Int J Cancer. 2009;124(6):1483–9.

    PubMed  CAS  PubMed Central  Google Scholar 

  59. Krishnan R, et al. Map location and gene structure of the Homo sapiens mitotic arrest deficient 2 (MAD2L1) gene at 4q27. Genomics. 1998;49(3):475–8.

    PubMed  CAS  Google Scholar 

  60. Rashid A, et al. Genetic alterations in hepatocellular carcinomas: association between loss of chromosome 4q and p53 gene mutations. Br J Cancer. 1999;80(1–2):59–66.

    PubMed  CAS  PubMed Central  Google Scholar 

  61. Shivapurkar N, et al. Multiple regions of chromosome 4 demonstrating allelic losses in breast carcinomas. Cancer Res. 1999;59(15):3576–80.

    PubMed  CAS  Google Scholar 

  62. Alizadeh AA, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–11.

    PubMed  CAS  Google Scholar 

  63. Garber ME, et al. Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A. 2001;98(24):13784–9.

    PubMed  CAS  PubMed Central  Google Scholar 

  64. Heighway J, et al. Expression profiling of primary non-small cell lung cancer for target identification. Oncogene. 2002;21(50):7749–63.

    PubMed  CAS  Google Scholar 

  65. Kato T, et al. Overexpression of MAD2 predicts clinical outcome in primary lung cancer patients. Lung Cancer. 2011;74(1):124–31.

    PubMed  Google Scholar 

  66. Chen X, et al. Gene expression patterns in human liver cancers. Mol Biol Cell. 2002;13(6):1929–39.

    PubMed  CAS  PubMed Central  Google Scholar 

  67. Zhang SH, et al. Clinicopathologic significance of mitotic arrest defective protein 2 overexpression in hepatocellular carcinoma. Hum Pathol. 2008;39(12):1827–34.

    PubMed  CAS  Google Scholar 

  68. Rimkus C, et al. Expression of the mitotic checkpoint gene MAD2L2 has prognostic significance in colon cancer. Int J Cancer. 2007;120(1):207–11.

    PubMed  CAS  Google Scholar 

  69. Hisaoka M, Matsuyama A, Hashimoto H. Aberrant MAD2 expression in soft-tissue sarcoma. Pathol Int. 2008;58(6):329–33.

    PubMed  Google Scholar 

  70. Wang L, et al. MAD2 as a key component of mitotic checkpoint: a probable prognostic factor for gastric cancer. Am J Clin Pathol. 2009;131(6):793–801.

    PubMed  CAS  Google Scholar 

  71. Sotillo R, et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell. 2007;11(1):9–23.

    PubMed  CAS  PubMed Central  Google Scholar 

  72. Sotillo R, et al. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature. 2010;464(7287):436–40.

    PubMed  CAS  PubMed Central  Google Scholar 

  73. Malureanu LA, et al. BubR1 N terminus acts as a soluble inhibitor of cyclin B degradation by APC/C(Cdc20) in interphase. Dev Cell. 2009;16(1):118–31.

    PubMed  CAS  PubMed Central  Google Scholar 

  74. Lara-Gonzalez P, et al. BubR1 blocks substrate recruitment to the APC/C in a KEN-box-dependent manner. J Cell Sci. 2011;124(Pt 24):4332–45.

    PubMed  CAS  PubMed Central  Google Scholar 

  75. Wang Q, et al. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood. 2004;103(4):1278–85.

    PubMed  CAS  Google Scholar 

  76. Baker DJ, et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet. 2004;36(7):744–9.

    PubMed  CAS  Google Scholar 

  77. Hartman TK, et al. Mutant mice with small amounts of BubR1 display accelerated age-related gliosis. Neurobiol Aging. 2007;28(6):921–7.

    PubMed  CAS  Google Scholar 

  78. Matsumoto T, et al. Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke. 2007;38(3):1050–6.

    PubMed  CAS  Google Scholar 

  79. Dai W, et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res. 2004;64(2):440–5.

    PubMed  CAS  Google Scholar 

  80. Rao CV, et al. Colonic tumorigenesis in BubR1+/−ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc Natl Acad Sci U S A. 2005;102(12):4365–70.

