Roles for negative cell regulator 14-3-3σ in control of MDM2 activities

被引：0
作者：
H-Y Yang
Y-Y Wen
Y-l Lin
L Pham
C-H Su
H Yang
J Chen
M-H Lee
机构：
[1] The University of Texas MD Anderson Cancer Center,Department of Molecular and Cellular Oncology
[2] Programs in Genes and Development,Department of Pathophysiology
[3] The University of Texas Graduate School of Biomedical Sciences at Houston,undefined
[4] Programs in Cancer Biology,undefined
[5] The University of Texas Graduate School of Biomedical Sciences at Houston,undefined
[6] Zhongshan University,undefined
[7] H Lee Moffitt Cancer Center,undefined
来源：
Oncogene | 2007年 / 26卷
关键词：
MDM2; 14-3-3; NEDDylation; p53; RB;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
The 14-3-3σ, upregulated by p53 in response to DNA damage, can have a positive-feedback impact driving p53 activities and is a human cancer epithelial marker downregulated in various tumors. However, the precise roles of 14-3-3σ during tumorigenesis are not well characterized. Here, we show that 14-3-3σ is a critical regulator of murine double minute oncogene (MDM2). 14-3-3σ interacts with MDM2 at the RING domain. The C-terminal region of 14-3-3σ binds to MDM2 very efficiently. Importantly, 14-3-3σ overexpression leads to destabilization of MDM2 through enhancing MDM2 self-ubiquitination and accelerating turnover rate. Conversely, loss of 14-3-3σ results in a significant increase in MDM2 protein. Moreover, live-cell images indicated that 14-3-3σ can affect the location of MDM2 from the nucleus to the cytoplasm, and that MDM2-mediated cytoplasmic localization of p53 can be reversed by the presence of 14-3-3σ. Significantly, we further showed that 14-3-3σ causes MDM2 downregulation, thereby stabilizing p53 and inhibiting tumor growth in animal tumors. Also, 14-3-3σ blocks MDM2-mediated retinoblastoma degradation and p53 NEDDylation. Our results provide evidence that 14-3-3σ is a pivotal MDM2 regulator involved in blocking a variety of activities of MDM2.
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页码：7355 / 7362
页数：7
相关论文
共 107 条
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