Breast Cancer

, Volume 25, Issue 5, pp 529–538 | Cite as

The ubiquitin ligase COP1 regulates cell cycle and apoptosis by affecting p53 function in human breast cancer cell lines

  • Won Hye Ka
  • Seok Keun Cho
  • Byung Nyun Chun
  • Sang Yo ByunEmail author
  • Jong Cheol AhnEmail author
Original Article



The E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) mediates cell survival, growth, and development, and interacts with the tumor suppressor protein p53 to induce its ubiquitination and degradation. Recent studies reported that COP1 overexpression is associated with increased cell proliferation, transformation, and disease progression in a variety of cancer types. In this study, we investigated whether COP1 regulates p53-mediated cell cycle arrest and apoptosis in human breast cancer cell lines.


We downregulated COP1 expression using lentiviral particles expressing short hairpin RNA (shRNA) targeting COP1 and measured the effects of the knockdown in three different breast cancer cell lines.


COP1 silencing resulted in p53 activation, which induced the expression of p21 and p53-upregulated modulator of apoptosis (PUMA) expression, and reduced the levels of cyclin-dependent kinase 2 (CDK2). Notably, knockdown of COP1 was associated with cell cycle arrest during the G0/G1 phase.


The COP1-mediated degradation of p53 regulates cancer cell growth and apoptosis. Our results indicate that COP1 regulates human breast cancer cell proliferation and apoptosis in a p53-dependent manner. These findings suggest that COP1 might be a promising potential target for breast cancer-related gene therapy.