    PubMed  CAS  PubMed Central  Google Scholar 

  81. Krishnamurthy J, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004;114(9):1299–307.

    PubMed  CAS  PubMed Central  Google Scholar 

  82. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127(2):265–75.

    PubMed  CAS  Google Scholar 

  83. Baker DJ, et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol. 2008;10(7):825–36.

    PubMed  CAS  PubMed Central  Google Scholar 

  84. Baker DJ, et al. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol. 2013;15(1):96–102.

    PubMed  CAS  PubMed Central  Google Scholar 

  85. Kalitsis P, et al. Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. Genes Dev. 2000;14(18):2277–82.

    PubMed  CAS  PubMed Central  Google Scholar 

  86. Kalitsis P, et al. Increased chromosome instability but not cancer predisposition in haploinsufficient Bub3 mice. Genes Chromosomes Cancer. 2005;44(1):29–36.

    PubMed  CAS  Google Scholar 

  87. Babu JR, et al. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J Cell Biol. 2003;160(3):341–53.

    PubMed  CAS  PubMed Central  Google Scholar 

  88. Baker DJ, et al. Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J Cell Biol. 2006;172(4):529–40.

    PubMed  CAS  PubMed Central  Google Scholar 

  89. Hsu JY, et al. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nat Cell Biol. 2002;4(5):358–66.

    PubMed  CAS  Google Scholar 

  90. Reimann JD, et al. Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Cell. 2001;105(5):645–55.

    PubMed  CAS  Google Scholar 

  91. Guardavaccaro D, et al. Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo. Dev Cell. 2003;4(6):799–812.

    PubMed  CAS  Google Scholar 

  92. Margottin-Goguet F, et al. Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev Cell. 2003;4(6):813–26.

    PubMed  CAS  Google Scholar 

  93. Hansen DV, et al. Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC inhibitor Emi1. Mol Biol Cell. 2004;15(12):5623–34.

    PubMed  CAS  PubMed Central  Google Scholar 

  94. Moshe Y, et al. Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc Natl Acad Sci U S A. 2004;101(21):7937–42.

    PubMed  CAS  PubMed Central  Google Scholar 

  95. Lee H, et al. Mouse emi1 has an essential function in mitotic progression during early embryogenesis. Mol Cell Biol. 2006;26(14):5373–81.

    PubMed  CAS  PubMed Central  Google Scholar 

  96. Lehman NL, et al. Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells. Cell Cycle. 2006;5(14):1569–73.

    PubMed  CAS  Google Scholar 

  97. Min KW, et al. Clear cell carcinomas of the ovary: a multi-institutional study of 129 cases in Korea with prognostic significance of Emi1 and Galectin-3. Int J Gynecol Pathol. 2013;32(1):3–14.

    PubMed  CAS  Google Scholar 

  98. Liu X, et al. The expression and prognosis of Emi1 and Skp2 in breast carcinoma: associated with PI3K/Akt pathway and cell proliferation. Med Oncol. 2013;30(4):735.

    PubMed  Google Scholar 

  99. Shimizu N, et al. Selective enhancing effect of early mitotic inhibitor 1 (Emi1) depletion on the sensitivity of doxorubicin or X-ray treatment in human cancer cells. J Biol Chem. 2013;288(24):17238–52.

    PubMed  CAS  Google Scholar 

  100. Stewart S, Fang G. Destruction box-dependent degradation of aurora B is mediated by the anaphase-promoting complex/cyclosome and Cdh1. Cancer Res. 2005;65(19):8730–5.

    PubMed  CAS  Google Scholar 

  101. Nguyen HG, et al. Mechanism of Aurora-B degradation and its dependency on intact KEN and A-boxes: identification of an aneuploidy-promoting property. Mol Cell Biol. 2005;25(12):4977–92.

    PubMed  CAS  PubMed Central  Google Scholar 

  102. Zhao WM, Fang G. Anillin is a substrate of anaphase-promoting complex/cyclosome (APC/C) that controls spatial contractility of myosin during late cytokinesis. J Biol Chem. 2005;280(39):33516–24.

    PubMed  CAS  Google Scholar 

  103. Li R, et al. APC/C(Cdh1) targets brain-specific kinase 2 (BRSK2) for degradation via the ubiquitin-proteasome pathway. PLoS One. 2012;7(9):e45932.

