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Role of the ubiquitin ligase Fbw7 in cancer progression

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Abstract

Fbw7 is a member of F-box family proteins, which constitute one subunit of Skp1, Cul1, and F-box protein (SCF) ubiquitin ligase complex. SCFFbw7 targets a set of well-known oncoproteins, including c-Myc, cyclin E, Notch, c-Jun, and Mcl-1, for ubiquitylation and degradation. Fbw7 provides specificity of the ubiquitylation of these substrate proteins via recognition of a consensus phosphorylated degron. Through regulation of several important proteins, Fbw7 controls diverse cellular processes, including cell-cycle progression, cell proliferation, differentiation, DNA damage response, maintenance of genomic stability, and neural cell stemness. As reduced Fbw7 expression level and loss-of-function mutations are found in a wide range of human cancers, Fbw7 is generally considered as a tumor suppressor. However, the exact mechanisms underlying Fbw7-induced tumor suppression is unclear. This review focuses on regulation network, biological functions, and genetic alteration of Fbw7 in connection with its role in cancer development.

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References

  1. Crusio, K. M., King, B., Reavie, L. B., & Aifantis, I. (2010). The ubiquitous nature of cancer: the role of the SCF(Fbw7) complex in development and transformation. Oncogene, 29, 4865–4873.

    Article  PubMed  CAS  Google Scholar 

  2. Hershko, A. (1983). Ubiquitin: roles in protein modification and breakdown. Cell, 34, 11–12.

    Article  PubMed  CAS  Google Scholar 

  3. Schwartz, A. L., & Ciechanover, A. (2009). Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annual Review of Pharmacology and Toxicology, 49, 73–96.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Yada, M., Hatakeyama, S., Kamura, T., et al. (2004). Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. The EMBO Journal, 23, 2116–2125.

    Article  PubMed  CAS  Google Scholar 

  6. Strohmaier, H., Spruck, C. H., 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, 316–322.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Oberg, C., Li, J., Pauley, A., et al. (2001). The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog. Journal of Biological Chemistry, 276, 35847–35853.

    Article  PubMed  CAS  Google Scholar 

  9. Inuzuka, H., Shaik, S., Onoyama, I., et al. (2011). SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature, 471, 104–109.

    Article  PubMed  CAS  Google Scholar 

  10. Mao, J. H., Kim, I. J., Wu, D., et al. (2008). FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science, 321, 1499–1502.

    Article  PubMed  CAS  Google Scholar 

  11. Tan, Y., Sangfelt, O., & Spruck, C. (2008). The Fbxw7/hCdc4 tumor suppressor in human cancer. Cancer Letters, 271, 1–12.

    Article  PubMed  CAS  Google Scholar 

  12. Maser, R. S., Choudhury, B., Campbell, P. J., et al. (2007). Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature, 447, 966–971.

    Article  PubMed  CAS  Google Scholar 

  13. Mao, J. H., Perez-Losada, J., Wu, D., et al. (2004). Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature, 432, 775–779.

    Article  PubMed  CAS  Google Scholar 

  14. Matsuoka, S., Oike, Y., Onoyama, I., et al. (2008). Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL. Genes & Development, 22, 986–991.

    Article  CAS  Google Scholar 

  15. Moberg, K. H., Bell, D. W., Wahrer, D. C., Haber, D. A., & Hariharan, I. K. (2001). Archipelago regulates cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature, 413, 311–316.

    Article  PubMed  CAS  Google Scholar 

  16. Kemp, Z., Rowan, A., Chambers, W., et al. (2005). CDC4 mutations occur in a subset of colorectal cancers but are not predicted to cause loss of function and are not associated with chromosomal instability. Cancer Research, 65, 11361–11366.

    Article  PubMed  CAS  Google Scholar 

  17. Calhoun, E. S., Jones, J. B., Ashfaq, R., et al. (2003). BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. American Journal of Pathology, 163, 1255–1260.

    Article  PubMed  CAS  Google Scholar 

  18. Akhoondi, S., Sun, D., von der Lehr, N., et al. (2007). FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Research, 67, 9006–9012.

    Article  PubMed  CAS  Google Scholar 

  19. Skaar, J. R., Pagan, J. K., & Pagano, M. (2009). SnapShot: F box proteins I. Cell, 137(1160–1160), e1161.

    Google Scholar 

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

    Google Scholar 

  21. Ho, M. S., Tsai, P. I., & Chien, C. T. (2006). F-box proteins: the key to protein degradation. Journal of Biomedical Science, 13, 181–191.

