14-3-3sigma exerts tumor-suppressor activity mediated by regulation of COP1 stability.
Constitutive photomorphogenic 1 (COP1) is a p53-targeting E3 ubiquitin ligase that is downregulated by DNA damage through mechanisms that remain obscure. Here, we report that COP1 is not downregulated following DNA damage in 14-3-3σ null cells, implicating 14-3-3σ as a critical regulator in the response of COP1 to DNA damage. We also identified that 14-3-3σ, a p53 target gene product, interacted with COP1 and controlled COP1 protein stability after DNA damage. Mechanistic studies revealed that 14-3-3σ enhanced COP1 self-ubiquitination, thereby preventing COP1-mediated p53 ubiquitination, degradation, and transcriptional repression. In addition, we found that COP1 expression promoted cell proliferation, cell transformation, and tumor progression, manifesting its role in cancer promotion, whereas 14-3-3σ negatively regulated COP1 function and prevented tumor growth in a mouse xenograft model of human cancer. Immunohistochemical analysis of clinical breast and pancreatic cancer specimens demonstrated that COP1 protein levels were inversely correlated with 14-3-3σ protein levels. Together, our findings define a mechanism for posttranslational regulation of COP1 after DNA damage that can explain the correlation between COP1 overexpression and 14-3-3σ downregulation during tumorigenesis.
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Chun-Hui
CH
Su
Ruiying
R
Zhao
Fanmao
F
Zhang
Changju
C
Qu
Bo
B
Chen
Yin-Hsun
YH
Feng
Liem
L
Phan
Jian
J
Chen
Hua
H
Wang
Huamin
H
Wang
Sai-Ching J
SC
Yeung
Mong-Hong
MH
Lee
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism*; D005095:Exoribonucleases; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human