    PubMed  CAS  PubMed Central  Google Scholar 

  104. Qi W, Yu H. KEN-box-dependent degradation of the Bub1 spindle checkpoint kinase by the anaphase-promoting complex/cyclosome. J Biol Chem. 2007;282(6):3672–9.

    PubMed  CAS  Google Scholar 

  105. Visintin C, et al. APC/C-Cdh1-mediated degradation of the Polo kinase Cdc5 promotes the return of Cdc14 into the nucleolus. Genes Dev. 2008;22(1):79–90.

    PubMed  CAS  PubMed Central  Google Scholar 

  106. Petersen BO, et al. Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. Genes Dev. 2000;14(18):2330–43.

    PubMed  CAS  PubMed Central  Google Scholar 

  107. Huang JN, et al. Activity of the APC(Cdh1) form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p. J Cell Biol. 2001;154(1):85–94.

    PubMed  CAS  PubMed Central  Google Scholar 

  108. Hyun SY, et al. APC/C(Cdh1)-dependent degradation of Cdc20 requires a phosphorylation on CRY-box by Polo-like kinase-1 during somatic cell cycle. Biochem Biophys Res Commun. 2013;436(1):12–8.

    PubMed  CAS  Google Scholar 

  109. Donzelli M, et al. Dual mode of degradation of Cdc25 A phosphatase. EMBO J. 2002;21(18):4875–84.

    PubMed  CAS  PubMed Central  Google Scholar 

  110. Sugimoto N, et al. Identification of novel human Cdt1-binding proteins by a proteomics approach: proteolytic regulation by APC/CCdh1. Mol Biol Cell. 2008;19(3):1007–21.

    PubMed  CAS  PubMed Central  Google Scholar 

  111. Benanti JA, et al. Functionally distinct isoforms of Cik1 are differentially regulated by APC/C-mediated proteolysis. Mol Cell. 2009;33(5):581–90.

    PubMed  CAS  PubMed Central  Google Scholar 

  112. Seki A, Fang G. CKAP2 is a spindle-associated protein degraded by APC/C-Cdh1 during mitotic exit. J Biol Chem. 2007;282(20):15103–13.

    PubMed  CAS  Google Scholar 

  113. Hong KU, et al. Functional importance of the anaphase-promoting complex-Cdh1-mediated degradation of TMAP/CKAP2 in regulation of spindle function and cytokinesis. Mol Cell Biol. 2007;27(10):3667–81.

    PubMed  CAS  PubMed Central  Google Scholar 

  114. Gao D, et al. Cdh1 regulates cell cycle through modulating the claspin/Chk1 and the Rb/E2F1 pathways. Mol Biol Cell. 2009;20(14):3305–16.

    PubMed  CAS  PubMed Central  Google Scholar 

  115. Liot C, et al. APC(cdh1) mediates degradation of the oncogenic Rho-GEF Ect2 after mitosis. PLoS One. 2011;6(8):e23676.

    PubMed  CAS  PubMed Central  Google Scholar 

  116. Ping Z, et al. APC/C (Cdh1) controls the proteasome-mediated degradation of E2F3 during cell cycle exit. Cell Cycle. 2012;11(10):1999–2005.

    PubMed  CAS  PubMed Central  Google Scholar 

  117. Sun J, et al. The phosphatase-transcription activator EYA1 is targeted by anaphase-promoting complex/Cdh1 for degradation at M-to-G1 transition. Mol Cell Biol. 2013;33(5):927–36.

    PubMed  CAS  PubMed Central  Google Scholar 

  118. Lai F, et al. Human KIAA1018/FAN1 nuclease is a new mitotic substrate of APC/C(Cdh1). Chin J Cancer. 2012;31(9):440–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  119. Woodbury EL, Morgan DO. Cdk and APC activities limit the spindle-stabilizing function of Fin1 to anaphase. Nat Cell Biol. 2007;9(1):106–12.

    PubMed  CAS  Google Scholar 

  120. Park HJ, et al. Anaphase-promoting complex/cyclosome-CDH1-mediated proteolysis of the forkhead box M1 transcription factor is critical for regulated entry into S phase. Mol Cell Biol. 2008;28(17):5162–71.

