TY - JOUR
T1 - Nuclear export regulation of COP1 by 14-3-3σ in response to DNA damage
AU - Su, Chun Hui
AU - Zhao, Ruiying
AU - Velazquez-Torres, Guermarie
AU - Chen, Jian
AU - Gully, Christopher
AU - Yeung, Sai Ching J.
AU - Lee, Mong Hong
N1 - Funding Information:
We are grateful to Drs. Y.Y. Wen, E. Bianchi, and R. Pardi for material support. Also, we thank L. Pham, and J. Tseng for technical support. We thank Dr. Zhenbo Han and Bill Spohn for microscopy support. This work was supported by grants from the National Institutes of Health (NIH) (R01CA089266), Directed Medical Research Programs (DOD SIDA BC062166 to S.J.Y. and M.H.L.) and Susan G. Komen Breast Cancer Foundation (KG081048). This research was supported in part, by a cancer prevention fellowship for G.V.T. supported by the National Cancer Institute grant R25T CA57730, Shine Chang, Ph.D., PI”. The University of Texas M. D. Anderson Cancer Center is supported by NIH core grant CA16672.
PY - 2010/9/15
Y1 - 2010/9/15
N2 - Mammalian constitutive photomorphogenic 1 (COP1) is a p53 E3 ubiquitin ligase involved in regulating p53 protein level. In plants, the dynamic cytoplasm/nucleus distribution of COP1 is important for its function in terms of catalyzing the degradation of target proteins. In mammalian cells, the biological consequence of cytoplasmic distribution of COP1 is not well characterized. Here, we show that DNA damage leads to the redistribution of COP1 to the cytoplasm and that 14-3-3σ, a p53 target gene product, controls COP1 subcellular localization. Investigation of the underlying mechanism suggests that COP1 S387 phosphorylation is required for COP1 to bind 14-3-3σ. Significantly, upon DNA damage, 14-3-3σ binds to phosphorylated COP1 at S387, resulting in COP1's accumulation in the cytoplasm. Cytoplasmic COP1 localization leads to its enhanced ubiquitination. We also show that N-terminal 14-3-3σ interacts with COP1 and promotes COP1 nuclear export through its NES sequence. Further, we show that COP1 is important in causing p53 nuclear exclusion. Finally, we demonstrate that 14-3-3σ targets COP1 for nuclear export, thereby preventing COP1-mediated p53 nuclear export. Together, these results define a novel, detailed mechanism for the subcellular localization and regulation of COP1 after DNA damage and provide a mechanistic explanation for the notion that 14-3-3σ's impact on the inhibition of p53 E3 ligases is an important step for p53 stabilization after DNA damage.
AB - Mammalian constitutive photomorphogenic 1 (COP1) is a p53 E3 ubiquitin ligase involved in regulating p53 protein level. In plants, the dynamic cytoplasm/nucleus distribution of COP1 is important for its function in terms of catalyzing the degradation of target proteins. In mammalian cells, the biological consequence of cytoplasmic distribution of COP1 is not well characterized. Here, we show that DNA damage leads to the redistribution of COP1 to the cytoplasm and that 14-3-3σ, a p53 target gene product, controls COP1 subcellular localization. Investigation of the underlying mechanism suggests that COP1 S387 phosphorylation is required for COP1 to bind 14-3-3σ. Significantly, upon DNA damage, 14-3-3σ binds to phosphorylated COP1 at S387, resulting in COP1's accumulation in the cytoplasm. Cytoplasmic COP1 localization leads to its enhanced ubiquitination. We also show that N-terminal 14-3-3σ interacts with COP1 and promotes COP1 nuclear export through its NES sequence. Further, we show that COP1 is important in causing p53 nuclear exclusion. Finally, we demonstrate that 14-3-3σ targets COP1 for nuclear export, thereby preventing COP1-mediated p53 nuclear export. Together, these results define a novel, detailed mechanism for the subcellular localization and regulation of COP1 after DNA damage and provide a mechanistic explanation for the notion that 14-3-3σ's impact on the inhibition of p53 E3 ligases is an important step for p53 stabilization after DNA damage.
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U2 - 10.1186/1476-4598-9-243
DO - 10.1186/1476-4598-9-243
M3 - Article
C2 - 20843328
AN - SCOPUS:77956534974
SN - 1476-4598
VL - 9
JO - Molecular cancer
JF - Molecular cancer
M1 - 243
ER -