    Article  PubMed  CAS  Google Scholar 

  22. Skowyra, D., Craig, K. L., Tyers, M., Elledge, S. J., & Harper, J. W. (1997). F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin–ligase complex. Cell, 91, 209–219.

    Article  PubMed  CAS  Google Scholar 

  23. Spruck, C. H., Strohmaier, H., Sangfelt, O., et al. (2002). hCDC4 gene mutations in endometrial cancer. Cancer Research, 62, 4535–4539.

    PubMed  CAS  Google Scholar 

  24. Grim, J. E., Gustafson, M. P., Hirata, R. K., et al. (2008). Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase. The Journal of Cell Biology, 181, 913–920.

    Article  PubMed  CAS  Google Scholar 

  25. Matsumoto, A., Tateishi, Y., Onoyama, I., et al. (2011). Fbxw7beta resides in the endoplasmic reticulum membrane and protects cells from oxidative stress. Cancer Science, 102, 749–755.

    Article  PubMed  CAS  Google Scholar 

  26. Welcker, M., Orian, A., Grim, J. E., Eisenman, R. N., & Clurman, B. E. (2004). A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size. Current Biology, 14, 1852–1857.

    Article  PubMed  CAS  Google Scholar 

  27. Zhang, W., & Koepp, D. M. (2006). Fbw7 isoform interaction contributes to cyclin E proteolysis. Molecular Cancer Research, 4, 935–943.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. Perkins, G., Drury, L. S., & Diffley, J. F. (2001). Separate SCF(CDC4) recognition elements target Cdc6 for proteolysis in S phase and mitosis. The EMBO Journal, 20, 4836–4845.

    Article  PubMed  CAS  Google Scholar 

  30. Orlicky, S., Tang, X., Willems, A., Tyers, M., & Sicheri, F. (2003). Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell, 112, 243–256.

    Article  PubMed  CAS  Google Scholar 

  31. Hao, B., Oehlmann, S., Sowa, M. E., Harper, J. W., & Pavletich, N. P. (2007). Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases. Molecular Cell, 26, 131–143.

    Article  PubMed  CAS  Google Scholar 

  32. Nash, P., Tang, X., Orlicky, S., et al. (2001). Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature, 414, 514–521.

    Article  PubMed  CAS  Google Scholar 

  33. Welcker, M., & Clurman, B. E. (2007). Fbw7/hCDC4 dimerization regulates its substrate interactions. Cell Div, 2, 7.

    Article  PubMed  CAS  Google Scholar 

  34. Tang, X., Orlicky, S., Lin, Z., et al. (2007). Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination. Cell, 129, 1165–1176.

    Article  PubMed  CAS  Google Scholar 

  35. Pawar, S. A., Sarkar, T. R., Balamurugan, K., et al. (2010). C/EBP{delta} targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression. Proceedings of the National Academy of Sciences of the United States of America, 107, 9210–9215.

    Article  PubMed  CAS  Google Scholar 

  36. Balamurugan, K., Wang, J. M., Tsai, H. H., et al. (2010). The tumour suppressor C/EBPdelta inhibits FBXW7 expression and promotes mammary tumour metastasis. The EMBO Journal, 29, 4106–4117.

    Article  PubMed  CAS  Google Scholar 

  37. Strimpakos, A. S., Karapanagiotou, E. M., Saif, M. W., & Syrigos, K. N. (2009). The role of mTOR in the management of solid tumors: an overview. Cancer Treatment Reviews, 35, 148–159.

    Article  PubMed  CAS  Google Scholar 

  38. Isobe, T., Hattori, T., Kitagawa, K., et al. (2009). Adenovirus E1A inhibits SCF(Fbw7) ubiquitin ligase. Journal of Biological Chemistry, 284, 27766–27779.

    Article  PubMed  CAS  Google Scholar 

  39. Koo, E. H., & Kopan, R. (2004). Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration. Nature Medicine, 10(Suppl), S26–S33.

    Article  PubMed  CAS  Google Scholar 

  40. De Strooper, B., Annaert, W., Cupers, P., et al. (1999). A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature, 398, 518–522.

    Article  PubMed  CAS  Google Scholar 

  41. Rocher-Ros, V., Marco, S., Mao, J. H., et al. (2010). Presenilin modulates EGFR signaling and cell transformation by regulating the ubiquitin ligase Fbw7. Oncogene, 29, 2950–2961.