    PubMed  CAS  PubMed Central  Google Scholar 

  121. McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell. 1998;93(6):1043–53.

    PubMed  CAS  Google Scholar 

  122. Fu AK, et al. APC(Cdh1) mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity. Nat Neurosci. 2011;14(2):181–9.

    PubMed  CAS  Google Scholar 

  123. Colombo SL, et al. Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells. Proc Natl Acad Sci U S A. 2011;108(52):21069–74.

    PubMed  CAS  PubMed Central  Google Scholar 

  124. Takahashi A, et al. DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells. Mol Cell. 2012;45(1):123–31.

    PubMed  CAS  Google Scholar 

  125. Li L, et al. Anaphase-promoting complex/cyclosome controls HEC1 stability. Cell Prolif. 2011;44(1):1–9.

    PubMed  Google Scholar 

  126. Lasorella A, et al. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature. 2006;442(7101):471–4.

    PubMed  CAS  Google Scholar 

  127. Ko N, et al. Identification of yeast IQGAP (Iqg1p) as an anaphase-promoting-complex substrate and its role in actomyosin-ring-independent cytokinesis. Mol Biol Cell. 2007;18(12):5139–53.

    PubMed  CAS  PubMed Central  Google Scholar 

  128. Gutierrez GJ, et al. Interplay between Cdh1 and JNK activity during the cell cycle. Nat Cell Biol. 2010;12(7):686–95.

    PubMed  CAS  PubMed Central  Google Scholar 

  129. Feine O, et al. Human Kid is degraded by the APC/C(Cdh1) but not by the APC/C(Cdc20). Cell Cycle. 2007;6(20):2516–23.

    PubMed  CAS  Google Scholar 

  130. Teng FY, Tang BL. APC/C regulation of axonal growth and synaptic functions in postmitotic neurons: the Liprin-alpha connection. Cell Mol Life Sci. 2005;62(14):1571–8.

    PubMed  CAS  Google Scholar 

  131. van Roessel P, et al. Independent regulation of synaptic size and activity by the anaphase-promoting complex. Cell. 2004;119(5):707–18.

    PubMed  Google Scholar 

  132. Nishimura K, et al. APC(CDH1) targets MgcRacGAP for destruction in the late M phase. PLoS One. 2013;8(5):e63001.

    PubMed  CAS  PubMed Central  Google Scholar 

  133. Huang NJ, et al. The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1. J Cell Biol. 2012;197(3):361–7.

    PubMed  CAS  PubMed Central  Google Scholar 

  134. Doucet C, et al. Multiple phosphorylation events control mitotic degradation of the muscle transcription factor Myf5. BMC Biochem. 2005;6:27.

    PubMed  PubMed Central  Google Scholar 

  135. Lu L, et al. HECT type ubiquitin ligase NEDL2 is degraded by APC/C-Cdh1 and its tight regulation maintains the metaphase to anaphase transition. J Biol Chem. 2013;288(50):35637–50.

    PubMed  CAS  Google Scholar 

  136. Klitzing C, et al. APC/C(Cdh1)-mediated degradation of the F-box protein NIPA is regulated by its association with Skp1. PLoS One. 2011;6(12):e28998.

    PubMed  Google Scholar 

  137. Ostapenko D, Solomon MJ. Anaphase promoting complex-dependent degradation of transcriptional repressors Nrm1 and Yhp1 in Saccharomyces cerevisiae. Mol Biol Cell. 2011;22(13):2175–84.

    PubMed  CAS  PubMed Central  Google Scholar 

  138. Herrero-Mendez A, et al. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol. 2009;11(6):747–52.

    PubMed  CAS  Google Scholar 

  139. Lindon C, Pines J. Ordered proteolysis in anaphase inactivates Plk1 to contribute to proper mitotic exit in human cells. J Cell Biol. 2004;164(2):233–41.

    PubMed  CAS  PubMed Central  Google Scholar 

  140. Wu S, et al. Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression. Genes Dev. 2010;24(22):2531–42.

    PubMed  CAS  PubMed Central  Google Scholar 

  141. Naoe H, et al. The anaphase-promoting complex/cyclosome activator Cdh1 modulates Rho GTPase by targeting p190 RhoGAP for degradation. Mol Cell Biol. 2010;30(16):3994–4005.