COP1 p53 RNA silencing Gene therapy 


Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Shah R, Rosso K, Nathanson SD. Pathogenesis, prevention, diagnosis and treatment of breast cancer. World J Clin Oncol. 2014;5(3):283–98. Scholar
  2. 2.
    Harbeck N, Gnant M. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2017;389(10074):1134–50. Scholar
  3. 3.
    Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6:909–23. Scholar
  4. 4.
    Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. 2009;137:413–31. Scholar
  5. 5.
    Gu L, Zhu N, Findley HW, Zhou M. MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2. Leukemia. 2008;22:730–9. Scholar
  6. 6.
    Bargonetti J, Manfredi JJ. Multiple roles of the tumor suppressor p53. Curr Opin Oncol. 2002;14:86–91. Scholar
  7. 7.
    Teodoro JG, Evans SK, Green MR. Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med (Berl). 2007;85:1175–86. Scholar
  8. 8.
    Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene. 2003;22:9030–40. Scholar
  9. 9.
    Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–10. Scholar
  10. 10.
    He G, Siddik ZH, Huang Z, Wang R, Koomen J, Kobayashi R, et al. Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities. Oncogene. 2005;24:2929–43. Scholar
  11. 11.
    Nilausen K, Green H. Reversible arrest of growth in G1 of an established fibroblast line (3T3). Exp Cell Res. 1965;40:166–8. Scholar
  12. 12.
    Bianchi E, Denti S, Catena R, Rossetti G, Polo S, Gasparian S, et al. Characterization of human constitutive photomorphogenesis protein 1, a RING finger ubiquitin ligase that interacts with Jun transcription factors and modulates their transcriptional activity. J Biol Chem. 2003;278:19682–90. Scholar
  13. 13.
    Jain AK, Barton MC. Making sense of ubiquitin ligases that regulate p53. Cancer Biol Ther. 2010;10:665–72. Scholar
  14. 14.
    Deng XW, Caspar T, Quail PH. COP1: a regulatory locus involved in light-controlled development and gene expression in Arabidopsis. Genes Dev. 1991;5:1172–82. Scholar
  15. 15.
    Choi HH, Phan L, Chou PC, Su CH, Yeung SC, Chen JS, et al. COP1 enhances ubiquitin-mediated degradation of p27Kip1 to promote cancer cell growth. Oncotarget. 2015;6:19721–34. Scholar
  16. 16.
    Vitari AC, Leong KG, Newton K, Yee C, O’Rourke K, Liu J, et al. COP1 is a tumor suppressor that causes degradation of ETS transcription factors. Nature. 2011;474:403–6. Scholar
  17. 17.
    Li YF, Wang DD, Zhao BW, Wang W, Huang CY, Chen YM, et al. High level of COP1 expression is associated with poor prognosis in primary gastric cancer. Int J Biol Sci. 2012;8:1168–77. Scholar
  18. 18.
    Marine JC. Spotlight on the role of COP1 in tumorigenesis. Nat Rev Cancer. 2012;12:455–64. Scholar
  19. 19.
    Dornan D, Bheddah S, Newton K, Ince W, Frantz GD, Dowd P, et al. COP1, the negative regulator of p53, is overexpressed in breast and ovarian adenocarcinomas. Cancer Res. 2004;64:7226–30. Scholar
  20. 20.
    Ouyang M, Wang H, Ma J, Lu W, Li J, Yao C, et al. COP1, the negative regulator of ETV1, influences prognosis in triple-negative breast cancer. BMC Cancer. 2015;15:132. Scholar
  21. 21.
    Lu G, Zhang Q, Huang Y, Song J, Tomaino R, Ehrenberger T, et al. Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor. Cancer Cell. 2014;26:222–34. Scholar
  22. 22.
    Kato S, Ding J, Pisck E, Jhala US, Du K. COP1 functions as a FoxO1 ubiquitin E3 ligase to regulate FoxO1-mediated gene expression. J Biol Chem. 2008;283:35464–73. Scholar
  23. 23.
    Wang L, He G, Zhang P, Wang X, Jiang M, Yu L. Interplay between MDM2, MDMX, PIRH2, and COP1: the negative regulators of p53. Mol Biol Rep. 2011;38:229–36. Scholar
  24. 24.
    Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci USA. 2006;103:1888–93. Scholar
  25. 25.
    Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, et al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature. 2004;429:86–92.CrossRefPubMedGoogle Scholar
  26. 26.
    Corcoran CA, Huang Y, Sheikh MS. The p53 paddy wagon: COP1, PIRH2, and MDM2 are found resisting apoptosis and growth arrest. Cancer Biol Ther. 2004;3:721–5. Scholar
  27. 27.
    Wertz IE, O’Rourke KM, Zhang Z, Dornan D, Arnott D, Deshaies RJ, et al. Human de-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. Science. 2004;303:1371–4. Scholar
  28. 28.
    Shao J, Teng Y, Padia R, Hong S, Noh H, Xie X, et al. COP1 and GSK3beta cooperate to promote c-Jun degradation and inhibit breast cancer cell tumorigenesis. Neoplasia. 2013;15:1075–85. Scholar
  29. 29.
    Li DQ, Ohshiro K, Reddy SD, Pakala SB, Lee MH, Zhang Y, et al. E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. Proc Natl Acad Sci USA. 2009;106:17493–8. Scholar
  30. 30.
    Ray D, Murphy KR, Gal S. The DNA binding and accumulation of p53 from breast cancer cell lines and the link with serine 15 phosphorylation. Cancer Biol Ther. 2012;13:848–57. Scholar
  31. 31.
    Graves B, Thompson T, Xia M, Janson C, Lukacs C, Deo D, et al. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci USA. 2012;109:11788–93. Scholar

Copyright information

© The Japanese Breast Cancer Society 2018

Authors and Affiliations

  1. 1.WJ R&D CenterWOOJUNG BSC, Advanced Institutes of Convergence TechnologySuwon-siRepublic of Korea
  2. 2.Applied Biotechnology DepartmentAjou UniversitySuwonRepublic of Korea
  3. 3.Department of Systems Biology, College of Life Science and BiotechnologyYonsei UniversitySeoulRepublic of Korea

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