    Article  PubMed  CAS  Google Scholar 

  42. Kim, J., & Bartel, D. P. (2009). Allelic imbalance sequencing reveals that single-nucleotide polymorphisms frequently alter microRNA-directed repression. Nature Biotechnology, 27, 472–477.

    Article  PubMed  CAS  Google Scholar 

  43. Xu, Y., Sengupta, T., Kukreja, L., & Minella, A. C. (2010). MicroRNA-223 regulates cyclin E activity by modulating expression of F-box and WD-40 domain protein 7. Journal of Biological Chemistry, 285, 34439–34446.

    Article  PubMed  CAS  Google Scholar 

  44. Lerner, M., Lundgren, J., Akhoondi, S., et al. (2011). MiRNA-27a controls FBW7/hCDC4-dependent cyclin E degradation and cell cycle progression. Cell Cycle, 10, 2172–2183.

    Article  PubMed  CAS  Google Scholar 

  45. Mo, J. S., Ann, E. J., Yoon, J. H., et al. (2011). Serum- and glucocorticoid-inducible kinase 1 (SGK1) controls Notch1 signaling by downregulation of protein stability through Fbw7 ubiquitin ligase. Journal of Cell Science, 124, 100–112.

    Article  PubMed  CAS  Google Scholar 

  46. BelAiba, R. S., Djordjevic, T., Bonello, S., et al. (2006). The serum- and glucocorticoid-inducible kinase Sgk-1 is involved in pulmonary vascular remodeling: role in redox-sensitive regulation of tissue factor by thrombin. Circulation Research, 98, 828–836.

    Article  PubMed  CAS  Google Scholar 

  47. Kinugawa, K., Yonekura, K., Ribeiro, R. C., et al. (2001). Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy. Circulation Research, 89, 591–598.

    Article  PubMed  CAS  Google Scholar 

  48. Schulein, C., Eilers, M., & Popov, N. (2011). PI3K-dependent phosphorylation of Fbw7 modulates substrate degradation and activity. FEBS Letters, 585, 2151–2157.

    Article  PubMed  CAS  Google Scholar 

  49. Durgan, J., & Parker, P. J. (2010). Regulation of the tumour suppressor Fbw7alpha by PKC-dependent phosphorylation and cancer-associated mutations. Biochemistry Journal, 432, 77–87.

    Article  CAS  Google Scholar 

  50. Evans, T., Rosenthal, E. T., Youngblom, J., Distel, D., & Hunt, T. (1983). Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell, 33, 389–396.

    Article  PubMed  CAS  Google Scholar 

  51. Harper, J. W., Burton, J. L., & Solomon, M. J. (2002). The anaphase-promoting complex: it’s not just for mitosis any more. Genes & Development, 16, 2179–2206.

    Article  CAS  Google Scholar 

  52. Castro, A., Bernis, C., Vigneron, S., Labbe, J. C., & Lorca, T. (2005). The anaphase-promoting complex: a key factor in the regulation of cell cycle. Oncogene, 24, 314–325.

    Article  PubMed  CAS  Google Scholar 

  53. Nakayama, K. I., & Nakayama, K. (2006). Ubiquitin ligases: cell-cycle control and cancer. Nature Reviews. Cancer, 6, 369–381.

    Article  PubMed  CAS  Google Scholar 

  54. Hartwell, L. H., Mortimer, R. K., Culotti, J., & Culotti, M. (1973). Genetic control of the cell division cycle in yeast: V. Genetic Analysis of cdc Mutants. Genetics, 74, 267–286.

    CAS  Google Scholar 

  55. Hubbard, E. J., Wu, G., Kitajewski, J., & Greenwald, I. (1997). sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. Genes & Development, 11, 3182–3193.

    Article  CAS  Google Scholar 

  56. Koepp, D. M., Schaefer, L. K., Ye, X., et al. (2001). Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science, 294, 173–177.

    Article  PubMed  CAS  Google Scholar 

  57. Welcker, M., Orian, A., Jin, J., et al. (2004). The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proceedings of the National Academy of Sciences of the United States of America, 101, 9085–9090.

    Article  PubMed  CAS  Google Scholar 

  58. Wei, W., Jin, J., Schlisio, S., Harper, J. W., & Kaelin, W. G., Jr. (2005). The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell, 8, 25–33.

    Article  PubMed  CAS  Google Scholar 

  59. Ishikawa, Y., Onoyama, I., Nakayama, K. I., & Nakayama, K. (2008). Notch-dependent cell cycle arrest and apoptosis in mouse embryonic fibroblasts lacking Fbxw7. Oncogene, 27, 6164–6174.

