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TIP30 Induces Apoptosis under Oxidative Stress through Stabilization of p53 Messenger RNA in Human Hepatocellular Carcinoma

¹ International Joint Cancer Institute and Eastern Hospital of Hepatobiliary Surgery, The Second Military Medical University; ² E-Institute of Universities, Immunology Division, Shanghai Jiao Tong University and Shanghai Center for Cell Engineering and Antibody; ³ Shanghai Institute of Applied Physics, China Academy of Sciences, Shanghai, P.R. China; and ⁴ Guangxi Cancer Hospital, Guangxi Medical University, Guangxi, P.R. China

Requests for reprints: Yajun Guo, International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, New Building 10th-11th Floor, Shanghai 200433, P.R. China. Phone: 86-21-25070241; Fax: 86-21-25074349; E-mail: yjguo{at}smmu.edu.cn.

Key Words: Tumor suppressor • Reactive oxygen species • mRNA stability • Apoptosis • HuR

Reactive oxygen species (ROS) and cellular oxidant stress have long been associated with cancer. Here, we show that TIP30, also called CC3, regulates p53 mRNA stability and induces apoptosis by sensing of intracellular oxidative stress in human hepatocellular carcinoma (HCC) cells. Introduction of TIP30 induced more cell death in HepG2 cells with a high level of intracellular ROS than that in normal liver cell line, HL7702, which had low level of intracellular ROS. Treatment with an antioxidant agent attenuated TIP30-induced cell death in HepG2 cells, whereas oxidant H₂O₂ augmented TIP30-induced cell death in HL7702 cells. The conformation of TIP30 was altered with the formation of an intermolecular disulfide bridge under oxidative stress. TIP30 greatly enhanced p53 expression and its transcriptional activity under oxidative stress, which was probably through stabilization of p53 mRNA. TIP30 induced apoptosis and mitochondrial dysfunction were blocked by silencing of p53 expression. The nuclear import of mRNA-binding protein HuR was blocked upon TIP30 introduction, which might be due to the interruption of the association of HuR with importin β2. The elevated cytoplasmic HuR bound to p53 mRNA 3'-untranslated region, resulting in prolonged half-life of p53 mRNA. Our results suggest that TIP30 is involved in cellular oxidative stress surveillance and induces apoptosis through stabilization of p53 mRNA in HCC cells. [Cancer Res 2008;68(11):4133–41]