Nuclear export regulation of COP1 by 14-3-3σ in response to DNA damage

Molecular Cancer

Research

Sai-Ching J Yeung¹  Christopher Gully²  Jian Chen²  Guermarie Velazquez-Torres³  Ruiying Zhao⁴  Chun-Hui Su⁴  Mong-Hong Lee⁵ 

[1] Department of General Internal Medicine, Ambulatory Treatment, and Emergency Care, University of Texas M. D. Anderson Cancer Center, 77030, Houston, TX, USA;Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 77030, Houston, TX, USA;Program in Cancer Biology, University of Texas Graduate School of Biomedical Sciences at Houston, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 77030, Houston, TX, USA;Program in Genes & Development, University of Texas Graduate School of Biomedical Sciences at Houston, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 77030, Houston, TX, USA;Program in Genes & Development, University of Texas Graduate School of Biomedical Sciences at Houston, 77030, Houston, TX, USA;Program in Cancer Biology, University of Texas Graduate School of Biomedical Sciences at Houston, 77030, Houston, TX, USA;

关键词: Nuclear Export;    U2OS Cell;    Nuclear Export Signal;    Nuclear Export Signal Sequence;    COP1 Axis;   

DOI  :  10.1186/1476-4598-9-243

 received in 2010-06-28, accepted in 2010-09-15,  发布年份 2010

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Su et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.