    Article  PubMed  CAS  Google Scholar 

  60. Zhao, D., Zheng, H. Q., Zhou, Z., & Chen, C. (2010). The Fbw7 tumor suppressor targets KLF5 for ubiquitin-mediated degradation and suppresses breast cell proliferation. Cancer Research, 70, 4728–4738.

    Article  PubMed  CAS  Google Scholar 

  61. Clurman, B. E., Sheaff, R. J., Thress, K., Groudine, M., & Roberts, J. M. (1996). Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes & Development, 10, 1979–1990.

    Article  CAS  Google Scholar 

  62. Won, K. A., & Reed, S. I. (1996). Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E. The EMBO Journal, 15, 4182–4193.

    PubMed  CAS  Google Scholar 

  63. Spruck, C. H., Won, K. A., & Reed, S. I. (1999). Deregulated cyclin E induces chromosome instability. Nature, 401, 297–300.

    Article  PubMed  CAS  Google Scholar 

  64. Minella, A. C., Grim, J. E., Welcker, M., & Clurman, B. E. (2007). p53 and SCFFbw7 cooperatively restrain cyclin E-associated genome instability. Oncogene, 26, 6948–6953.

    Article  PubMed  CAS  Google Scholar 

  65. Ye, X., Nalepa, G., Welcker, M., et al. (2004). Recognition of phosphodegron motifs in human cyclin E by the SCF(Fbw7) ubiquitin ligase. Journal of Biological Chemistry, 279, 50110–50119.

    Article  PubMed  CAS  Google Scholar 

  66. Eilers, M., Schirm, S., & Bishop, J. M. (1991). The MYC protein activates transcription of the alpha-prothymosin gene. The EMBO Journal, 10, 133–141.

    PubMed  CAS  Google Scholar 

  67. Bahram, F., von der Lehr, N., Cetinkaya, C., & Larsson, L. G. (2000). c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. Blood, 95, 2104–2110.

    PubMed  CAS  Google Scholar 

  68. Grandori, C., Cowley, S. M., James, L. P., & Eisenman, R. N. (2000). The Myc/Max/Mad network and the transcriptional control of cell behavior. Annual Review of Cell and Developmental Biology, 16, 653–699.

    Article  PubMed  CAS  Google Scholar 

  69. Adhikary, S., & Eilers, M. (2005). Transcriptional regulation and transformation by Myc proteins. Nature Reviews Molecular Cell Biology, 6, 635–645.

    Article  PubMed  CAS  Google Scholar 

  70. Hann, S. R., & Eisenman, R. N. (1984). Proteins encoded by the human c-myc oncogene: differential expression in neoplastic cells. Molecular and Cellular Biology, 4, 2486–2497.

    PubMed  CAS  Google Scholar 

  71. Amati, B. (2004). Myc degradation: dancing with ubiquitin ligases. Proceedings of the National Academy of Sciences of the United States of America, 101, 8843–8844.

    Article  PubMed  CAS  Google Scholar 

  72. Salghetti, S. E., Muratani, M., Wijnen, H., Futcher, B., & Tansey, W. P. (2000). Functional overlap of sequences that activate transcription and signal ubiquitin-mediated proteolysis. Proceedings of the National Academy of Sciences of the United States of America, 97, 3118–3123.

    Article  PubMed  CAS  Google Scholar 

  73. Flinn, E. M., Busch, C. M., & Wright, A. P. (1998). myc boxes, which are conserved in myc family proteins, are signals for protein degradation via the proteasome. Molecular and Cellular Biology, 18, 5961–5969.

    PubMed  CAS  Google Scholar 

  74. Sears, R., Nuckolls, F., Haura, E., et al. (2000). Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes & Development, 14, 2501–2514.

    Article  CAS  Google Scholar 

  75. Popov, N., Schulein, C., Jaenicke, L. A., & Eilers, M. (2010). Ubiquitylation of the amino terminus of Myc by SCF(beta-TrCP) antagonizes SCF(Fbw7)-mediated turnover. Nature Cell Biology, 12, 973–981.

    Article  PubMed  CAS  Google Scholar 

  76. Hartl, M., Bader, A. G., & Bister, K. (2003). Molecular targets of the oncogenic transcription factor jun. Current Cancer Drug Targets, 3, 41–55.

    Article  PubMed  CAS  Google Scholar 

  77. Behrens, A., Sibilia, M., & Wagner, E. F. (1999). Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nature Genetics, 21, 326–329.

    Article  PubMed  CAS  Google Scholar 

  78. Shaulian, E., Schreiber, M., Piu, F., et al. (2000). The mammalian UV response: c-Jun induction is required for exit from p53-imposed growth arrest. Cell, 103, 897–907.

    Article  PubMed  CAS  Google Scholar 

  79. Szabowski, A., Maas-Szabowski, N., Andrecht, S., et al. (2000). c-Jun and JunB antagonistically control cytokine-regulated mesenchymal–epidermal interaction in skin. Cell, 103, 745–755.

    Article  PubMed  CAS  Google Scholar 

  80. Fuchs, S. Y., Xie, B., Adler, V., et al. (1997). c-Jun NH2-terminal kinases target the ubiquitination of their associated transcription factors. Journal of Biological Chemistry, 272, 32163–32168.

    Article  PubMed  CAS  Google Scholar 

  81. Musti, A. M., Treier, M., & Bohmann, D. (1997). Reduced ubiquitin-dependent degradation of c-Jun after phosphorylation by MAP kinases. Science, 275, 400–402.

    Article  PubMed  CAS  Google Scholar 

  82. Radtke, F., Schweisguth, F., & Pear, W. (2005). The Notch ‘gospel’. EMBO Reports, 6, 1120–1125.

    Article  PubMed  CAS  Google Scholar 

  83. Artavanis-Tsakonas, S., Rand, M. D., & Lake, R. J. (1999). Notch signaling: cell fate control and signal integration in development. Science, 284, 770–776.

    Article  PubMed  CAS  Google Scholar 

  84. Demarest, R. M., Ratti, F., & Capobianco, A. J. (2008). It’s T-ALL about Notch. Oncogene, 27, 5082–5091.

    Article  PubMed  CAS  Google Scholar 

  85. Radtke, F., Wilson, A., Mancini, S. J., & MacDonald, H. R. (2004). Notch regulation of lymphocyte development and function. Nature Immunology, 5, 247–253.

    Article  PubMed  CAS  Google Scholar 

  86. Gupta-Rossi, N., Le Bail, O., Gonen, H., et al. (2001). Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor. Journal of Biological Chemistry, 276, 34371–34378.

    Article  PubMed  CAS  Google Scholar 

  87. Wu, G., Lyapina, S., Das, I., et al. (2001). SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Molecular and Cellular Biology, 21, 7403–7415.

    Article  PubMed  CAS  Google Scholar 

  88. Wu, G., Hubbard, E. J., Kitajewski, J. K., & Greenwald, I. (1998). Evidence for functional and physical association between Caenorhabditis elegans SEL-10, a Cdc4p-related protein, and SEL-12 presenilin. Proceedings of the National Academy of Sciences of the United States of America, 95, 15787–15791.

    Article  PubMed  CAS  Google Scholar 

  89. Fryer, C. J., White, J. B., & Jones, K. A. (2004). Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Molecular Cell, 16, 509–520.

    Article  PubMed  CAS  Google Scholar 

  90. O’Neil, J., Grim, J., Strack, P., et al. (2007). FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. The Journal of Experimental Medicine, 204, 1813–1824.

    Article  PubMed  CAS  Google Scholar 

  91. Thompson, B. J., Buonamici, S., Sulis, M. L., et al. (2007). The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. The Journal of Experimental Medicine, 204, 1825–1835.

    Article  PubMed  CAS  Google Scholar 

  92. Weng, A. P., Ferrando, A. A., Lee, W., et al. (2004). Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science, 306, 269–271.

    Article  PubMed  CAS  Google Scholar 

  93. Girard, L., Hanna, Z., Beaulieu, N., et al. (1996). Frequent provirus insertional mutagenesis of Notch1 in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notch1 for oncogenesis. Genes & Development, 10, 1930–1944.

    Article  CAS  Google Scholar 

  94. Feldman, B. J., Hampton, T., & Cleary, M. L. (2000). A carboxy-terminal deletion mutant of Notch1 accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice. Blood, 96, 1906–1913.

    PubMed  CAS  Google Scholar 

  95. Beverly, L. J., & Capobianco, A. J. (2003). Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis. Cancer Cell, 3, 551–564.

    Article  PubMed  CAS  Google Scholar 

  96. Rohn, J. L., Lauring, A. S., Linenberger, M. L., & Overbaugh, J. (1996). Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma. Journal of Virology, 70, 8071–8080.

    PubMed  CAS  Google Scholar 

  97. Yan, X. Q., Sarmiento, U., Sun, Y., et al. (2001). A novel Notch ligand, Dll4, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer. Blood, 98, 3793–3799.

    Article  PubMed  CAS  Google Scholar 

  98. Dorsch, M., Zheng, G., Yowe, D., et al. (2002). Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease. Blood, 100, 2046–2055.

    PubMed  CAS  Google Scholar 

  99. Kuiperij, H. B., van der Horst, A., Raaijmakers, J., et al. (2005). Activation of FoxO transcription factors contributes to the antiproliferative effect of cAMP. Oncogene, 24, 2087–2095.

    Article  PubMed  CAS  Google Scholar 

  100. Fan, X., Matsui, W., Khaki, L., et al. (2006). Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Research, 66, 7445–7452.

    Article  PubMed  CAS  Google Scholar 

  101. Fernandez-Majada, V., Aguilera, C., Villanueva, A., et al. (2007). Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America, 104, 276–281.

    Article  PubMed  CAS  Google Scholar 

  102. Moriyama, M., Osawa, M., Mak, S. S., et al. (2006). Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. The Journal of Cell Biology, 173, 333–339.

    Article  PubMed  CAS  Google Scholar 

  103. Miyamoto, Y., Maitra, A., Ghosh, B., et al. (2003). Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell, 3, 565–576.

    Article  PubMed  CAS  Google Scholar 

  104. Sriuranpong, V., Borges, M. W., Ravi, R. K., et al. (2001). Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Research, 61, 3200–3205.

    PubMed  CAS  Google Scholar 

  105. Nicolas, M., Wolfer, A., Raj, K., et al. (2003). Notch1 functions as a tumor suppressor in mouse skin. Nature Genetics, 33, 416–421.

    Article  PubMed  CAS  Google Scholar 

  106. Qi, R., An, H., Yu, Y., et al. (2003). Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Research, 63, 8323–8329.

    PubMed  CAS  Google Scholar 

  107. Nguyen, B. C., Lefort, K., Mandinova, A., et al. (2006). Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes & Development, 20, 1028–1042.

    Article  CAS  Google Scholar 

  108. Onoyama, I., Tsunematsu, R., Matsumoto, A., et al. (2007). Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis. The Journal of Experimental Medicine, 204, 2875–2888.

    Article  PubMed  CAS  Google Scholar 

  109. Liu, Y., Wen, J. K., Dong, L. H., Zheng, B., & Han, M. (2010). Kruppel-like factor (KLF) 5 mediates cyclin D1 expression and cell proliferation via interaction with c-Jun in Ang II-induced VSMCs. Acta Pharmacologica Sinica, 31, 10–18.

    Article  PubMed  CAS  Google Scholar 

  110. Nandan, M. O., Chanchevalap, S., Dalton, W. B., & Yang, V. W. (2005). Kruppel-like factor 5 promotes mitosis by activating the cyclin B1/Cdc2 complex during oncogenic Ras-mediated transformation. FEBS Letters, 579, 4757–4762.

    Article  PubMed  CAS  Google Scholar 

  111. Chen, C., Benjamin, M. S., Sun, X., et al. (2006). KLF5 promotes cell proliferation and tumorigenesis through gene regulation and the TSU-Pr1 human bladder cancer cell line. International Journal of Cancer, 118, 1346–1355.

    Article  CAS  Google Scholar 

  112. Zheng, H. Q., Zhou, Z., Huang, J., et al. (2009). Kruppel-like factor 5 promotes breast cell proliferation partially through upregulating the transcription of fibroblast growth factor binding protein 1. Oncogene, 28, 3702–3713.

    Article  PubMed  CAS  Google Scholar 

  113. Yagi, N., Manabe, I., Tottori, T., et al. (2009). A nanoparticle system specifically designed to deliver short interfering RNA inhibits tumor growth in vivo. Cancer Research, 69, 6531–6538.

    Article  PubMed  CAS  Google Scholar 

  114. Chen, C., Zhou, Z., Guo, P., & Dong, J. T. (2007). Proteasomal degradation of the KLF5 transcription factor through a ubiquitin-independent pathway. FEBS Letters, 581, 1124–1130.

    Article  PubMed  CAS  Google Scholar 

  115. Oh, I. H., & Reddy, E. P. (1999). The myb gene family in cell growth, differentiation and apoptosis. Oncogene, 18, 3017–3033.

    Article  PubMed  CAS  Google Scholar 

  116. Slamon, D. J., Boone, T. C., Murdock, D. C., et al. (1986). Studies of the human c-myb gene and its product in human acute leukemias. Science, 233, 347–351.

    Article  PubMed  CAS  Google Scholar 

  117. Siegert, W., Beutler, C., Langmach, K., Keitel, C., & Schmidt, C. A. (1990). Differential expression of the oncoproteins c-myc and c-myb in human lymphoproliferative disorders. European Journal of Cancer, 26, 733–737.

    Article  PubMed  CAS  Google Scholar 

  118. Kitagawa, K., Hiramatsu, Y., Uchida, C., et al. (2009). Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb. Oncogene, 28, 2393–2405.

    Article  PubMed  CAS  Google Scholar 

  119. Kanei-Ishii, C., Nomura, T., Takagi, T., et al. (2008). Fbxw7 acts as an E3 ubiquitin ligase that targets c-Myb for nemo-like kinase (NLK)-induced degradation. Journal of Biological Chemistry, 283, 30540–30548.

    Article  PubMed  CAS  Google Scholar 

  120. Kern, S. E., Kinzler, K. W., Bruskin, A., et al. (1991). Identification of p53 as a sequence-specific DNA-binding protein. Science, 252, 1708–1711.

    Article  PubMed  CAS  Google Scholar 

  121. Kimura, T., Gotoh, M., Nakamura, Y., & Arakawa, H. (2003). hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53. Cancer Science, 94, 431–436.

    Article  PubMed  CAS  Google Scholar 

  122. Finkin, S., Aylon, Y., Anzi, S., Oren, M., & Shaulian, E. (2008). Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy. Oncogene, 27, 4411–4421.

    Article  PubMed  CAS  Google Scholar 

  123. Flores, E. R., Sengupta, S., Miller, J. B., et al. (2005). Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell, 7, 363–373.

    Article  PubMed  CAS  Google Scholar 

  124. Yang, A., Schweitzer, R., Sun, D., et al. (1999). p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature, 398, 714–718.

    Article  PubMed  CAS  Google Scholar 

  125. Mills, A. A., Zheng, B., Wang, X. J., et al. (1999). p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature, 398, 708–713.

    Article  PubMed  CAS  Google Scholar 

  126. Thurfjell, N., Coates, P. J., Uusitalo, T., et al. (2004). Complex p63 mRNA isoform expression patterns in squamous cell carcinoma of the head and neck. International Journal of Oncology, 25, 27–35.

    PubMed  CAS  Google Scholar 

  127. van Bokhoven, H., & McKeon, F. (2002). Mutations in the p53 homolog p63: allele-specific developmental syndromes in humans. Trends in Molecular Medicine, 8, 133–139.

    Article  PubMed  Google Scholar 

  128. Laurikkala, J., Mikkola, M. L., James, M., et al. (2006). p63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation. Development, 133, 1553–1563.

    Article  PubMed  CAS  Google Scholar 

  129. Rossi, M., De Simone, M., Pollice, A., et al. (2006). Itch/AIP4 associates with and promotes p63 protein degradation. Cell Cycle, 5, 1816–1822.

    Article  PubMed  CAS  Google Scholar 

  130. Rossi, M., Aqeilan, R. I., Neale, M., et al. (2006). The E3 ubiquitin ligase Itch controls the protein stability of p63. Proceedings of the National Academy of Sciences of the United States of America, 103, 12753–12758.

    Article  PubMed  CAS  Google Scholar 

  131. Galli, F., Rossi, M., D’Alessandra, Y., et al. (2010). MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation. Journal of Cell Science, 123, 2423–2433.

    Article  PubMed  CAS  Google Scholar 

  132. Massague, J., & Wotton, D. (2000). Transcriptional control by the TGF-beta/Smad signaling system. The EMBO Journal, 19, 1745–1754.

    Article  PubMed  CAS  Google Scholar 

  133. Miyazono, K., Suzuki, H., & Imamura, T. (2003). Regulation of TGF-beta signaling and its roles in progression of tumors. Cancer Science, 94, 230–234.

    Article  PubMed  CAS  Google Scholar 

  134. Bengoechea-Alonso, M. T., & Ericsson, J. (2010). Tumor suppressor Fbxw7 regulates TGFbeta signaling by targeting TGIF1 for degradation. Oncogene, 29, 5322–5328.

    Article  PubMed  CAS  Google Scholar 

  135. Besirli, C. G., Wagner, E. F., & Johnson, E. M., Jr. (2005). The limited role of NH2-terminal c-Jun phosphorylation in neuronal apoptosis: identification of the nuclear pore complex as a potential target of the JNK pathway. The Journal of Cell Biology, 170, 401–411.

    Article  PubMed  CAS  Google Scholar 

  136. Hoeck, J. D., Jandke, A., Blake, S. M., et al. (2010). Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun. Nature Neuroscience, 13, 1365–1372.

    Article  PubMed  CAS  Google Scholar 

  137. Matsumoto, A., Onoyama, I., Sunabori, T., et al. (2011). Fbxw7-dependent degradation of Notch is required for control of “stemness” and neuronal-glial differentiation in neural stem cells. Journal of Biological Chemistry, 286, 13754–13764.

    Article  PubMed  CAS  Google Scholar 

  138. Willis, S. N., Fletcher, J. I., Kaufmann, T., et al. (2007). Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science, 315, 856–859.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  140. Sporn, M. B. (1996). The war on cancer. Lancet, 347, 1377–1381.

    Article  PubMed  CAS  Google Scholar 

  141. Howe, A., Aplin, A. E., Alahari, S. K., & Juliano, R. L. (1998). Integrin signaling and cell growth control. Current Opinion in Cell Biology, 10, 220–231.

    Article  PubMed  CAS  Google Scholar 

  142. Coussens, L. M., & Werb, Z. (1996). Matrix metalloproteinases and the development of cancer. Chemistry & Biology, 3, 895–904.

    Article  CAS  Google Scholar 

  143. Chambers, A. F., & Matrisian, L. M. (1997). Changing views of the role of matrix metalloproteinases in metastasis. Journal of the National Cancer Institute, 89, 1260–1270.

    Article  PubMed  CAS  Google Scholar 

  144. Wolfer, A., & Ramaswamy, S. (2011). MYC and metastasis. Cancer Research, 71, 2034–2037.

    Article  PubMed  CAS  Google Scholar 

  145. Massague, J., Blain, S. W., & Lo, R. S. (2000). TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 103, 295–309.

    Article  PubMed  CAS  Google Scholar 

  146. Knuutila, S., Aalto, Y., Autio, K., et al. (1999). DNA copy number losses in human neoplasms. American Journal of Pathology, 155, 683–694.

    Article  PubMed  CAS  Google Scholar 

  147. Rajagopalan, H., Jallepalli, P. V., Rago, C., et al. (2004). Inactivation of hCDC4 can cause chromosomal instability. Nature, 428, 77–81.

    Article  PubMed  CAS  Google Scholar 

  148. Woo Lee, J., Hwa Soung, Y., Young Kim, S., et al. (2006). Somatic mutation of hCDC4 gene is rare in lung adenocarcinomas. Acta Oncologica, 45, 487–488.

    Article  PubMed  CAS  Google Scholar 

  149. Nowak, D., Mossner, M., Baldus, C. D., et al. (2006). Mutation analysis of hCDC4 in AML cells identifies a new intronic polymorphism. International Journal of Medical Sciences, 3, 148–151.

    Article  PubMed  Google Scholar 

  150. Kwak, E. L., Moberg, K. H., Wahrer, D. C., et al. (2005). Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer. Gynecologic Oncology, 98, 124–128.

    Article  PubMed  CAS  Google Scholar 

  151. Yan, T., Wunder, J. S., Gokgoz, N., et al. (2006). hCDC4 variation in osteosarcoma. Cancer Genetics and Cytogenetics, 169, 138–142.

    Article  PubMed  CAS  Google Scholar 

  152. Fresno Vara, J. A., Casado, E., de Castro, J., et al. (2004). PI3K/Akt signalling pathway and cancer. Cancer Treatment Reviews, 30, 193–204.

    Article  PubMed  CAS  Google Scholar 

  153. Larson Gedman, A., Chen, Q., Kugel Desmoulin, S., et al. (2009). The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Leukemia, 23, 1417–1425.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Canadian Institutes of Health Research (MOP-84559, MOP-93810, and MOP-110974), Canadian Cancer Society Research Institute (2011-700714), and Canadian Dermatology Foundation to G. Li. Y. Cheng is a recipient of the trainee award from Canadian Institute of Health Research Skin Research Training Centre and University of British Columbia Graduate Fellowship.

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  1. Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 2660 Oak Street, Vancouver, B C, V6H 3Z6, Canada

    Yabin Cheng & Gang Li

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  1. Yabin Cheng
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Cheng, Y., Li, G. Role of the ubiquitin ligase Fbw7 in cancer progression. Cancer Metastasis Rev 31, 75–87 (2012). https://doi.org/10.1007/s10555-011-9330-z

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