    PubMed  CAS  PubMed Central  Google Scholar 

  142. Zhang L, et al. Proteolysis of Rad17 by Cdh1/APC regulates checkpoint termination and recovery from genotoxic stress. EMBO J. 2010;29(10):1726–37.

    PubMed  CAS  PubMed Central  Google Scholar 

  143. Zhao WM, et al. RCS1, a substrate of APC/C, controls the metaphase to anaphase transition. Proc Natl Acad Sci U S A. 2008;105(36):13415–20.

    PubMed  CAS  PubMed Central  Google Scholar 

  144. Karamysheva Z, et al. Multiple anaphase-promoting complex/cyclosome degrons mediate the degradation of human Sgo1. J Biol Chem. 2009;284(3):1772–80.

    PubMed  CAS  PubMed Central  Google Scholar 

  145. Christensen KL, et al. Cell cycle regulation of the human Six1 homeoprotein is mediated by APC(Cdh1). Oncogene. 2007;26(23):3406–14.

    PubMed  CAS  Google Scholar 

  146. Stegmuller J, et al. Cell-intrinsic regulation of axonal morphogenesis by the Cdh1-APC target SnoN. Neuron. 2006;50(3):389–400.

    PubMed  CAS  Google Scholar 

  147. Jeng JC, et al. Cdh1 controls the stability of TACC3. Cell Cycle. 2009;8(21):3529–36.

    PubMed  Google Scholar 

  148. Ke PY, et al. Control of dTTP pool size by anaphase promoting complex/cyclosome is essential for the maintenance of genetic stability. Genes Dev. 2005;19(16):1920–33.

    PubMed  CAS  PubMed Central  Google Scholar 

  149. Ke PY, et al. Hiding human thymidine kinase 1 from APC/C-mediated destruction by thymidine binding. FASEB J. 2007;21(4):1276–84.

    PubMed  CAS  Google Scholar 

  150. Stewart S, Fang G. Anaphase-promoting complex/cyclosome controls the stability of TPX2 during mitotic exit. Mol Cell Biol. 2005;25(23):10516–27.

    PubMed  CAS  PubMed Central  Google Scholar 

  151. Ohoka N, et al. Anaphase-promoting complex/cyclosome-cdh1 mediates the ubiquitination and degradation of TRB3. Biochem Biophys Res Commun. 2010;392(3):289–94.

    PubMed  CAS  Google Scholar 

  152. Cotto-Rios XM, et al. APC/CCdh1-dependent proteolysis of USP1 regulates the response to UV-mediated DNA damage. J Cell Biol. 2011;194(2):177–86.

    PubMed  CAS  PubMed Central  Google Scholar 

  153. Gurden MD, et al. Cdc20 is required for the post-anaphase, KEN-dependent degradation of centromere protein F. J Cell Sci. 2010;123(Pt 3):321–30.

    PubMed  CAS  PubMed Central  Google Scholar 

  154. Hadjihannas MV, et al. Cell cycle control of Wnt/beta-catenin signalling by conductin/axin2 through CDC20. EMBO Rep. 2012;13(4):347–54.

    PubMed  CAS  PubMed Central  Google Scholar 

  155. Kim AH, et al. A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons. Cell. 2009;136(2):322–36.

    PubMed  CAS  PubMed Central  Google Scholar 

  156. Sedgwick GG, et al. Mechanisms controlling the temporal degradation of Nek2A and Kif18A by the APC/C-Cdc20 complex. EMBO J. 2013;32(2):303–14.

    PubMed  CAS  PubMed Central  Google Scholar 

  157. Harley ME, et al. Phosphorylation of Mcl-1 by CDK1-cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO J. 2010;29(14):2407–20.

    PubMed  CAS  PubMed Central  Google Scholar 

  158. Hayes MJ, et al. Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C. Nat Cell Biol. 2006;8(6):607–14.

    PubMed  CAS  Google Scholar 

  159. Hames RS, et al. APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box. EMBO J. 2001;20(24):7117–27.

    PubMed  CAS  PubMed Central  Google Scholar 

  160. Yang Y, et al. A Cdc20-APC ubiquitin signaling pathway regulates presynaptic differentiation. Science. 2009;326(5952):575–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  161. Lim HJ, et al. The G2/M regulator histone demethylase PHF8 is targeted for degradation by the anaphase-promoting complex containing CDC20. Mol Cell Biol. 2013;33(21):4166–80.

    PubMed  CAS  PubMed Central  Google Scholar 

  162. Amador V, et al. APC/C(Cdc20) controls the ubiquitin-mediated degradation of p21 in prometaphase. Mol Cell. 2007;27(3):462–73.

    PubMed  CAS  PubMed Central  Google Scholar 

  163. Chun AC, Kok KH, Jin DY. REV7 is required for anaphase-promoting complex-dependent ubiquitination and degradation of translesion DNA polymerase REV1. Cell Cycle. 2013;12(2):365–78.

    PubMed  CAS  PubMed Central  Google Scholar 

  164. Wang R, et al. Cdc20 mediates D-box-dependent degradation of Sp100. Biochem Biophys Res Commun. 2011;415(4):702–6.

    PubMed  CAS  Google Scholar 

  165. Song L, Rape M. Regulated degradation of spindle assembly factors by the anaphase-promoting complex. Mol Cell. 2010;38(3):369–82.

    PubMed  CAS  PubMed Central  Google Scholar 

  166. den Elzen N, Pines J. Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase. J Cell Biol. 2001;153(1):121–36.

    Google Scholar 

  167. Geley S, et al. Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint. J Cell Biol. 2001;153(1):137–48.

    PubMed  CAS  PubMed Central  Google Scholar 

  168. Clute P, Pines J. Temporal and spatial control of cyclin B1 destruction in metaphase. Nat Cell Biol. 1999;1(2):82–7.

    PubMed  CAS  Google Scholar 

  169. Budhavarapu VN, et al. Regulation of E2F1 by APC/C Cdh1 via K11 linkage-specific ubiquitin chain formation. Cell Cycle. 2012;11(10):2030–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  170. Cui Y, et al. Degradation of the human mitotic checkpoint kinase Mps1 is cell cycle-regulated by APC-cCdc20 and APC-cCdh1 ubiquitin ligases. J Biol Chem. 2010;285(43):32988–98.

    PubMed  CAS  PubMed Central  Google Scholar 

  171. Wang Y, Zhan Q. Cell cycle-dependent expression of centrosomal ninein-like protein in human cells is regulated by the anaphase-promoting complex. J Biol Chem. 2007;282(24):17712–9.

    PubMed  CAS  Google Scholar 

  172. Cho HJ, et al. Degradation of human RAP80 is cell cycle regulated by Cdc20 and Cdh1 ubiquitin ligases. Mol Cancer Res. 2012;10(5):615–25.

    PubMed  CAS  Google Scholar 

  173. Michaelis C, Ciosk R, Nasmyth K. Cohesins: chromosomal proteins that prevent premature separation of sister chromatids. Cell. 1997;91(1):35–45.

    PubMed  CAS  Google Scholar 

  174. Nasmyth K. Disseminating the genome: joining, resolving, and separating sister chromatids during mitosis and meiosis. Annu Rev Genet. 2001;35:673–745.

    PubMed  CAS  Google Scholar 

  175. Ichim G, et al. The histone acetyltransferase component TRRAP is targeted for destruction during the cell cycle. Oncogene. 2014;33(2):181–92.

    PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

    Authors and Affiliations

    1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

      Jinfang Zhang, Lixin Wan, Brian J. North, Hiroyuki Inuzuka & Wenyi Wei

    Authors
    1. Jinfang Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Lixin Wan
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Brian J. North
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Hiroyuki Inuzuka
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Wenyi Wei
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Wenyi Wei .

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2014 The Author(s)

    About this chapter

    Cite this chapter

    Zhang, J., Wan, L., North, B.J., Inuzuka, H., Wei, W. (2014). The Role of APC E3 Ubiquitin Ligase Complex in Tumorigenesis. In: SCF and APC E3 Ubiquitin Ligases in Tumorigenesis. SpringerBriefs in Cancer Research. Springer, Cham. https://doi.org/10.1007/978-3-319-05026-3_5

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation